Abeloff's Clinical Oncology, 4th Edition

Part I – Science of Clinical Oncology

Section C – Diagnosing Cancer: Pathology and Laboratory Medicine

Chapter 18 – Conventional and Molecular Cytogenetics of Neoplasia

Linda D. Cooley,Kathleen S. Wilson

SUMMARY OF KEY POINTS

  

 

Key Methods

  

   

Conventional cytogenetic analysis uses chromosome banding to analyze structural and numeric chromosomal aberrations; dividing cells are required.

  

   

Molecular cytogenetic or fluorescence in situ hybridization (FISH) analysis complements and extends analysis for specific genetic aberrations; viable tumor is not required.

  

   

Additional methods include multiplex (M-FISH), spectral karyotyping (SKY), comparative genomic hybridization (CGH), and microarray-based CGH (aCGH).

  

 

Applications

  

 

Acute Leukemias

  

   

Document clonal aberrations at diagnosis.

  

   

Subclassify genetic types of leukemias; provide diagnostic, prognostic, and patient management information.

  

   

Monitor response to therapy; assess disease progression.

  

   

Monitor post-transplantation engraftment; detect minimal residual disease.

  

 

Lymphoma and Chronic

  

 

Lymphoproliferative Disorders

  

   

Subclassify lymphomas with specific translocations.

  

   

Provide prognostic genetic information for lymphoproliferative disorders.

  

   

Detect diagnostic translocations in many tissue types.

  

 

Solid Tumors

  

   

Differentiate and subtype small round cell tumors; differentiate spindle cell tumors.

  

   

Detect prognostic or therapy-specific genetic information in many solid tumors.

  

   

Detect and assess gene amplification.

INTRODUCTION

Cytogenetic analysis uses tissue culture and specialized techniques to provide genetic information about cells and tissues. Cancer cytogenetic analysis focuses on defining the genetic aberrations of neoplastic tissues. As early as 1890, David von Hansemann speculated that the abnormal mitotic figures in cancer biopsies were important to the origin and development of malignancy, and in 1914, Theodor Boveri[1] published a systematic somatic mutation theory of cancer positing that chromosome abnormalities were responsible for cellular changes that caused normal cells to become malignant. However, it was not until the 1960s that the first nonrandom chromosome abnormality was associated with a particular neoplastic disorder.

In 1960, Nowell and Hungerford[2] noted a very small “deleted” chromosome in cases of chronic myelocytic leukemia. Methods for banding and identifying individual chromosomes, developed in the early 1970s, made it possible to identify this chromosome as a deleted chromosome 22. This deletion chromosome 22 was named the “Philadelphia chromosome.” Rowley[3] showed in 1973 that the del(22) was part of a reciprocal translocation with chromosome 9 [i.e., t(9;22)]. Since that discovery, rapid scientific and technological advances have profoundly changed the understanding of tumorigenesis and the genetics of cancer.

Conventional cytogenetic analysis, although one of the oldest methods, remains a powerful tool for genetic diagnosis and classification of hematologic malignancies and solid tumors. Cytogenetic detection of acquired clonal chromosome aberrations confirms that a process is neoplastic and rules out a reactive or non-neoplastic disorder. Chromosomal abnormalities occur nonrandomly and continually bring newly identified recurring breakpoints to attention as the sites of “disease” genes.[4] Molecular cytogenetic or fluorescence in situ hybridization (FISH) analysis targets these sites, permitting detection of specific diagnostic rearrangements. Disease or disease-subtype-specific chromosomal anomalies provide diagnostic information when histopathologic parameters are indeterminate. In addition, many abnormalities contribute prognostic information and guide therapeutic decisions.

Investigators have elucidated the physiologic function of many “disease” genes and shed light on the mechanisms of their mutations. This information provides the basis for the recent and rapid increase in tumor-specific or gene-mutation-specific therapeutic agents.[5] One example of this is the advent of tyrosine kinase inhibitors (TKIs), small molecules designed to affect molecular targets identified by recurrent cytogenetic aberrations. The efficacy of TKIs for several hematologic malignancies is now well established, [6] [7] and there is increasing evidence that TKIs will play a major role in treatment of solid tumors.[8] The future holds promise for ever more effective therapies for preventing and treating malignancies. Conventional cytogenetic analysis, FISH, and newer array-based technologies have an increasingly important role in contributing information needed for optimal individualized patient management.

This chapter provides a brief overview of cytogenetics, clinical indications for conventional and molecular cytogenetic testing, and a synopsis of what the clinician should expect from a cytogenetic laboratory. A summary of diagnostic, prognostic, and clinically relevant chromosome aberrations is provided in tabular form.

METHODS AND APPLICATIONS

Specimens

Successful conventional cytogenetic studies of neoplastic tissues and cells require an adequate specimen of viable tumor cells, pertinent patient information, and prompt delivery to the processing laboratory. Tumor cell viability is crucial, because metaphase chromosomes for cytogenetic analysis can be obtained only from dividing cells. Although tumor cells may be long-lived in the human body, they quickly lose viability once removed, making prompt delivery to the laboratory essential. Appropriate specimen processing depends on the information that accompanies the sample. Critical information includes patient demographics, differential diagnosis, symptoms, and other laboratory findings. The cytogenetics laboratory uses the information to choose the best methods for the suspected disease process. In the absence of adequate information, the specimen may not be processed optimally to yield the malignant clone.

For hematologic tumors, 2 to 3 mL of bone marrow aspirate collected in sodium heparin is the specimen of choice. When a bone marrow aspirate cannot be obtained because of marrow fibrosis, a packed marrow, or other reasons, a bone marrow trephine biopsy or a peripheral blood specimen may be successful. For a blood specimen to yield information about clonal chromosome aberrations, however, the peripheral blood white cell differential must be abnormal (i.e., abnormal or immature cells must be present). The laboratory needs the white blood cell count and differential to inoculate the cell cultures correctly with appropriate numbers of cells. For routine studies of neoplastic hematologic disorders, no cell mitogens are used in culture. The malignant cell population will divide spontaneously to yield metaphase cells. Only when the disease process is known to be a T-cell or B-cell disorder will T- or B-cell mitogens, respectively, be used in one of several initiated cultures.

Depending on the disease process, other specimen types may be appropriate for cytogenetic analysis. Virtually all body fluids and tissues are candidates for tissue culture and capture of metaphase cells. Useful sources include ascitic and pleural fluids, effusions, and, occasionally, cerebrospinal fluid. Tissues with solid aggregates of tumor cells (e.g., spleen or lymph node involved by lymphoma, or masses of myeloid sarcoma or neuroblastoma) also may be used. Such specimens should be acquired in a sterile fashion and placed in medium supplied by the cytogenetic laboratory for transport. The tissue sample should be selected to contain viable tumor, avoiding normal and necrotic tissues. Adequate sample size is variable, but if available, a sample volume of 500 mg or a sample measuring in aggregate 0.5 × 0.5 × 0.5 cm is recommended.

Many specimen types may be used for FISH analysis. Cytogenetically prepared metaphase and/or interphase cells are most commonly used. However, formalin-fixed paraffin-embedded tumor, air-dried or alcohol fixed touch preparations, cytospin preparations, and blood or bone marrow smears may be used when fresh tumor material is unavailable or conventional cytogenetic analysis is unsuccessful. Tissues that have been processed with B-5 fixative or decalcified are not recommended, because probe hybridization may be suboptimal.

Assays

Conventional cytogenetic analysis allows visualization and screening of the entire genome for anomalies and remains one of the most basic and essential methods for genetic evaluation of hematolymphoid and solid tumors. Conventional analysis uses chromosome-banding methods to bring out the A-T and G-C rich band pattern intrinsic to each chromosome. This unique band pattern permits identification and description of each chromosome, normal or abnormal ( Fig. 18-1 ). The chromosome bands are numbered so recurring chromosome breakpoints can be recognized, recorded, and communicated with a descriptive human cytogenetic nomenclature[9] ( Table 18-1 ).

 
 

Figure 18-1  Karyotype illustrates standard arrangement and Giemsa-trypsin banding of chromosomes in a female patient with chronic myeloid leukemia. The karyotype nomenclature is written as 46,XX,t(9;22)(q34;q11.2) (arrows to derivative chromosomes 9 and 22).

 

 


Table 18-1   -- Cytogenetic Nomenclature

  

 

NOMENCLATURE ABBREVIATIONS

  

 

t(9;22)(q34;q11.2) example

  

 

t, translocation

  

 

(9;22), chromosomes involved

  

 

(q34;q11.2), breakpoints of chromosomes involved

  

 

q34, breakpoint of chromosome 9

  

 

q11.2, breakpoint of chromosome 22

  

 

q, long arm

  

 

p, short arm

  

 

del, deletion

  

 

dup, duplication

  

 

inv, inversion

  

 

add, added unidentified material

  

 

mar, marker; unidentified chromosome + or -, gain or loss of chromosome noted

  

 

XX, female

  

 

XY, male

  

 

TUMOR CELL DNA CONTENT: “PLOIDY”

  

 

Diploid, 2n or 46 chromosomes

  

 

Haploid, 1n or 23 chromosomes

  

 

DNA Index (DI), DNA content of cell

  

 

46 chromosomes, DNA Index of 1.0

  

 

Pseudodiploid, 46 chromosomes with aberrations

  

 

Tetraploid, 4n or 92 chromosomes

  

 

Aneuploid, chr number not exact multiple of haploid set

  

 

DI × 46 = approx chr number in clone: 1.16 × 46 = ∼53 chr

Chr, Chromosome.

 

 

 

Molecular cytogenetic or FISH analysis[10] uses known fluorochrome-labeled DNA sequences or probes to hybridize to the DNA or chromosomes of the cells under investigation. The basis for the test is the natural tendency for a DNA strand to hybridize with its complementary DNA sequence. The specificity of the hybridization provides explicit information about the region probed.

At the time of diagnosis, conventional cytogenetic analysis, with or without FISH analysis, should be done to characterize all malignancies as completely as possible to aid diagnosis, therapy selection, and patient management. If assessment is inadequate at diagnosis, the interpretation and clinical utility of future studies will be compromised significantly. For example, without diagnostic genetic data, it would not be possible to determine whether clonal evolution had occurred; it might not be possible to distinguish between recurrent disease and a new disease process; and follow-up FISH studies might be misinterpreted.[11] Chronic myelogenous leukemia (CML) exemplifies the need for both cytogenetic and FISH evaluation at diagnosis, because certain FISH patterns that are associated with BCR/ABL1gene rearrangement may mimic a remission pattern. Monitoring these patients by FISH for minimal residual disease (MRD) requires knowledge of that particular patient's diagnostic pattern. Results from subsequent specimens in patients with this type of pattern must be interpreted using explicitly defined validation and control parameters to prevent an incorrect diagnosis of remission while BCR/ABL1-bearing cells with this unique pattern are actually still present.

