Nevoid basal cell carcinoma syndrome •• PATCH Hereditary nonpolyposis colon cancer •• MSH2, MLH1, MSH6 Multiple endocrine neoplasia 1 and 2 •• MEN1, RET Breast and ovarian tumors •• BRCA1, BRCA2 Neurofibromatosis 1 and 2 •• NF1, NF2 Familial adenomatous polyposis/colon cancer APC Melanoma p16INK4A Li-Fraumeni syndrome (various tumors) p53 Retinoblastoma RB PREDISPOSITION GENE
Figure 7-39 Interaction between cancer susceptibility genes and DNA repair. ATM (ataxia-telangiectasia mutated) senses a double-strand break in DNA, induced by agents such as ionizing radiation. ATM and CHEK2 phosphorylate BRCA1, promoting its migration to the break site. The Fanconi's anemia protein complex (proteins A, C, E, F, G) triggers the ubiquitination and colocalization of the Fanconi protein D2 with BRCA1 at the break site. BRCA2 carries RAD51, an enzyme involved in DNA recombination repair, to the same site. BRCA1, BRCA2, and RAD51 repair the DNA break by an error-free recombination mechanism. RAD51 is a component of cell cycle check points. (Redrawn from Venkitaraman AR: A growing network of cancer-susceptibility genes. N Engl J Med 348:1917, 2003.)
Figure 7-38 A, The role of APC in regulating the stability and function of b-catenin. APC and b-catenin are components of the WNT signaling pathway. In resting cells (not exposed to WNT), b-catenin forms a macromolecular complex containing the APC protein. This complex leads to the destruction of b-catenin, and intracellular levels of b-catenin are low. B, When cells are stimulated by secreted WNT molecules, the destruction complex is deactivated, b-catenin degradation does not occur, and cytoplasmic levels increase. b-catenin translocates to the nucleus, where it binds to TCF, a transcription factor that activates several genes involved in the cell cycle. C, When APC is mutated or absent, the destruction of b-catenin cannot occur. b-Catenin translocates to the nucleus and coactivates genes that promote the cell cycle, and cells behave as if they are under constant stimulation by the WNT pathway.