A 32-year-old woman comes to the office for evaluation of a breast lump. She noticed the lump a few months ago but thinks it might be getting larger. The patient has a history of right lower limb amputation at age 17 due to osteosarcoma. The patient's mother died of an adrenal tumor, and her younger sister died of leukemia. Examination of the left breast shows a 5-cm, firm immobile mass with irregular borders. Which of the following gene mutations is the most likely etiology for this patient's condition?

Question

A 32-year-old woman comes to the office for evaluation of a breast lump.  She noticed the lump a few months ago but thinks it might be getting larger.  The patient has a history of right lower limb amputation at age 17 due to osteosarcoma.  The patient's mother died of an adrenal tumor, and her younger sister died of leukemia.  Examination of the left breast shows a 5-cm, firm immobile mass with irregular borders.  Which of the following gene mutations is the most likely etiology for this patient's condition?

Quizplus · Accepted Answer

11ec160b_39f7_6a91_9249_4545cde255b7_MD0001_00 A history of sarcoma, leukemia, adrenal, and breast cancer is suggestive of Li-Fraumeni syndrome. Cancers of the brain are also common. The syndrome is the result of an autosomal dominant mutation in TP53, a gene that codes for the tumor suppressor protein p53. Patients with this disorder are genetically predisposed to cancer development at a young age. Patients with Li-Fraumeni syndrome inherit one mutated allele of TP53, but somatic mutation of the second allele is needed for tumor development (2-hit hypothesis). p53 plays an essential role in maintaining the integrity of the human genome by causing cells with mutant DNA to arrest in the G1/S stage of the cell cycle until the damage is repaired. Normally, cells with irreversible DNA damage are not allowed to divide and proceed to apoptosis. Without a functioning p53 protein, the defective cells divide unchecked and become cancerous. (Choice A) The adenomatous polyposis coli (APC) gene mutation is found in patients with familial polyposis syndromes, sporadic colon cancer, and melanomas. APC is responsible for maintaining low levels of β-catenin (oncogenic protein) and for intercellular adhesion. (Choice B) Mutation of the BRCA1 tumor suppressor gene increases the risk for breast and ovarian cancers, and it is the most common hereditary breast cancer. This mutation is not associated with sarcomas, leukemia, or brain tumors. (Choice C) NF2 is a tumor suppressor gene. Mutation of NF2 increases the risk for developing neurofibromatosis type 2. Patients present with bilateral acoustic neuromas (schwannomas of the cerebellopontine angle). Symptoms include bilateral hearing loss, vertigo, and tinnitus. (Choice E) RB1 is a tumor suppressor gene that codes for the Rb protein, which regulates the G1-S checkpoint of the cell cycle. Mutation of RB1 predisposes to the development of retinoblastomas and osteosarcomas, but not breast cancer or leukemia. The 2-hit hypothesis has been proposed to account for hereditary retinoblastoma. Educational objective: Li-Fraumeni syndrome is caused by an autosomal dominant mutation in the tumor suppressor gene TP53. Leukemia, sarcomas, and tumors of the breast, brain, and adrenal cortex are most common. __________ References: Revisiting Li-Fraumeni Syndrome From TP53 Mutation Carriers. (http://www.ncbi.nlm.nih.gov/pubmed/26014290)

A 32-Year-Old Woman Comes to the Office for Evaluation of a Breast