Although conventional chromosomal analysis plays a defining role in characterizing tumors, FISH analysis now is an integral component of the diagnostic evaluation in a large percentage of cases ( Table 18-2 ). FISH analysis has unique utility in the detection of gene rearrangements or gene amplification, chromosomal deletions, duplications, and aneuploidies, low-frequency chromosome aberrations, and elucidation of unbalanced or complex chromosome rearrangements[12] ( Table 18-3 ). FISH analysis is the best method in diagnostic scenarios where a rapid result is needed,[13] such as in newly diagnosed acute promyelocytic leukemia, and an important adjunct when the yield of clonal aberrations by conventional cytogenetics is low,[14] as in chronic lymphocytic leukemia. FISH analysis is the preferred method when breakpoint heterogeneity compromises the usefulness of PCR-based assays or when detection of numerical aberrations is indicated. Although histopathologic evaluation is the currently accepted method to assess response to therapy in leukemias, FISH analysis offers a more reliable and sensitive method for detection of residual disease. FISH analysis is particularly useful in post-transplantation patients who have an identified clonal abnormality and an opposite-sex donor. A combination of sex chromosome- and clone-detecting probes can screen thousands of cells quickly for host cells and then determine whether the host cells carry the original clonal aberration.[15] This method provides crucial information for patient management that may not be obtained with other technologies.


Table 18-2   -- Cytogenetic Analysis

  

 

INDICATIONS

  

 

Provide diagnostic and prognostic information

  

 

Provide information for therapy selection

  

 

Determine genetic subtype of myeloid disorders

  

 

Subclassify lymphoproliferative disorders

  

 

Distinguish prognostic groups in childhood ALL

  

 

Differentiate small round cell tumors

  

 

Differentiate sarcomas

  

 

Subtype solid tumors

  

 

Obtain information for follow-up testing

  

 

Detect clone after therapy or after transplantation

  

 

Determine donor cell engraftment status

  

 

Reassess clone at relapse for new anomalies

  

 

BENEFITS

  

 

Visualize entire genome with karyotype

  

 

Determine genetic aberrations at diagnosis

  

 

Detect disease progression

  

 

DISADVANTAGES

  

 

Turnaround time is days to weeks (solid tumors)

ALL, acute lymphoblastic leukemia.

 

 

 


Table 18-3   -- Fluorescence in situ Hybridization Analysis

  

 

INDICATIONS

  

 

Identify specific diagnostic and/or prognostic aberrations

  

 

Detect reciprocal translocations, gene rearrangements

  

 

Detect deletions, duplications

  

 

Detect chromosome or gene copy number

  

 

Detect gene amplification

  

 

Identify unrecognized chromosome material

  

 

Identify clonal aberrations for follow-up testing

  

 

Assess donor cell engraftment (opposite-sex donor)

  

 

Assess remission status

  

 

Detect recurrent disease

  

 

Detect minimal residual disease

  

 

BENEFITS

  

 

Analyze dividing and nondividing cells

  

 

Analyze fixed tissues

  

 

Easy to examine large numbers of cells

  

 

Rapid turnaround

  

 

DISADVANTAGES

  

 

Provides information only for locus of probe tested

  

 

Requires knowledge of chromosome anomaly or diagnosis

 

 

Most cytogenetic laboratories provide a broad FISH test menu using commercially available FISH DNA probes. Other laboratories augment their capabilities by making “home brew” probes. In addition to identifying reciprocal translocations, deletions, and chromosome copy number aberrations, FISH may also provide additional patient-specific information beyond that obtained with conventional cytogenetic analysis. These data can be used to create FISH strategies for patients with unique aberrations that are not detectable with rt-PCR-based assays or specific translocation probe sets. This information, gathered at the time of diagnosis, is invaluable for follow-up assessment for therapy response and detection of residual disease.

FISH probes are designed to detect gene rearrangement in different ways with (1) “break-apart probes” that separate when a translocation has occurred, or (2) “single fusion, dual fusion, or extra signal translocation probes” that come together when a translocation has occurred. Chromosome enumeration probes and locus-specific probes detect copy number of either the centromere of a specific chromosome or a specific chromosome locus, respectively. Whole or partial chromosome paint probes cover the entire area of the chromosome for which they are designed with fluorescence.[12]Combinations of chromosome probes are available for specific disease entities, for example, Chronic Lymphocytic Leukemia panel (Vysis, Inc.) for use in assessing prognostic genetic anomalies in CLL, and Chromoprobe Multiprobe—System Octochrome (Cytocell Technologies) whole chromosome paint probes for use in determining unknown chromosomal material. New probes are coming on the market ever more rapidly, permitting detection of a much wider range of chromosome aberrations than was possible just a few years ago. This trend is likely to continue as individuals and companies use the genome database to design probes to keep up with the emerging gene-specific therapies.

Other molecular cytogenetic methods[16] include comparative genomic hybridization (CGH), multiplex FISH (M-FISH), spectral karyotyping (SKY), and chromosomal microarray-based CGH[17] (aCGH). These specialized methods have been primarily the purview of research laboratories, but as technological advances occur, they are being brought on board in diagnostic laboratories. Conventional CGH uses a cocktail of tumor DNA and normal reference DNA, each labeled with a different fluorochrome. This cocktail is hybridized to normal metaphase chromosomes to detect regional genomic DNA gains and losses. This computer-based method screens the genome and allows analysis of tumor DNA when chromosomes cannot be obtained. Both SKY and M-FISH methods use multiple fluorochrome labels and computer software to “paint” each chromosome a different color. When the fluorochromes are hybridized to the abnormal tumor metaphase-cell chromosomes, computer analysis of the painted chromosomes can detect rearrangements and provide information about unidentified marker chromosomes and chromosome rearrangements that are not recognized by conventional banded cytogenetic analysis. Microarray CGH, still in its infancy, is a high-throughput and high-resolution method for the detection of microscopic and submicroscopic chromosomal imbalances. Microarrays are small, solid supports, usually glass slides, onto which thousands of different gene sequences are fixed. DNA from tumor cells and normal control cells is tagged with fluorescent molecules and hybridized to the microarray. A “reader” detects the fluorescent tags, and a computer program calculates the red-to-green fluorescence ratio to detect changes in the copy number of DNA sequences.

Cytogenetic Aberrations

Chromosomal aberrations in neoplasia can be grouped according to type. In the first type, no loss of genetic material occurs. Rearrangements of this type include reciprocal translocations and inversions that are known to relocate genes with resultant expression of altered gene products. The second type results in loss or gain of genetic material, and the pathogenic effect depends on which genes are gained or lost. Included in this type are nonreciprocal translocations, deletions, and duplications, as well as loss or gain of whole chromosomes. A third type of aberration results in amplification of genetic material from a specific gene or gene region. This is seen at the chromosome level as double minute chromosomes (small, paired, dot-like acentric chromosomes) or as homogeneously stained regions within a chromosome. Gene amplification, an uncommon aberration, is associated with specific neoplasias and most often correlated with aggressive disease, as, for example, in neuroblastoma.

The karyotype of a tumor may show single or multiple aberrations.[18] Some tumors demonstrate a single anomaly, such as a reciprocal translocation or a gain of an extra chromosome. Other tumors show many aberrations that may include reciprocal or nonreciprocal translocations, deletions, loss, or gain of chromosomes, and so forth. For some types of tumors, a complex karyotype indicates advanced or aggressive disease. The prognostic significance of a karyotype, however, depends on the specific aberrations present. Whereas some tumors have characteristic single anomalies, other tumors have patterns of multiple chromosome aberrations. An example of the former would be the reciprocal t(9;22) in poor-prognosis childhood acute lymphoblastic leukemia (ALL), and the latter example could be the favorable-prognosis hyperdiploid karyotype of childhood ALL that typically shows 53 or more chromosomes and extra copies of specific chromosomes, most commonly X, 4, 6, 10, 14, 17, 18, and 21.[19]

The utility of a cytogenetic analysis of tumor tissue depends on finding the abnormal population of cells that represents the neoplastic process. Cytogenetically, a clone is defined as present when two or more cells with the same chromosomal anomaly are found. A subclone is a second population of cells that contains the original chromosome anomaly and one or more additional anomalies in two or more cells. A subclone indicates clonal evolution and may portend a change to a more aggressive disease state. For instance, chronic-phase CML with the t(9;22) often shows clonal evolution when the disease transforms to the accelerated phase by the gain of an extra der(22) or “Ph” chromosome, trisomy 8, or an isochromosome 17q ( Fig. 18-2 ).

 
 

Figure 18-2  Karyotype of clonal evolution in a male patient with chronic myeloid leukemia in blast crisis. The karyotype is 47,X,-Y,+8,t(9;22)(q34;q11.2),+der(22)t(9;22) (arrows to derivative chromosomes 9 and 22, extra chromosome 8, and missing sex chromosome).

 

 

Cytogenetic analysis is a valuable tool in the workup of a patient with a neoplastic process. In addition to defining the clonal chromosome abnormality of a tumor at diagnosis, conventional and molecular cytogenetic studies are indispensable for assessing disease status after therapy or transplantation and at disease relapse.

Chromosomal aberrations that provide diagnostic, prognostic, and patient management information are summarized in Tables 18-4, 18-5, and 18-6 [4] [5] [6], and the genes known to be affected by the chromosomal aberrations are listed. Today the majority of these chromosomal aberrations and gene rearrangements can be detected by FISH methods. In some disorders, for example, CML, the genetic abnormality defines the disease process. In others, for example, AML with recurrent cytogenetic abnormalities, the aberrations define distinct entities within a heterogeneous disease. Cytogenetic aberrations within a disease category, for example, glial brain tumors, may provide critical information for therapy selection. No attempt is made in the tables to include all known chromosomal aberrations or their associations; only those with proven diagnostic or clinical significance are shown. Many of these aberrations are discussed in more detail in the discussion of specific tumors elsewhere in this book.


