Pocket Oncology (Pocket Notebook Series), 1st Ed.


Elizabeth Won and Zsofia K. Stadler


• Over 200 hereditary CA susceptibility syndromes described, most are very rare. Inherited CA arise from highly penetrant germline Mt; “Familial” CA may be caused by interaction of low-penetrance genes, gene–environment interactions, or both.

Genetic High-Risk Assessment

• Requires detailed & thorough FHx

• Refer to genetic specialists for risk assessment & genetic counseling

• Genetic testing should be done based on individual’s probability of being a Mt carrier & after careful discussion & informed consent of potential benefits, limitations, & risks

Figure 7-1 Reprinted w/permission from Oncogene 2004;23:6445.

Li–Fraumeni Syndrome (LFS)

• Mt: TP53 (TSG)

• Genetics: Autosomal dominant; 100% lifetime risk of CA in women; risk slightly lower in men 73% (Br J Cancer 2000;82;1932)

• Clinical characteristics: Sarcomas, breast CA, brain tumors, adrenocortical carcinoma (ACC), acute leukemias

• Diagnostic criteria:

Classical Li–Fraumeni criteria: Proband w/sarcoma <45 yo & 1st degree relative w/any CA <45 yo & 1st or 2nd degree relative any CA <45 yo or a sarcoma at any age

Chompret criteria: Proband w/LFS tumor age <46 yo & 1st or 2nd relative w/ LFS tumor OR Proband dx w/ACC or choroid plexus tumor, irrespective of FHx (J Med Genet 2001;38;43)

• Management of Mt carriers: High-risk breast screening, consider prophylactic mastectomy; RT to be used w/caution (pts at ↑ risk of RT-induced CA)

VHL Disease

• Mt: VHL gene in chromosome 3p25

• Genetics: Autosomal dominant; 90% penetrance by age 65. Type 1 = low risk of pheochromocytoma; Type 2 = high risk. Type 2A low risk of RCC; 2B high-risk RCC.

• Clinical characteristics: CNS Hemangioblastoma; retinal angiomas, clear cell RCC; pheochromocytomas; pancreas serous cystadenomas & neuroendocrine tumors; epididymal cystadenomas

• Diagnostic criteria: Pts w/FHx of VHL w/hemangioblastoma, pheochromocytoma or RCC. If no FHx, ≥2 hemangioblastomas & a visceral tumor. Genetic testing for VHL can detect almost all cases of VHL disease.

• Management of Mt carriers: Annual retinal exam starting at age 1 w/close monitoring for signs of neurologic disturbance; annual testing for metanephrines starting age 5–15; annual abd U/S by age 8; age 16 & beyond → MRI of brain & cervical spine q2y & auditory testing. (Recommendations of the VHL Family Alliance)

Hereditary Diffuse Gastric Cancer

• Mt: CDH1 (E-cadherin) gene

• Genetics: Autosomal dominant; >80% lifetime risk of gastric CA, median age is 38.

• Clinical characteristics: Diffuse-type gastric CA age <50, ↑ risk of lobular-type breast CA

• Diagnostic criteria: Int’l Gastric CA Linkage Consortium guidelines (J Med Genet. 2010:47;436)—one of the following:

-2 gastric CA cases in family, one diffuse gastric type before age 50

-3 diffuse gastric CA cases in 1st/2nd-degree relatives

-Diffuse gastric CA in pt <40

-Pt or FHx of diffuse gastric & lobular breast CA, 1 dx before 50

• Management of Mt carriers: Consider prophylactic total gastrectomy (gastric CA extremely rare age <20), EGD screening & surveillance (efficacy not proven); high-risk breast CA screening

Cowden Syndrome

• Mt: Phosphatase & tensin homolog (PTEN)

• Genetics: Autosomal dominant; high penetrance

• Clinical characteristics: Hamartomatous tumors in multiple organs including skin, mucosa, GI tract; breast CA, endometrial CA, thyroid CA, macrocephaly. Trichilemmomas (skin-colored warty papules) & papillomatous papules are pathognomonic.

• Diagnostic criteria: International Cowden Syndrome Consortium criteria (J Med Genet. 2000;37:828); NCCN criteria.

• Management of Mt carriers: Annual skin & pelvic exams, thyroid U/S, high-risk breast CA screening, discussion of prophylactic mastectomy & hysterectomy, early colonoscopy

Other Hereditary Cancer Predisposition Syndromes