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

MECHANISMS OF ONCOGENESIS

Alexander Drilon

Carcinogenesis often proceeds in a multistep fashion w/the acquisition of several genomic aberrations via Mt, amp, rearrangements, & infxn

Mutations

• Alterations in DNA sequence or structure 2° to replication errors or carcinogens: Mt may be activating or inactivating

DNA Amplification

• Selective ↑ in the number of copies of a gene (copy number alteration), mechanism by w/c the expression of a gene is enhanced above physiologic levels

• Clinically relevant egs:

ERBB2 (HER2) Amp: BC (average of >6 gene copies/nucleus or HER2/CEP17 ratio >2.2 via FISH), gastric CA, predictive of response to HER2-targeted therapies (Nat Rev Clin Oncol 2011;9:16)

FGFR1 Amp: In squamous cell NSCLCs (Sci Transl Med 2010;2:62ra93)

Chromosomal Rearrangements

• Result in creation of a gene fusion w/potent oncogenic activities: Novel sequences are juxtaposed to coding sequence of a TK domain or transcription factor → constitutive activation of TK or downstream target genes of transcription factor

Infections

• Play important roles as carcinogens in several diseases (see Cancer Epidemiology Chap. for more extensive list), carcinogenesis occurs through a variety of mechanisms eg, via the actions of viral/bacterial proteins, insertional mutagenesis

Viruses: HPV (cervical CA, oropharyngeal squamous cell CAs of the head & neck, viral proteins E6 & E7 inhibit TP53 & Rb1, respectively), EBV, KSHV

Bacteria: H. pylori (gastric CA), bacterial CagA protein → activates tyrosine phosphatase SHP2 affecting various pathways involved in cell migration, adhesion, & apoptosis