]> 2026-07-31T09:41:33+00:00 WBR0770 0 en DNA repair protein ''BRCA1'' and ''BRCA2'' are tumor suppressor genes whose protein products are critical to repairing DNA double strand breaks. Transcription factor 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. Tyrosine kinase 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. GTPase 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. Cytokine receptor 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. ''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.<br> 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'').<br> 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.<br/> '''Educational Objective:''' ''BRCA'' tumor suppressor genes encode DNA double strand break repair proteins.<br/> '''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.<br> First Aid 2014 page 232, 582, 585 Genetics 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? A Oncology 2020-10-28T01:38:55Z 2459150.5686921 WBR0770