Table 18-4   -- Myeloid Disorders: Cytogenetic Aberrations with Diagnostic or Clinical Significance

Disease Entity

FISH Chromosomal Aberration

Genes Involved

Clinical Significance

References

Acute myelocytic leukemia

t(8;21)(q22;q22)

RUNX1T1/RUNX1

Favorable prognosis

Marcucci et al[a]; Schlenk et al[b]

 

inv(16)/t(16;16)

CBFB/MYH11

Favorable prognosis; increased risk of CNS disease/relapse

Delaunay et al[c]

 

t(15;17)(q22;q21)

PML/RARA and variants

Favorable prognosis; responsive to ATRA

Arber et al[d]

 

 

ZBTB16/RARA and variants

Variant translocation—poor response to ATRA

Jaffe et al[e]

 

t(11q23;v)

MLL

Short overall survival

Arber et al[d]; Ravindranath et al[f]

AML-M7

t(1;22)(p13;q13)

RBM15/MKL1

Defines infant AML-M7 subgroup

Dastague et al[g]

CEL, HES

del(4q12)

FIP1L1/PDGFRA

TKI responsive; CHIC2 surrogate gene for testing purposes; unresponsive to TKI w/non-activating KIT mutation (D816V)

Pardanani et al[h]; Cortes et al[i]

 

Normal karyotype

CEBPA mutation

Increased survival; decreased relapse rate

Marcucci et al[j]; Jabbour et al[k]

 

 

NPM1 mutation

Increased survival; must be present without FLT3-ITD/mutation

Mrozek et al[l]

 

 

BAALCoverexpression

Decreased survival; expression studies from peripheral blood

Jabbour et al[k]; Bloomfield et al[m]

 

 

ERG overexpression

Shorter overall survival; expression studies from blood

Bloomfield et al[m]; Mrozek et al[l]

 

 

FLT3 ITD/mutation

Decreased survival; increased relapse rate; worst prognosis with no or low

Kottaridis et al[n]; Mrozek et al[l]

 

 

 

FLT3 wild type expression

 

 

 

MLL PTD

Increased relapse rate

Bloomfield et al[m]; Jabbour et al[k]

 

 

 

Potential TKI responsive

Jabbour et al[k]; Kindler et al[o]

Systemic mastocytosis

 

KIT activating mutation

Less responsive with nonactivating KIT mutation D816V

Pardanani et al[h]; Droogendijk et al[p]

Myelodysplasticsyndromes and AML

5q-sole abnormality

 

Longer survival; 5q-syndrome elderly w/macrocytic anemia

Germing et al[q]; Giagounidis et al[r]

 

- 7

 

Poor outcome; short survival

Greenberg et al[s]; Frohling et al[t]; van der Holt et al[u]

 

- 5/5q-; - 7/7q- together

 

Poor outcome; often in complex karyotype

Greenberg et al[s]; Frohling et al[t]; Giagounidis et al[r]

 

+8 in noncomplex k-type

 

Intermediate <60 yrs; poor >60 yrs

Frohling et al[t]; Wolman et al[v]

 

+11 in noncomplex k-type

 

Intermediate <60 yrs; poor >60 yrs

Frohling et al[t]

 

t/del(11q)

MLL

Intermediate to poor prognosis

Greenberg et al[s]; Frohling et al[t]

 

inv(3)(q21q26.2), t(3;21)

RPN1 and EVI1

Poor outcome; short survival

Greenberg et al[s]; van der Holt

 

 

 

 

et al[u]

 

complex k-type (≥3 abn)

 

Poor outcome; short survival

Greenberg et al[s]; Chen et al[w]

 

20q-, - Y

 

Good outcome; generally indolent course

Greenberg et al[s]; van der Holt et al[u]

CMML

t(5;12)(q31-q32;p13)

PDGFRB/ETV6

TKI responsive

Pardanani et al[h]; Apperley et al[x]

 

t(5;17)(q31-q32;p13.2)

PDGFRB/RABEP1

TKI responsive

Pardanani et al[h]; Apperley et al[x]

Aplastic anemia

+6

 

Poor response to immunosuppressive therapy

Ohga et al[y]; Gupta et al[z]

Therapy-related

t(8;21), inv(16), t(15;17)

Same genes as de novo

t(8;21) longer survival than other

Shali et al[aa]; Schoch et al[bb]

AML/MDS

 

 

21q22 abnormalities

 

 

21q22 abnormalities

RUNX1

More common with topoisomerase II inhibitors

Shali et al[aa]

 

11q23

MLL

More common with topoisomerase II inhibitors

Shali et al[aa]; Schoch et al[bb]; Mauritzon et al[cc]

 

3q26.2 abnormalities

EVI1

Short overall survival

Shali et al[aa]; Schoch et al[bb]

 

Chr 5 and 7 abnormalities

 

More common with alkylating or radiation therapy

Schoch et al[bb]; Mauritzon et al[cc]

 

17p abnormalities

TP53

Short overall survival

Schoch et al[bb]

Chronic myelocytic leukemia

t(9;22)(q34;q11.2)

BCR/ABL1

TKI responsive; TKI resistance due to ABL1 amplification or ABL1 kinase domain mutations, specific testing is available

Baccarani et al[dd]; Hughes et al[ee] Lahaye et al[ff]; Arora et al[gg]

 

t(9;22), + del(9q)

ASS1 deletion

Reduced survival with ABL1/BCR/

Huntly et al[hh]; Cohen et al[ii]

 

 

 

ASS1 deletions

 

 

t(9;22), +Ph, +8, +19, i(17q)

 

Indicates transition to blast phase

Johansson et al[jj]; O'Dwyer et al[kk]

Other MPD

13q, 20q, +9, +8, +1q

BCR/ABL1 negative

Distinguish from CML; JAK2 mutation analysis permits diagnosis and predicts response to treatment

Campbell et al[ll]

MM/Myelofibrosis

20q, 13q

BCR/ABL1 negative

Favorable in myelofibrosis

Tefferi et al[mm]

CMPD, atypical

t(5;10)(q31q32;q21)

PDGFRB/CCDC6

TKI responsive

Pardanani et al[h]

 

t(1;5)(q21;q33)

PDE4DIP/PDGFRB

TKI responsive

Pardanani et al[h]

 

t(4;22)(q12;q11.2)

PDGFRA/BCR

TKI responsive

Pardanani et al[h]

abn, abnormalities; ATRA, all-trans retinoic acid; CEL, chronic eosinophilic leukemia; CMML, chronic myelomonocytic leukemia; CMPD, chronic MPD; CNS, central nervous system; FISH, fluorescence in situ hybridization; HES, hypereosinophilic syndrome; ITD, internal tandem duplication; k-type, karyotype; MM myeloid metaplasia; MPD, myeloproliferative disorders; Ph, Philadelphia chromosome; PTD, partial tandem duplication; TKI, tyrosine kinase inhibitor.

 

a

Marcucci G, Mrozek K, Ruppert AS, et al: Prognostic factors and outcome of core binding factor acute myeloid leukemia patients with t(8;21) differ from those of patients with inv(16): a Cancer and Leukemia Group B study. J Clin Oncol 2005;23:5705–5717.

b

Schlenk RF, Benner A, Krauter J, et al: Individual patient data-based meta-analysis of patients aged 16 to 60 years with core binding factor acute myeloid leukemia: a survey of the German Acute Myeloid Leukemia Intergroup. J Clin Oncol 2004;22:3741–3750.

c

Delaunay J, Vey N, Leblanc T, et al: Prognosis of (inv)(IL)/t(16;16) acute myeloid leukemia: a survey of 110 cases from the French AML Intergroup. Blood 2003;102:462–469.

d

Arber D, Stein AS, Carter NH, et al: Prognostic impact of acute myeloid leukemia classification. Am J Clin Pathol 2003;119:672–680.

e

Jaffe ES, Harris NL, Stein H, Vardiman JW (eds): World Health Organization Classification of Tumors. Pathology and Genetics of Tumors of Haematopoietic and Lymphoid Tissues. Lyon, IARC Press, 2001.

f

Ravindranath Y, Change M, Steuber CP, et al: Pediatric Oncology Group (POG) studies of acute myeloid leukemia (AML): a review of four consecutive childhood AML trials conducted between 1981 and 2000. Leukemia 2005;19:2101–2116.

g

Dastague N, Lafage-Pochitaloff M, Pages M-P, et al: Cytogenetic profile of childhood and adult megakaryoblastic leukemia (M7): a study of the Groupe Francais de Cytogenetique Hematologique (GFCH). Blood 2002;100:618–626.

h

Pardanani A, Tefferi A: Imatinib targets other than bcr/abl [sic] and their clinical relevance in myeloid disorders. Blood 2004;104:1931–1938.

i

Cortes J, Kantarjian H: Beyond chronic myelogenous leukemia. Cancer 2004;100:2064–2078.

j

Marcucci G, Mrozek K, Bloomfield CD: Molecular heterogeneity and prognostic biomarkers in adults with acute myeloid leukemia and normal cytogenetics. Curr Opin Hematol 2004;12:68–75.

k

Jabbour EJ, Estey E, Kantarjian HM: Adult acute myeloid leukemia. Mayo Clin Proc 2006;81:247–260.

l

Mrozek K, Bloomfield CD: Chromosome aberrations, gene mutations and expression changes, and prognosis in adult acute myeloid leukemia. Hematology 2006;169–177.

m

Bloomfield CD, Mrozek K, Caligiuri MA: Cancer and Leukemia Group B Leukemia Correlative Science Committee: major accomplishments and future directions. Clin Cancer Res 2006;12:3564–3571.

n

Kottaridis PD, Gale RE, Frew ME, et al: The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood 2001;98:1752–1759.

o

Kindler T, Breitenbuecher F, Marx A, et al: Efficacy and safety of imatinib in adult patients with c-kit-positive acute myeloid leukemia. Blood 2004;103:3644–3654.

p

Droogendijk H, Kluin-Nelemans H, van Doormall J, et al: Imatinib mesylate in the treatment of systemic mastocytosis. Cancer 2006;107:345–351.

q

Germing U, Strupp C, Kuendgen A, et al: Prospective validation of the WHO proposals for the classification of myelodysplastic syndromes. Haematologica 2006;91:1596–1604.

r

Giagounidis AAN, Germing U, Carlo A: Biological and prognostic significance of chromosome 5q deletions in myeloid malignancies. Clin Cancer Res 2006;12:5–10.

s

Greenberg P, Cox C, LeBeau M, et al: International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1997;89:2079–2088.

t

Frohling S, Schlenk R, Kayser S, et al: Cytogenetics and age are major determinants of outcome in intensively treated acute myeloid leukemia patients older than 60 years: results from AMLSG trial AML HD 98-B. Blood 2006;108:3280–3288.

