WBR0770

Author	[[PageAuthor::Yazan Daaboul, M.D. (Reviewed by Will Gibson and Yazan Daaboul, M.D.)]]
Exam Type	ExamType::USMLE Step 1
Main Category	MainCategory::Genetics
Sub Category	SubCategory::Oncology
Prompt	[[Prompt::A 48-year-old woman with no past medical history presents to the physician's office for a left breast lump that she recently noticed on self-exam. She explains that she incidentally palpated the lump during showering, but she does not complain of any pain or breast discharge. Following appropriate work-up, she is diagnosed with triple-negative breast cancer of ductal histological subtype. Genetic analysis demonstrates a germline c.185delAG frameshift mutation in the BRCA1 gene. When asked, the physician explains the normal function of BRCA1 protein. Which of the following best describes the molecular classification of the BRCA1 gene product?]]
Answer A	AnswerA::DNA repair protein
Answer A Explanation	AnswerAExp::''BRCA1'' and ''BRCA2'' are tumor suppressor genes whose protein products are critical to repairing DNA double strand breaks.
Answer B	AnswerB::Transcription factor
Answer B Explanation	AnswerBExp::Examples of genes that encode transcription factors are ''C-MYC'', and ''N-MYC'', which are oncogenes associated with the development of Burkitt's lymphoma and a worse prognosis in neuroblastoma, respectively.
Answer C	AnswerC::Tyrosine kinase
Answer C Explanation	AnswerCExp::Examples of genes that encode tyrosine kinase are ''ABL'', ''HER2/NEU'', and ''RET'' oncogenes, which are associated with development of CML, breast cancer, and MEN II A/B syndromes, respectively.
Answer D	AnswerD::GTPase
Answer D Explanation	[[AnswerDExp::An example of a gene that encodes GTPase is the RAS proto-oncogene. Mutations in RAS results in an abnormal GTPase activity that is always in the "on" GTP-bound state. Mutations in KRAS are associated with the development of pancreatic cancer, colon cancer, and lung cancer.]]
Answer E	AnswerE::Cytokine receptor
Answer E Explanation	[[AnswerEExp::An example of a gene that encodes a cytokine receptor is C-KIT oncogene whose mutation is associated with development of gastrointestinal stromal tumors (GIST). JAK1 is a gene that encodes a cytokine receptor and is mutated in polycythemia vera, a myeloproliferative disorder.]]
Right Answer	RightAnswer::A
Explanation	[[Explanation::BRCA1 and BRCA2 are tumor suppressor genes whose mutation is associated with development of breast and ovarian cancers. Breast tissue normally expresses BRCA1 to protect dividing cells from DNA damage. During replication, if one strand of DNA breaks, a repair is easy, and the opposing strand can be used as template. If both strands of DNA are broken (double strand break), a seamless repair is much more difficult as the intervening sequence can be ambiguous. There are two methods of resolving a double strand break: 1. Non-homologous end joining (NHEJ) and 2. Homologous recombination. NHEJ is an error-prone method in which random sequence is inserted and ligated to bridge the break. Conversely, homologous recombination uses homologous sequence from a sister chromatid as template to facilitate perfect repair. BRCA1 is a key coordinator of homologous recombination based pair. BRCA1 binds to other proteins to form a complex that repairs DNA double strand break repairs by homologous recombination. Germline mutation of BRCA1 predisposes individuals to the development of both breast and ovarian cancers. BRCA1 protein does not act as a tumor suppressor in the traditional sense that a protein like Retinoblastoma (Rb) protein does. Biallelic loss of BRCA1 itself is not thought to confer a growth advantage to cells. Instead, BRCA1 loss is a mechanism that allows for an increased probability of developing other oncogenic mutations. In this sense, BRCA1 is more similar to a "caretaker" gene whose protein product brakes on cellular growth control. From a molecular perspective, Hereditary Breast and Ovarian Cancer (HBOC) syndrome is very similar to Hereditary Non-Polyposis Colorectal Cancer (HNPCC), which is caused by mutation in "caretaker" genes involved in DNA mismatch repair (MSH2 and MLH1). A woman with a germline mutation in BRCA1 has an 85% lifetime risk of developing breast cancer without intervention. The coding sequence of BRCA1 is very long, and both inherited and sporadic mutations in it are common. BRCA2 is also involved in DNA double strand break repair, and mutation in BRCA2 causes a similarly increased risk of breast and ovarian cancers. Educational Objective: BRCA tumor suppressor genes encode DNA double strand break repair proteins. References: John EM, Miron A, Gong G, et al. Prevalence of pathogenic BRCA1 mutation carriers in 5 US racial/ethnic groups. JAMA. 2007;298(24):2869-76. First Aid 2015 page 232, 582, 585]]
Approved	Approved::Yes
Keyword	WBRKeyword::Breast, WBRKeyword::Cancer, WBRKeyword::Breast cancer, WBRKeyword::Oncogene, WBRKeyword::Tumor, WBRKeyword::Tumor suppressor, WBRKeyword::Tumor Suppressor gene, WBRKeyword::Genetics, WBRKeyword::DNA, WBRKeyword::DNA repair, WBRKeyword::BRCA1, WBRKeyword::BRCA2, WBRKeyword::Hereditary Breast and Ovarian cancer, WBRKeyword::HBOC
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