What tumor-suppressor protein is targeted by the virus causing this patient’s rectal cancer? A 37-year-old HIV-positive man presents for evaluation of anogenital lesions. He states that the lesions have been present for years, but have recently grown in size and become pruritic and tender. On examination he is circumcised and has multiple hyperkeratotic papules on his penis shaft, perineum, and anal area. He also has a palpable rectal mass with guaiacpositive stool and conjunctival pallor. On further questioning, he admits to recent unintentional weight loss, constipation, and bloating. His CD4+ cell count is 150/mm3 and his hematocrit is 26%. CT scan of the abdomen shows a 3 × 4-cm rectal mass with multiplemetastatic lesions in his liver.

P53

The correct answer is E. This HIV-positive patient has multiple anogenital warts, or condylomata acuminata, which are commonly caused by human papilloma virus (HPV) types 6 and 11. A feared complication of condylomata acuminata is anorectal cancer, as seen here. Immunodefi ciency predisposes to the development of HPV-induced transformation. The mechanism of HPV-induced transformation involves the production of a viral protein, E6, which binds to a cellular ubiquitin ligase E6AP. On binding to E6, E6AP polyubiquitinates the tumor suppressor p53, leading to dysregulated cell proliferation and, eventually, oncogenesis. Answer A is incorrect. APC is a tumor suppressor gene mutated in certain hereditary forms of colon cancer. The APC protein normally degrades the transcription factor -catenin, which is involved in colonic epithelial cell proliferation. In the absence of APC, increased levels of -catenin accumulate, eventually leading to oncogenesis. Answer B is incorrect. BRCA1 is a tumor suppressor gene commonly mutated in hereditary forms of breast and ovarian cancers. The BRCA1 protein functions in DNA repair processes, and inherited mutations in BRCA1 interfere with DNA repair, leading to the accumulation of mutations and, eventually, oncogenesis. Answer C is incorrect. The MSH2 gene regulates a mismatch repair enzyme and is mutated in certain hereditary forms of colon cancer. In the absence of MSH2, increased levels of DNA mutations accumulate, leading to eventual cellular transformation. Answer D is incorrect. NF1 is a tumor suppressor gene mutated in neurofi bromatosis type 1. The NF1 protein functions as a GTPase activating protein for the small G protein Ras. Because Ras is only active when it is GTPbound, NF1-mediated GTP hydrolysis leads to inactivation of Ras. In the absence of NF1, Ras is hyperactive, leading to enhanced growth factor signal transduction and, eventually, oncogenesis.