u

Van der Holt B, Breems D, Beverloo H, et al: Various distinctive cytogenetic abnormalities in patients with acute myeloid leukaemia aged 60 years and older express adverse prognostic value: results from a prospective clinical trial. Br J Haematol 2006;136:96–105.

v

Wolman S, Gundacker H, Appelbaum F, et al: Impact of trisomy 8(+8) on clinical presentation, treatment response, and survival in acute myeloid leukemia: a Southwest Oncology Group study. Blood 2002;100:29–35.

w

Chen B, Zhao WL, Jin J, et al: Clinical and cytogenetic features of 508 Chinese patients with myelodysplastic syndrome and comparison with those in Western countries. Leukemia 2005;19:767–775.

x

Apperley J, Gardembas M, Melo J, et al: Response to imatinib mesylate in patients with chronic myeloproliferative disease with rearrangements of the platelet-derived growth factor receptor beta. N Engl J Med 2002;347:481–489.

y

Ohga S, Ohara A, Hibi S, et al: Treatment responses of childhood aplastic anaemia with chromosomal aberrations at diagnosis. Br J Haematol 2002;118:313–319.

z

Gupta V, Brooker C, Tooze J, et al: Clinical relevance of cytogenetic abnormalities at diagnosis of acquired aplastic anaemia in adults. Br J Haematol 2006;134:95–99.

aa

Shali W, Helias C, Fohrer C, et al: Cytogenetic studies of a series of 43 consecutive secondary myelodysplastic syndromes/acute myeloid leukemias: conventional cytogenetics, FISH, and multiplex FISH. Cancer Genet Cytogenet 2006;168:133–145.

bb

Schoch C, Kern W, Schnittger S, et al: Karyotype is an independent prognostic parameter in therapy-related acute myeloid leukemia (t-AML): an analysis of 93 patients with t-AML in comparison to 1091 patients with de novo AML. Leukemia 2004;18:120–125.

cc

Mauritzson N, Albin M, Rylander L, et al: Pooled analysis of clinical and cytogenetic features in treatment-related and de novo adult acute myeloid leukemia and myelodysplastic syndromes based on a consecutive series of 761 patients analyzed 1976–1993 and on 5098 unselected cases reported in the literature 1974–2001. Leukemia 2002;16:2366–2378.

dd

Baccarani M, Saglio G, Goldman J, et al: Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 2006;108:1809–1820.

ee

Hughes T, Deininger M, Hochhaus A, et al: Monitoring CML patients responding to treatment with tyrosine kinase inhibitors—review and recommendations for “harmonizing” current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. Blood 2006;108:28–37.

ff

Lahaye T, Riehm B, Berger U, et al: Response and resistance in 300 patients with BCR-ABL-positive leukemias treated with imatinib in a single center. Cancer 2005;103:1659–1669.

gg

Arora A, Scholar E: Role of tyrosine kinase inhibitors in cancer therapy. J Pharmacol Exp Ther 2005;315:971–979.

hh

Huntly BJP, Reid A, Bench A, et al: Deletions of the derivative chromosome 9 occur at the time of the Philadelphia translocation and provide a powerful and independent prognostic indicator in chronic myeloid leukemia. Blood 2001;98:1732–1738.

ii

Cohen N, Rozenfeld-Granot G, Hardan I, et al: Subgroup of patients with Philadelphia-positive chronic myelogenous leukemia characterized by a deletion of 9q proximal to ABL gene: expression profiling, resistance to interferon therapy, and poor prognosis. Cancer Genet Cytogenet 2001;128:114–119.

jj

Johansson B, Fioretos T, Mitelman F, et al: Cytogenetic and molecular genetic evolution of chronic myeloid leukemia. Acta Haematol 2002;107:76–94.

kk

O'Dwyer M, Mauro M, Kurilik G, et al: The impact of clonal evolution on response to imatinib mesylate (STI571) in accelerated phase CML. Blood 2002;100:1628–1633.

ll

Campbell P, Green A: The myeloproliferative disorders. N Engl J Med 2006;355:2452–2466.

mm

Tefferi A, Strand J, Lasho T, et al: Respective clustering of unfavorable and favorable cytogenetic clones in myelofibrosis and myeloid metaplasia with homozygosity for JAK2 and response to erythropoietin therapy. Cancer 2006;106:1739–1743.

 


Table 18-5   -- Lymphoproliferative Disorders: Chromosome Aberrations with Diagnostic or Clinical Significance

Disease Entity

Chromosomal Aberration

FISH Genes Involved

Clinical Significance

References

Acute leukemia

 

 

 

 

 ALL

 

 

 

 

  B-precursor

t(9;22)(q34;q11.2)

BCR/ABL1

Very high risk disease; response to TKIs

Pui et al[a]; Jones et al[b]; Heerema et al[c]

 

t(9;22)(q34;q11.2), - 7, 7p-, 9p-

BCR/ABL1, CDKN2A

Worst outcome risk with high WBC

Heerema et al[c]

 

t(4;11)(q21;q23)

AF4/MLL

High risk disease; often found in infants

Hilden et al[d]

 

t(11q23) variants

MLL

>80% of infants with ALL

Hilden et al[d]

 

t(12;21)(p13;q22)

ETV6/RUNX1

Low risk disease

Pui et al[e]; Al-Sweedan et al[f]; Stams et al[g]

 

t(1;19)(q23;)(p13.3)

TCF3/PBX1

Favorable with intensified therapy

Pui et al[h]

 

54–65 chr with +4, +10, +17

Chromosome enumeration

Low risk

Sutcliffe et al[i]

 

<44 chr

Chromosome enumeration

High risk

Harrison et al[j]; Heerema et al[k]

 

Near-haploid 23–29 chr

Chromosome enumeration

Very high risk

Harrison et al[j]; Heerema et al[k]

 

Low hypodiploid 33–39 chr

Chromosome enumeration

Very high risk

Harrison et al[j]; Heerema et al[k]; Charrin et al[l]

 

Near-tetraploidy

ETV6/RUNXI

Favorable; often associated withETV6/RUNX1

Raimondi et al[m]

 

der(21):RUNX1 amplification

RUNX1

Unfavorable; older youth

Harewood et al[n]

  B-cell

t(8;14)(q24.1;q32.3) or variants

MYC/IGH@

Improved outcome with lymphoma therapy

See below

  T-cell

t(1p32) or del(1p32)

TAL1

Favorable prognosis

Van Grotel et al[o]; Graux et al[p]

 

t(5;14)(q35;q32)

TLX3

?Favorable

Van Grotel et al[o]; Graux et al[p]; Cave et al[q]

 

t(10;14)(q24;q11)

TLX1

Favorable

Van Grotel et al[o]; Graux et al[p]

 

t(10;11)(p13;q14)

PICALM/MLLT10

Unfavorable

Van Grotel et al[o]; Graux et al[p]

 

t(11;19)(q23;p13.3)

MLL/MLLT1

Favorable prognosis

Rubnitz et al[r]

 

del(9p21)

CDKN2A, CDKN2B

?Favorable prognosis

Graux et al[s]

 

t(9;9)(q34;34), ABL1 amplification

NUP214/ABL1

Response to TKIs

Graux et al[p]

 Chronic leukemia

 

 

 

 

  CLL, β-cell

+12

 

Intermediate prognosis

Dohner et al[t]; Byrd et al[u]; Dewald et al[v]

 

del(13q14) or - 13

D13S319 or RB1 as surrogate FISH markers

Favorable as sole anomaly

Athanasiadou et al[w]

 

del(11q21)

ATM

Shortened survival

Dohner et al[t]; Byrd et al[u]; Dewald et al[v]

 

del(17p13)

TP53

Unfavorable

Dohner et al[t]; Byrd et al[u]; Dewald et al[v]

 

t(14;19)(q32;q13)

BCL3

Often young adults

Michaux et al[x]

Plasma cell

 

 

 

 

  Multiple myeloma/plasma cell leukemia

Hyperdiploid +3, 5, 7, 9, 11, 15, 19

 

Longer OS and EFS

Smadja et al[y]; Chng et al[z]

 

Nonhyperdiploid

 

Unfavorable; <46, 46, and >81 chromosomes

Smadja et al[y]; Fonseca et al[aa]

 

- 13 or del(13q14)

DBM/RB1

Unfavorable

Chiecchio et al[bb]; Zhan et al[cc]

 

del(17p13)

TP53

Unfavorable; common in PCL; CNS disease

Schilling et al[dd]

 

t(11;14)(q13;q32)

CCND1/IGH@

Improved survival with intensive therapy

Fonseca et al[ee]; Soverini et al[ff]

 

t(4;14)(p16;q32)

FGFR3/IGH@

Unfavorable; most common in PCL

Keats et al[gg]; Fonseca et al[hh]

 

t(8;14) & variants

MYC/IGH@

Present in ∼15% of MM

Avet-Loiseau et al[ii]

 

t(14;16)(q32;q24)

IGH@/MAF

Unfavorable; most common in PCL

Fonseca et al[hh]

 

t(14;20)(q32;q11.2)

IGH@/MAFB

Unfavorable

Boersma et al[jj]

Lymphoma

 

 

 

 

 Mature β-cell

 

 

 

 

 Follicular

t(14;18)(q32;q21)

IGH@/BCL2

Poor prognosis with MYCrearrangement

Kanungo et al[kk]

 MZBCL MALT

t(11;18)(q21;q21), t(1;14)(p22;q32), t(14;18)(q32;q21)

API2/MALT1, BCL10/IGH@ IGH@/MALT1

Resistant to Helicobacter pyloritherapy

Farinha et al[ll]

 t(11;18) negative MALT

+3, +18, +18q21

3, 18, MALT1

Poor outcome, risk to transform to DLBCL

Streubel et al[mm]; Remstein et al[nn]

  Mantle cell

t(11;14)(q13;q32)

CCND1/IGH@

Distinguish MCL from CLL; FISH best for dx

Bertoni et al[oo]; Belaud-Rotureau[pp]

  Burkitt

t(8;14)(q24.1;q32.3)

MYC/IGH@

Favorable with aggressive therapy

Bociek et al[qq]; Lones et al[rr]; Dave et al[ss]

 

t(8;22)(q24.1;q11.2)

MYC/IGL@

Favorable with aggressive therapy

Bociek et al[qq]; Lones et al[rr]

 

t(2;8)(p11.2;q24.1)

MYC/IGK@

Favorable with aggressive therapy

Bociek et al[qq]; Lones et al[rr]

  T-cell

t(14q11), t(7q35)

TCR sites

Most common rearrangements

Jaffe et al[tt]

  Anaplastic large cell

t(2;5)(p23;q35) and variants

ALK/NPM

ALK+ tumors better survival

Jaffe et al[uu]

ALL, acute lymphoblastic leukemia; CLL, chronic lymphocytic leukemia; CNS, central nervous system; EFS, event free survival; FISH, fluorescence in situ hybridization; MALT, mucosa-associated lymphoid tissue; MZBCL, marginal zone β-cell lymphoma; OS, overall survival; TCR, T-cell receptor; TKIs, tyrosine kinase inhibitors; WBC, white blood count.

