WBR0770
| Author | [[PageAuthor::Rim Halaby, M.D. [1] (Reviewed by Will Gibson)]] |
|---|---|
| Exam Type | ExamType::USMLE Step 1 |
| Main Category | MainCategory::Genetics |
| Sub Category | SubCategory::Oncology |
| Prompt | [[Prompt::A 48-year-old woman, previously healthy, presents to the physician's office for a left breast lump she noticed on self-exam. She explains that she incidentally palpated the lump during showering. She does not complain of any pain or breast discharge. Following appropriate work-up, she is diagnosed with triple-negative breast cancer with ductal histology. Genetic analysis demonstrates a germline c.185delAG frameshift mutation in the BRCA1 gene. When asked, the physician explains the normal function of BRCA1. 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 gene 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 Burkitt's lymphoma, and 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 CML, breast cancer, and MEN II syndromes, respectively. |
| Answer D | AnswerD::GTPase |
| Answer D Explanation | [[AnswerDExp::An example of a gene that encodes GTPase is the ras proto-oncogene. Mutations of ras proteins abrogate GTAPase activity and force the protein to stay in the "on" GTP-bound state. Mutations of KRAS occur in pancreatic cancer (95%), colon cancer (40%) and lung cancer (20%).]] |
| Answer E | AnswerE::Cytokine receptor |
| Answer E Explanation | AnswerEExp::An example of a gene that encodes a cytokine receptor is c-kit oncogene that is associated with gastrointestinal stromal tumors (GIST). JAK1 is also a cytokine receptor that is mutated in polycythemia vera. |
| Right Answer | RightAnswer::A |
| Explanation | [[Explanation::BRCA1 and BRCA2 are tumor suppressor genes that are associated with breast cancer and ovarian cancer. Breast and many other tissues normally express BRCA1 to protect dividing cells from DNA damage. During replication, if one strand of DNA breaks a repair is easy; 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 a host of 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 does not act as a tumor suppressor in the traditional sense that a protein like Retinoblastoma 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" than brakes on cellular growth control. From a molecular perspective, Hereditary Breast and Ovarian Cancer syndrome (HBOC) is very similar to Hereditary Nonpolyposis Colorectal Cancer, which is caused by mutation in "caretaker" genes involved in DNA mismatch repair (MSH2 and MLH1). A woman with a germline mutation of BRCA1 has an 85% lifetime risk of developing breast cancer without intervention. The coding sequence of BRCA1 is very long; both inherited and sporadic mutations in it are common. Frequently, a mutation is discovered b |
| 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 |
| Linked Question | Linked:: |
| Order in Linked Questions | LinkedOrder:: |