 

a

Pui C-H, Evans WE: Treatment of acute lymphoblastic leukemia. N Engl J Med 2006;354:166–178.

b

Jones LK, Saha V: Philadelphia positive acute lymphoblastic leukaemia of childhood. Br J Haematol 2005;130:489–500.

c

Heerema NA, Harbott J, Galimberti S, et al: Secondary cytogenetic aberrations in childhood Philadelphia chromosome positive acute lymphoblastic leukemia are nonrandom and may be associated with outcome. Leukemia 2004;18:693–702.

d

Hilden JM, Dinndorf PA, Meerbaum SO, et al: Analysis of prognostic factors of acute lymphoblastic leukemia in infants: report on CCG 1953 from the Children's Oncology Group. Blood 2006;108:441–451.

e

Pui CH, Sandlund JT, Pei D, et al: Improved outcome for children with acute lymphoblastic leukemia: results of Total Therapy Study XIIIB at St Jude Children's Research Hospital. Blood 2004;104:2690–2696.

f

Al-Sweedan SA, Neglia JP, Steiner ME, et al: Characteristics of patients with TEL-AML1-positive acute lymphoblastic leukemia with single or multiple fusions. Pediatr Blood Cancer 2007;48:510–514. Epub ahead of print, Pediatr Blood Cancer 2007;48:510–514.

g

Stams WAG, Beverloo HB, den Boer ML, et al: Incidence of additional genetic changes in the TEL and AML1 genes in DCOG and COALL-treated t(12;21)-positive pediatric ALL, and their relation with drug sensitivity and clinical outcome. Leukemia 2006;20:410–416.

h

Pui C-H, Relling M, Downing JR: Acute lymphoblastic leukemia. N Engl J Med 2004;350:1535–1548.

i

Sutcliffe MJ, Shuster JJ, Sather HN, et al: High concordance from independent studies by the Children's Oncology Group (CCG) and Pediatric Oncology Group (POG) associating favorable prognosis with combined trisomies 4, 10, and 17 in children with NCI standard-risk β-precursor acute lymphoblastic leukemia: a Children's Oncology Group (COG) initiative. Leukemia 2005;19:734–740.

j

Harrison CJ, Moorman AV, Broadfield ZJ, et al: Three distinct subgroups of hypodiploidy in acute lymphoblastic leukaemia. Br J Haematol 2004;125:552–559.

k

Heerema NA, Nachman JB, Sather HN, et al: Hypodiploidy with less than 45 chromosomes confers adverse risk in childhood acute lymphoblastic leukemia: a report from the Children's Oncology Group. Blood 1999;94:4036–4045.

l

Charrin C, Thomas X, Ffrench M, et al: A report from the LALA-94 and LALA-SA groups on hypodiploidy with 30–39 chromosomes and near-triploidy: 2 possible expressions of a sole entity conferring poor prognosis in adult acute lymphoblastic leukemia (ALL). Blood 2004;104:2444–2451.

m

Raimondi SC, Zhou Y, Shurtleff SA, et al: Near-triploidy and near-tetraploidy in childhood acute lymphoblastic leukemia: association with β-lineage blast cells carrying the ETV6-RUNX1 fusion, T-lineage immunophenotype, and favorable outcome. Cancer Genet Cytogenet 2006;169:50–57.

n

Harewood L, Robinson H, Harris R, et al: Amplification of AML1 on a duplicated chromosome 21 in acute lymphoblastic leukemia: a study of 20 cases. Leukemia 2003;17:547–553.

o

van Grotel M, Meijerink JPP, Beverloo HB, et al: The outcome of molecular-cytogenetic subgroups in pediatric T-cell acute lymphoblastic leukemia: a retrospective study of patients treated according to DCOG or COALL protocols. Haematologica 2006;91:1212–1221.

p

Graux C, Cools J, Melotte C, et al: Fusion of NUP214 to ABL1 on amplified episomes in T-cell acute lymphoblastic leukemia. Nat Genet 2004;36:1084–1089.

q

Cave H, Suciu S, Preudhomme C, et al: Clinical significance of HOX11L2 expression linked to t(5;14)(q35;q32), of HOX11 expression, and of SIL/Tal fusion in childhood T-cell malignancies: results of EORTC studies 58881 and 58951. Blood 2004;103:442–450.

r

Rubnitz JE, Camitta BM, Mahmoud H, et al: Childhood acute lymphoblastic leukemia with the MLL-ENL fusion and t(11;19)(q23;p13.3) translocation. J Clin Oncol 1999;17:191–196.

s

Graux C, Cools J, Michaux L, et al: Cytogenetics and molecular genetics of T-cell acute lymphoblastic leukemia: from thymocyte to lymphoblast. Leukemia 2006;20:1496–1510.

t

Dohner H, Stilgenbauer S, Benner A, et al: Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 2000;343:1910–1916.

u

Byrd JC, Gribben JG, Peterson BL, et al: Select high-risk genetic features predict earlier progression following chemoimmunotherapy with fludarabine and rituximab in chronic lymphocytic leukemia: justification for risk-adapted therapy. J Clin Oncol 2006;24:437–443.

v

Dewald GW, Brockman SR, Paternoster SF, et al: Chromosome anomalies detected by interphase fluorescence in situ hybridization: correlation with significant biological features of β-cell chronic lymphocytic leukaemia. Br J Haematol 2003;121:287–295.

w

Athanasiadou A, Stamatopoulos K, Tsompanakou A, et al: Clinical, immunophenotypic, and molecular profiling of trisomy 12 in chronic lymphocytic leukemia and comparison with other karyotypic subgroups defined by cytogenetic analysis. Cancer Genet Cytogenet 2006;168:109–119.

x

Michaux L, Dierlamm J, Wlodarska I, et al: t(14;19)/BCL3 rearrangements in lymphoproliferative disorders: a review of 23 cases. Cancer Genet Cytogenet 1997;94:36–43.

y

Smadja NV, Bastard C, Brigaudeau C, et al: Hypodiploidy is a major prognostic factor in multiple myeloma. Blood 2001;98:2229–2238.

z

Chng WJ, Santana-Dávila R, Van Wier SA, et al: Prognostic factors for hyperdiploid-myeloma: effects of chromosome 13 deletions and IgH translocations. Leukemia 2006;20:807–813.

aa

Fonseca R, Barlogie B, Bataille R, et al: Genetics and cytogenetics of multiple myeloma: a workshop report. Cancer Res 2004;64:1546–1558.

bb

Chiecchio L, Protheroe RKM, Ibrahim AH, et al: Deletion of chromosome 13 detected by conventional cytogenetics is a critical prognostic factor in myeloma. Leukemia 2006;20:1610–1617.

cc

Zhan F, Sawyer J, Tricot G: The role of cytogenetics in myeloma. Leukemia 2006;20:1484–1486.

dd

Schilling G, Dierlamm J, Hossfeld DK: Prognostic impact of cytogenetic aberrations in patients with multiple myeloma or monoclonal gammopathy of unknown significance. Hematol Oncol 2005;23:102–107.

ee

Fonseca R, Blood EA, Oken MM, et al: Myeloma and the t(11;14)(q13;q32); evidence for a biologically defined unique subset of patients. Blood 2002;99:3735–3741.

ff

Soverini S, Cavo M, Cellini C, et al: Cyclin D1 overexpression is a favorable prognostic variable for newly diagnosed multiple myeloma patients treated with high-dose chemotherapy and single or double autologous transplantation. Blood 2003;102:1588–1594.

gg

Keats JJ, Reiman T, Maxwell CA, et al: In multiple myeloma, t(4;14)(p16;q32) is an adverse prognostic factor irrespective of FGFR3 expression. Blood 2003;101;1520–1529.

hh

Fonseca R, Blood E, Rue M, et al: Clinical and biologic implications of recurrent genomic aberrations in myeloma. Blood 2003;101:4569–4575.

ii

Avet-Loiseau H, Facon T, Grosbois B, et al: Oncogenesis of multiple myeloma: 14q32 and 13q chromosomal abnormalities are not randomly distributed, but correlated with natural history, immunological features, and clinical presentation. Blood 2002;99:2185–2191.

jj

Boersma-Vreugdenhil GR, Kuipers J, van Stralen E, et al: The recurrent translocation t(14;20)(q32;q12) in multiple myeloma results in aberrant expression of MAFB: a molecular and genetic analysis of the chromosomal breakpoint. Br J Haematol 2004;126:355–363.

kk

Kanungo A, Medeiros LJ, Abruzzo LV, et al: Lymphoid neoplasms associated with concurrent t(14;18) and 8q24/c-MYC translocation generally have a poor prognosis. Mod Pathol 2006;19:25–33.

ll

Farinha P, Gascoyne RD: Molecular pathogenesis of mucosa-associated lymphoid tissue lymphoma. J Clin Oncol 2005;23:6370–6378.

mm

Streubel B, Seitz G, Stolte M, et al: MALT lymphoma associated genetic aberrations occur at different frequencies in primary and secondary intestinal MALT lymphomas. Gut 2006;55:1581–1585.

nn

Remstein ED, Kurtin PJ, James CD, et al: Mucosa-associated lymphoid tissue lymphoma with t(11;18)(q21;q21) and mucosa-associated lymphoid tissue lymphomas with aneuploidy develop along different pathogenetic pathways. Am J Pathol 2002;161:63–71.

oo

Bertoni F, Zucca E, Cavalli F: Mantle cell lymphoma. Curr Opin Hematol 2004;11:411–418.

pp

Belaud-Rotureau MA, Parrens M, Dubus P, et al: A comparative analysis of FISH, RT-PCR, PCR, and immunohistochemistry for the diagnosis of mantle cell lymphomas. Mod Pathol 2002;15:517–525.

qq

Bociek GR: Adult Burkitt's lymphoma. Clin Lymphoma 2005;6:11–20.

rr

Lones MA, Sanger WG, Le Beau MM, et al: Chromosome abnormalities may correlate with prognosis in Burkitt/Burkitt-like lymphomas of children and adolescents: a report from Children's Cancer Group study CCG-E08. J Pediatr Hematol Oncol 2004;26:169–178.

ss

Dave SS, Fu K, Wright GW, et al: Molecular diagnosis of Burkitt's lymphoma. N Engl J Med 2006;354:2431–2442.

tt

Jaffe ES, Harris NL, Stein H, Vardiman JW (eds): World Health Organization Classification of Tumors. Pathology and Genetics of Tumors of Haematopoietic and Lymphoid Tissues. Lyon, IARC Press, 2001.

uu

Jaffe ES: Anaplastic large cell lymphoma: the shifting sands of diagnostic hematopathology. Mod Pathol 2001;14:219–228.

 


Table 18-6   -- Solid Tumors: Chromosome Aberrations with Diagnostic or Clinical Significance

Disease Entity

Chromosomal Aberration

FISH Genes Involved

Clinical Significance

References

Genitourinary

 

 

 

 

 Renal

 

 

 

 

  Clear cell RCC

- 3 or del(3p)

3p, VHL, other unknown gene

Characterize nonpapillary RCC

Kardas et al[a]

 

del(3p) with gain 5q

3p, 5q

Favorable prognosis

Kardas et al[a]

 

del(3p) with loss 5q

3p, 5q

Metastasis, unfavorable

Kardas et al[a]

 

- 14/del(14q)

14, IGH@

Unfavorable, shorter survival

Kardas et al[a]

  Papillary RCC

+7, +17, - Y, 9p-

7, 17, Y, CDKN2A

Characterize adult papillary RCC

Hansel[b]

  t(Xp11.2) RCC

t(X;1)(p11.2;q21.2)

PRCC/TFE3

Characterize pediatric papillary RCC

Ramphal et al[c]

 

t(X;17)(p11.2;q25)

ASPLCR1/TFE3

Balanced translocation in RCC

Ramphal et al[c]

 

t(X;17)(p11.2;q23)

CLTC/TFE3

Characterize pediatric papillary RCC

Ramphal et al[c]

 

t(X;1)(p11.2;p34)

PSF/TFE3

Characterize pediatric papillary RCC

Ramphal et al[c]

  t(6;11) RCC

t(6;11)(p21;q12)

ALPHA/TFEB

Subset of RCC, children, young adult

Argani et al[d]

  Chromophobe

Loss 1, 2, 6, 10, 13, 17, 21

Chromosome enumeration

Distinguish from oncocytoma

Hes et al[e]

  RCC

 

 

 

 

  Oncocytoma

1p-, t(11q13)

1p, CCND1

Distinguish from chromophobe

Jhang et al[f]

  Rhabdoid

- 22/22q-

SMARCB1; BCR as surrogate

Diagnostic

Biegel et al[g]

  CMN

t(12;15)(p12;q25), +11, +17, +20

ETV6/NTRK3

Diagnostic

Sandberg et al[h]

 Bladder, papillary

del(9)(p21)

CDKN2A

Homozygous deletion higher grade, stage

Wolff et al[i]

 

8p-

8p, unknown gene

Higher recurrence rate, progression

Wolff et al[i]

 

+7, +17

FGFR3, TP53, MYC

Genetic instability

Wolff et al[i]

 Wilms' tumor

16q-, +1q, 1p-, - 22, 17p-

1p, 1q, 16q, 17p, 22, WT1

Unfavorable histology; augmented chemotherapy if 1p-, 16q-

Perlman[j]

 Prostate

+7q31, 8p22-, +8q24, 17p13-

7, LPL, MYC, TP53

High frequency in carcinoma

Qian et al[k]; Bastacky et al[l]

 

17p13-, +8q24

TP53, MYC

Progression, higher Gleason score

Qian et al[k]

 

10q-

PTEN

High grade PIN or carcinoma

Yoshimoto et al[m]

Gastrointestinal

 

 

 

 

 GIST

- 14/14q-, - 22/22q-

14, 22, KIT mutations

Distinguish from smooth muscle tumors

Sandberg et al[n]; Miettinsen et al[o]

 

 

 

Response to TKIs

 

 Liver

 

 

 

 

  Hepatoblastoma

+20, +2, +8, t(1q12-q21)

Chr 2, 8, 20, 1q

Distinguish from HCC, HMH

Tomlinson et al[p]

  HMH

t(11;19)(q13;q13.4), t(19q13.4)

19q

Distinguish from hemangioma or malignant tumor

Rakheja et al[q]

 Salivary gland

 

 

 

 

  Pleomorphic adenoma

t(3;8)(p21;q12)

PLAG1

Diagnostic benign

Martins et al[r]

  Mucoepidermoid cancer

t(11;19)(q21;p13)

MECT1/MAML2

Diagnostic malignant

Enlund et al[s]

  Warthin's tumor

t(11;19)(q21;p13)

MECT1/MAML2

Benign tumor

Enlund et al[s]

Breast

 

 

 

 

 Invasive intraductal

dmin, hsr

ERBB2 amp

Worst prognosis, response to TKIs, Mab

Tanner et al[t]; Geyer et al[u]

 

 

ERRB2, TOP2A co-amp

Co-amplification, better response to FEC

Tanner et al[t]

 Secretory breast

t(12;15)(p13;q25)

ETV6/NTRK3

Favorable; distinguish from IDC

Makretsov et al[v]

CNS

 

 

 

 

 Astrocytic tumors

+7, - 10/10q-

EGFRPTEN

Short survival, aggressive course

Fuller et al[w]

 

9p21-

CDKN2A

Sensitive to antimetabolite therapy

Fuller et al[w]

 

19q-

19q

Long-term survival

Fuller et al[w]

  Glioblastoma

+7, 10q-, 9p-

PTENEGFRCDKN2A

Short survival assoc w/10q-/PTEN loss

Ohgaki et al[x]

 Oligodendroglial tumors

 

 

 

 

  Anaplastic

1p-, 19q-, der(1;19)(q10;p10)

1p36, 19q13.3

Longer survival, sensitive to therapy

Eoli et al[y]; Brandes et al[z]; Griffin et al[aa]

  Mixed oligoastrocytoma

+7, - 10/10q-, 15q-

EGFR, PTEN

High grade, progression

Koschny et al[bb]

  Oligoastrocytoma

19q-

19q13.3

Favorable outcome

Fuller et al[w]

 

1p-

1p36

Favorable outcome

Eoli et al[y]

 Ependymoma

 

 

 

 

  Spinal

+7, - 22q, 14q-

7, 14, 22q, NF2

Distinguish subtype

Mendrzyk et al[cc]

  Intracranial

+1q, 6q-, +7, 9p-

1q25, p16, EGFR,CDKN2A

Pediatric, high risk

 

 Medulloblastoma

i(17q), 17p-, - 10/10q-, +7

MYCN, MYC

Large cell/anaplastic morphology

Pan et al[dd]; Lamont et al[ee]; Gajjar et al[ff]

 

 

ERBB2

High risk

 

 Supratentorial PNET

+1q, 16q-, 19p-

1q, 19p

Lacks i(17q), poor prognosis

Inda et al[gg]

 AT/RT

- 22 or del(22q11.23)

SMARCB1; BCR as surrogate

Distinguish from MB, PNET, CPC

Judkins et al[hh]; Biegel[ii]

 Meningioma

- 22 or del(22q11.2)

22q, NF2

Primary abnormality

Fuller et al[w]

 

1p-, - 14/14q-

1p, IGH@

Increased risk of recurrence, anaplastic

Espinosa et al[jj]

 Choroid plexus tumors

 

 

 

 

  Carcinoma

Loss 2, 3, 4, 5, 6, 8, 10, 11, 13, 14, 15, 16, 17, 18, 19, 22

Chromosome enumeration

Distinguish from papilloma

Rickert et al[kk]; Bhattacharjee et al[ll]

  Papilloma

Gain 7, 8, 9, 12, 14, 15, 17, 18, 19, 20

Chromosome enumeration

Distinguish from carcinoma

Rickert et al[kk]; Bhattacharjee et al[ll]

Small round cell tumors

 

 

 

 

 Alveolar RMS

t(2;13)(q37;q14)

PAX3/FOXO1A

Older youth, poorer outcome

Sorenson et al[mm]

 

t(1;13)(p36;q14)

PAX7/FOXO1A

Younger, extremity location

Sorenson et al[mm]

 

t(X;2)(q13;q35), t(2;2)(q35;p23)

PAX3/AFX, PAX3/NCOA1

Variant translocations

Nishio et al[nn]

 

 

IGF1R amp

Disease progression

Bridge et al[oo]

 Embryonal RMS

Gain 2, 7, 8, 11, 12, 13, 20

Chromosome enumeration

Distinguish from alveolar subtype

Bridge et al[oo]

 

Loss 1p, 3p, 9q, 10q, 16q, 17p, 22

IGF1R amp

Gene amplification with anaplasia

Bridge et al[oo]

 Neuroblastoma

del(1p), del(11q) w/o MYCN amp

1p, 11q, MYCN

Unfavorable in Stage I, II, IVS

Attiyeh et al[pp]; Spitz et al[qq]; Maris et al[rr]

 

del(1p), +17q, MYCN amp

1p, 17q, MYCN

Unfavorable all stages

Janoueix-Lerosey et al[ss]; Spitz et al[qq]

 

triploidy w/o above abn

Chromosome enumeration

Favorable

Maris et al[rr]

 EWS/pPNET

t(11;22)(q24;q12) & variants

FLI1/EWSR1

Diagnostic, distinguish from other SRCTs

Bernstein et al[tt]

 

t(21;22)(q22;q12)

ERG/EWSR1

 

Bernstein et al[tt]

 

del(9p), 17p-, der(1;16)(q10;p10)

CDKN2A, TP53

Unfavorable prognostic factor

Bernstein et al[tt]

 DSRCT

t(11;22)(p13;q12)

WT1/EWSR1

Distinguish from other SRCTs

Chang et al[uu]; Sandberg et al[vv]

 Clear cell sarcoma

t(12;22)(q13;q12)

ATF1/EWSR1

Absent in cutaneous MM

Patel et al[ww]; Sandberg et al[xx]

 Retinoblastoma

del(13q14), gain 1q, 6p

RB1, DEK, E2F3

Hallmark of retinoblastoma

Grasemann et al[yy]

 Lymphomas

specific translocations

 

Distinguish from other SRCTs

See Table 18-5

Bone, soft tissue

 

 

 

 

 CFS/CMN

t(12;15)(p12;q25), +11, +17, +20

ETV6/NTRK3

Distinguish CFS from fibrosarcoma

Sandberg et al[h]

 Synovial sarcoma

t(X;18)(p11.2;q11.2)

SSX1/SS18

Biphasic—most SYT/SSX1, unfavorable

Terry et al[zz]; Surace et al[aaa]

 

 

SSX2/SS18

Monophasic-SYT/SSX1 or SYT/SSX2

Sandberg et al[bbb]; Ladanyi et al[ccc]

 Lipoma

t(3;12)(q27–28;q14–15), variants

HMGA2/LPP

Distinguish from LPS

Sandberg[ddd]

 Liposarcoma

 

 

 

 

  Myxoid, round cell

t(12;16)(q13;p11)

FUS/DDIT3

Diagnostic for myxoid LPS

Sandberg[eee]

  Myxoid

t(12;22)(q13;q12) variant

DDIT3/EWSR1

Variant of t(12;16)

Sandberg[eee]

  Well-differentiated

rings, markers, dmin

MDM2, CDK4amplification

Distinguish from lipoma

Sandberg[eee]

 Leiomyoma

t(12;14)(q15;q24)

HMGA2

Distinguish from leiomyosarcoma

Sandberg[fff]; Sandberg[ggg]

 ASPS

der(17)t(X;17)(p11.2;q25)

ASPLCR1/TFE3

Unbalanced translocation specific for ASPS

Sandberg et al[hhh]; Huang et al[iii]

 EMC

t(9;22)(q22;q12)

NR4A3/EWSR1

Diagnostic, tumor specific

Sandberg et al[jjj]; Sandberg[kkk]

 

t(9;17)(q22;q11.2)

NR4A3/TAF15

Variant translocation

Sandberg et al[jjj]; Sandberg[kkk]

 

t(9;15)(q22;q21)

NR4A3/TCF12

Variant translocation

Sandberg et al[jjj]; Sandberg[kkk]

Dermal tumors

 

 

 

 

 DFSP

der(22)t(17;22)(q22;q13.1) or r(22)t(17;22)

COL1A1/PDGFB

Distinguish from atypical DF, MFH Response to TKIs

McArthur et al[lll]; Kaur et al[mmm]

 

 

 

 

Sirvent et al[nnn]

 GCF

t(17;22)(q22;q13.1)

COL1A1/PDGFB

Similar to DFSP

Sirvent et al[nnn]

 Bednar tumor

der(22)t(17;22)(q22;q13.1) or r(22)t(17;22)

COL1A1/PDGFB

Similar to DFSP

Sirvent et al[nnn]

 Hidradenoma

t(11;19)(q21;p13)

MECT1/MAML2

Same as Warthin's tumor

Behboudi et al[ooo]

Lung tumors

 

 

 

 

 NSCLC

3p, +7, EGFR high copy number or amplification

EGFR

Response to TKIs

Cappuzzo et al[ppp]

Germ cell tumor

 

 

 

 

 Dysgerminoma, ovary

i(12p), 12p overrepresentation

12p

Distinguish from non-GCTs

Cossu-Rocca et al[qqq]

 TGCTs, seminoma, NS

i(12p), 12p amplification

12p

Most common aberration, invasive disease

Zafarana et al[rrr]

ASPS, alveolar soft part sarcoma; AT/RT, atypical teratoid/rhabdoid tumor; CFS, congenital fibrosarcoma; CMN, congenital mesoblastic nephroma; CPC, choroid plexus carcinoma; DF, dermatofibroma; DFSP, dermatofibrosarcoma protuberans; DSRCT, desmoplastic small round cell tumor; EMC, extraskeletal myxoid chondrosarcoma; EWS, Ewing's sarcoma; FEC, fluorouracil, epirubicin, cyclophosphamide; GCF, giant cell fibroblastoma; GIST, gastrointestinal stromal tumor; HCC, hepatocellular carcinoma; HMH, hepatic mesenchymal hamartoma; IDC, intraductal carcinoma; Mab, monoclonal antibody; MFH, malignant fibrohistiocytoma; MM, malignant melanoma; NS, nonseminoma; NSCLC, non-small-cell lung cancer; PIN, prostate intraepithelial neoplasia; PNET, primitive neuroectodermal tumor; pPNET, peripheral primitive neuroectodermal tumor; RCC, renal cell carcinoma; RMS, rhabdomyosarcoma; TGCTs, testicular germ cell tumors; TKIs, tyrosine kinase inhibitors.

 

a

Kardas I, Mrozek K, Babinska M, et al: Cytogenetic and molecular findings in 75 clear cell renal cell carcinomas. Oncology Reports 2005;13:949–956.

b

Hansel DE: Genetic alterations and histopathologic findings in familial renal cell carcinoma. Histol Histopathol 2006;21:437–444.

c

Ramphal R, Pappo A, Zielenska M, et al: Pediatric renal cell carcinoma: clinical, pathological, and molecular abnormalities associated with the members of the MiT transcription factor family. Am J Clin Pathol 2006;126:349–364.

d

Argani P, Lae M, Hutchinson B, et al: Renal carcinomas with the t(6;11)(p21;q12): clinicopathologic features and demonstration of the specific alpha-TFEB gene fusion by immunohistochemistry, RT-PCR, and DNA PCR. Am J Surg Pathol 2005;29:230–240.

e

Hes O, Vanecek T, Perez-Montiel DM, et al: Chromophobe renal cell carcinoma with microcystic and adenomatous arrangement and pigmentation-a diagnostic pitfall. Virchows Arch 2005;446:383–393.

f

Jhang JS, Narayan G, Murty VV, Mansukhani MM: Renal oncocytomas with 11q13 rearrangements: cytogenetic, molecular, and immunohistochemical analysis of cyclin D1. Cancer Genet Cytogenet 2004;149:114–119.

g

Biegel JA, Tan L, Zhang F, et al: Alterations of the hSNF5/INI1 gene in central nervous system atypical teratoid/rhabdoid tumors and renal and extrarenal rhabdoid tumors. Clin Cancer Res 2002;8:3461–3467.

h

Sandberg AA, Bridge JA: Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors: congenital (infantile) fibrosarcoma and mesoblastic nephorma. Cancer Genet Cytogenet 2002;132:1–13.

i

Wolff EM, Liang G, Jones PA: Mechanisms of disease: genetic and epigenetic alterations that drive bladder cancer. Nat Clin Pract Urol 2005;2:502–510.

j

Perlman EJ: Pediatric renal tumors: practical updates for the pathologist. Pediatr Dev Pathol 2005;8:320–338.

k

Qian J, Hirasawa K, Bostwick DG, et al: Loss of p53 and c-myc overrepresentation in stage T2–3N1–3M0 prostate cancer are potential markers for cancer progression. Mod Pathol 2002;15:35–44.

l

Bastacky S, Cieply K, Sherer C, et al: Use of interphase fluorescence in situ hybridization in prostate needle biopsy specimens with isolated high-grade prostatic intraepithelial neoplasia as a predictor of prostate adenocarcinoma on follow-up biopsy. Hum Pathol 2004;35:281–289.

m

Yoshimoto M, Cutz J-C, Nuin PAS, et al: Interphase FISH analysis of PTEN in histologic sections shows genomic deletions in 68% of primary prostate cancer and 23% of high-grade prostatic intraepithelial neoplasias. Cancer Genet Cytogenet 2006;169:128–137.

n

Sandberg AA, Bridge JA: Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors: gastrointestinal stromal tumors. Cancer Genet Cytogenet 2002;135:1–22.

o

Miettinsen M, Lasota J: Gastrointestinal stromal tumors: review on morphology, molecular pathology, prognosis, and differential diagnosis. Arch Pathol Lab Med 2006;130:1466–1478.

p

Tomlinson GE, Douglass EC, Pollack BH, et al: Cytogenetic evaluation of a large series of hepatoblastomas: numerical abnormalities with recurring aberrations involving 1q12–q21. Genes Chrom Cancer 2005;44:177–184.

q

Rakheja D, Margraf LR, Tomlinson GE, Schneider NR: Hepatic mesenychymal hamartoma with translocation involving chromosome band 18q13.4: a recurrent abnormality. Genes Chrom Cancer 2004;153:60–63.

r

Martins C, Fonseca I, Roque L, et al: PLAG1 gene alterations in salivary gland pleomorphic adenoma and carcinoma ex-pleomorphic adenoma: a combined study using chromosome banding, in situ hybridization and immunocytochemistry. Mod Pathol 2005;18:1048–1055.

s

Enlund F, Behboudi A, Andren Y, et al: Altered Notch signaling resulting from expression of a WAMTP1-MAML2 gene fusion in mucoepidermoid carcinomas and benign Warthin's tumor. Exp Cell Res 2004;292:21–28.

t

Tanner M, Isola J, Wiklund T, et al: Topoisomerase IIα gene amplification predicts favorable treatment response to tailored and dose-escalated anthracycline-based adjuvant chemotherapy in HER-2/neu-amplified breast cancer: Scandinavian Breast Group Trial 9401. J Clin Oncol 2006;16:2428–2436.

u

Geyer CE, Forster J, Lindquist D, et al: Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 2006;355:2733–2743.

v

Makretsov N, He M, Hayes M, et al: A fluorescence in situ hybridization study of ETV6-NTRK3 fusion gene in secretory breast carcinoma. Genes Chrom Cancer 2004;40:152–157.

w

Fuller CE, Perry A: Molecular diagnostics in central nervous system tumor. Adv Anat Pathol 2005;12:180–194.

x

Ohgaki H, Kleihues P: Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas. J Neuropathol Exp Neurol 2005;64:479–489.

y

Eoli M, Bissola L, Bruzzone MG, et al: Reclassification of oligoastrocytomas by loss of heterozygosity studies. Int J Cancer 2006;119:84–90.

z

Brandes AA, Tosoni A, Cavallo G: Correlations between O6-methylguanine DNA methyltransferase promoter methylation status, 1p and 19q deletions, and response to Temozolamide in anaplastic and recurrent oligodendroglioma: a prospective GICNO study. J Clin Oncol 2006;24:4746–4753.

aa

Griffin CA, Burger P, Morsberger L, et al: Identification of der(1;19)(q10;p10) in five oligodendrogliomas suggests mechanism of concurrent 1p and 19q loss. J Neuropathol Exp Neurol 2006;65:988–994.

bb

Koschny R, Holland H, Koschny T, Vitzthum H-E: Comparative genomic hybridization pattern of non-anaplastic and anaplastic oligodendrogliomas—a meta-analysis. Pathol Res Pract 2006;202:23–30.

cc

Mendrzyk F, Korshunov A, Benner A, et al: Identification of gains on 1q and epidermal growth factor receptor overexpression as independent prognostic markers in intracranial ependymoma. Clin Cancer Res 2006;12:2070–2079.

dd

Pan E, Pellarin M, Holmes E: Isochromosome 17q is a negative prognostic factor in poor-risk childhood medulloblastoma patients. Clin Cancer Res 2005;11:4733–4740.

ee

Lamont JM, McManamy CS, Pearson AD, et al: Combined histopathological and molecular cytogenetic stratification of medulloblastoma patients. Clin Cancer Res 2004;10:5482–5493.

ff

Gajjar A, Hernan R, Kocak M, et al: Clinical, histopathologic, and molecular markers of prognosis: toward a new disease risk stratification system for medulloblastoma. J Clin Oncol 2004;22:984–993.

gg

Inda MM, Perot C, Guillaud-Bataille M, et al: Genetic heterogeneity in supratentorial and infratentorial primitive neuroectodermal tumours of the central nervous system. Histopathology 2005;47:631–637.

hh

Judkins AR, Mauger J, Rorke LB, Biegel JA: Immunohistochemical analysis of hSNF5/INI1 in pediatric CNS neoplasms. Am J Surg Pathol 2004;28:644–650.

ii

Biegel JA: Molecular genetics of atypical teratoid/rhabdoid tumors. Neurosurg Focus 2006;20:1–7.

jj

Espinosa AB, Tabernero MD, Maillo A, et al: The cytogenetic relationship between primary and recurrent meningiomas points to the need for new treatment strategies in cases at high risk of relapse. Clin Cancer Res 2006;12:772–780.

kk

Rickert CH, Wiestler OD, Paulus W: Chromosomal imbalances in choroid plexus tumors. Am J Pathol 2002;160:1105–1113.

ll

Bhattacharjee MB, Armstrong DD, Vogel H, Cooley LD: Cytogenetic analysis of 120 primary pediatric brain tumors and literature review. Cancer Genet Cytogenet 1997;97:39–53.

mm

Sorensen PH, Lynch JC, Qualman SJ, et al: PAX3-FKHR and PAX7-FKHR gene fusions are prognostic indicators in alveolar rhabdomyosarcoma: a report from the Children's Oncology Group. J Clin Oncol 2002;20:2672–2679.

nn

Nishio J, Althof PA, Bailey JM, et al: Use of a novel FISH assay on paraffin-embedded tissues as an adjunct to diagnosis of alveolar rhabdomyosarcoma. Lab Invest 2006;86:547–556.

oo

Bridge JA, Liu J, Qualman SJ, et al: Genomic gains and losses are similar in genetic and histologic subsets of rhabdomyosarcoma, whereas amplification predominates in embryonal with anaplasia and alveolar subtypes. Genes Chrom Cancer 2002;33:310–321.

pp

Attiyeh EF, London WB, Mosse YP, et al: Chromosome 1p and 11q deletions and outcome in neuroblastoma. N Engl J Med 2005;353:2243–2253.

qq

Spitz R, Hero B, Skowron M, et al: MYCN-status in neuroblastoma: characteristics of tumours showing amplification, gain, and non-amplification. Eur J Cancer 2004;40:2753–2759.

rr

Maris JM: The biologic basis for neuroblastoma heterogeneity and risk stratification. Curr Opin Pediatr 2005;17:7–13.

ss

Janoueix-Lerosey I, Penther D, Thioux M, et al: Molecular analysis of chromosome arm 17q gain in neuroblastoma. Genes Chrom Cancer 2000;28:276–284.

tt

Bernstein M, Kovar H, Paulussen M, et al: Ewing's sarcoma family of tumors: current management. The Oncologist 2006;11:503–519.

uu

Chang F: Desmoplastic small round cell tumors: cytologic, histologic, and immunohistochemical features. Arch Pathol Lab Med 2006;130:728–732.

vv

Sandberg AA, Bridge JA: Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors: desmoplastic small round-cell tumors. Cancer Genet Cytogenet 2002;138:1–10.

ww

Patel RM, Downs-Kelly E, Weiss SW, et al: Dual-color, break-apart fluorescence in situ hybridization for EWS gene rearrangement distinguishes clear cell sarcoma of soft tissue from malignant melanoma. Mod Pathol 2005;18:1585–1590.

xx

Sandberg AA, Bridge JA: Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors: clear cell sarcoma (malignant melanoma of soft parts). Cancer Genet Cytogenet 2001;130:1–7.

yy

Grasemann C, Gratias S, Stephan H, et al: Gains and overexpression identify DEK and E2F3 as targets of chromosome 6p gains in retinoblastoma. Oncogene 2005;24:6441–6449.

zz

Terry J, Barry TS, Horsman DE, et al: Fluorescence in situ hybridization for the detection of t(X;18)(p11.2;q11.2) in a synovial sarcoma tissue microarray using a breakapart-style probe. Diagn Mol Pathol 2005;14:77–82.

aaa

Surace C, Panagopoulos I, Palsson, et al: A novel FISH assay for SS18-SSX fusion type in synovial sarcoma. Lab Invest 2004;84:1185–1192.

bbb

Sandberg AA: Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors: synovial sarcoma. Cancer Genet Cytogenet 2002;133:1–23.

ccc

Ladanyi M, Antonescu CR, Leung DH, et al: Impact of SYT/SSX fusion type on the clinical behavior of synovial sarcoma: a multi-institutional retrospective study of 243 patients. Cancer Res 2002;62:135–140.

ddd

Sandberg AA: Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors: lipoma. Cancer Genet Cytogenet 2004;150:93–115.

eee

Sandberg AA: Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors: liposarcoma. Cancer Genet Cytogenet 2004;155:1–24.

fff

Sandberg AA: Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors: leiomyoma. Cancer Genet Cytogenet 2005;158:1–26.

ggg

Sandberg AA: Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors: leiomyosarcoma. Cancer Genet Cytogenet 2005;161:1–19.

hhh

Sandberg AA, Bridge JA: Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors: alveolar soft part sarcoma. Cancer Genet Cytogenet 2002;136:1–9.

iii

Huang HY, Lui MY, Ladanyi M: Nonrandom cell-cycle timing of a somatic chromosomal translocation: the t(X;17) of alveolar soft part sarcoma occurs in G2. Genes Chrom Cancer 2005:44:170–176.

jjj

Sandberg AA, Bridge JA: Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors: chondrosarcoma and other cartilaginous neoplasms. Cancer Genet Cytogenet 2003;143:1–31.

kkk

Sandberg AA: Genetics of chondrosarcoma and related tumors. Curr Opin Oncol 2004;16:342–354.

lll

McArthur GA, Demetri GD, van Oosterom A, et al: Molecular and clinical analysis of locally advanced dermatofibrosarcoma protuberans treated with imatinib: Imatinib Target Exploration Consortium Study B2225. J Clin Oncol 2005;23:866–873.

mmm

Kaur S, Vauhkonen H, Bohlin T, et al: Gene copy number changes in dermatofibrosarcoma protuberans—a fine-resolution study using array comparative genomic hybridization. Cytogenet Genome Res 2006;115:283–288.

nnn

Sirvent N, Maire G, Pedeutour F: Genetics of dermatofibrosarcoma protuberans family of tumors: from ring chromosomes to tyrosine kinase inhibitor treatment. Genes Chrom Cancer 2003;37:1–19.

ooo

Behboudi A, Winnes M, Gorunova L, et al: Clear cell hidradenoma of the skin-a third tumor type with a t(11;19)-associated TORC1-MAML2 gene fusion. Genes Chrom Cancer 2005;43:202–205.

ppp

Cappuzzo F, Hirsch FR, Rossi E, et al: Epidermal growth factor receptor gene and protein and Gefitinib sensitivity in non-small-cell lung cancer. J Natl Cancer Inst 2005;97:643–655.

qqq

Cossu-Rocca P, Zhang S, Roth LM, et al: Chromosome 12p abnormalities in dysgerminoma of the ovary: a FISH analysis. Mod Pathol 2006;19:611–615.

rrr

Zafarana G, Grygalewicz B, Gillis AJ, et al: 12p-amplicon structure analysis in testicular germ cell tumors of adolescents and adults by array CGH. Oncogene 2003;22:7695–7701.

 

SUMMARY AND FUTURE DIRECTIONS

Cytogenetic analysis of tumor material provides an opportunity to visualize all genetic material in a cell as chromosomes. Almost all neoplasms have shown cytogenetic aberrations, and many of these are disease- and subtype-specific. In addition to providing diagnostic information, clonal chromosomal aberrations provide information vital to therapeutic management.

Cytogenetic information about tumor tissues has been accumulating since the 1960s. Today, cytogenetic studies are used to provide information about a patient's particular disease process, the best way to manage it, and the outcomes that can be expected. Not all tumors yield specific diagnostic or prognostic information, but sufficient valuable information is obtained to warrant cytogenetic study with or without FISH at the time of diagnosis for all childhood hematopoietic disorders and solid tumors, all adult hematopoietic disorders, sarcomas, central nervous system tumors, and select epithelial tumors.

As technology and knowledge advance, cytogenetic laboratories will continue to provide the basic genetic picture of disease states using conventional cytogenetic analysis. FISH will play an expanding role in the diagnosis and management of neoplasias—for example by detection of molecular targets for therapeutic agents. FISH methods are evolving to accommodate tumor materials prepared, preserved, or stored in multiple ways. FISH commonly is used now to anchor a diagnosis or provide prognostic information, and is used as a post-therapy evaluation tool for residual disease for some tumors. Because FISH offers a more sensitive and specific method for residual disease detection than do histopathologic parameters,[20] it is likely to see increasing use for this purpose in the future. Combining FISH with other methods such as flow cytometry can provide an even better assessment of therapeutic response[21] As genomic information continues to be generated, new FISH probes and strategies will be developed to meet diagnostic needs. CGH, SKY, and M-FISH will continue to play a role in elucidation of genetic aberrations, and microarray-based CGH in particular appears to hold exciting potential for moving the field of molecular cytogenetics forward.

REFERENCES

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