(PQD3) Genetic Basis of Breast Cancer Resistance in BRCA1+ Carrier

描述（由申请人提供）：我们的提案解决了RFA-CA-12-022中的PQD3：“哪些潜在的因果事件-例如，遗传，表观遗传，生物，行为或环境-允许某些个体在其他高致命性癌症的预期限制之外存活？”BRCA1突变是乳腺癌最著名的遗传原因之一。在BRCA1+家族中，高达80%遗传了BRCA1突变的家族成员会在70岁时患上乳腺癌，而20%同样遗传了BRCA1突变的家族成员（BRCA1+携带者）是乳腺癌抵抗者，他们一生中不会患上乳腺癌。在本课题中，我们计划研究乳腺癌耐药的遗传基础。我们计划采用外显子组测序的方法，比较来自同一BRCA1+家族的乳腺癌患病和未患乳腺癌的对的全基因，以确定两类家族成员之间不同的突变基因，并确定其与乳腺癌的功能相关性。我们的建议直接通过识别保护BRCA1+个体免受乳腺癌的基因来解决PQD3问题。

DESCRIPTION (provided by applicant): Our proposal addresses the PQD3 in the RFA-CA-12-022: "What underlying causal events - e.g., genetic, epigenetic, biologic, behavioral, or environmental - allow certain individuals to survive beyond the expected limits of otherwise highly lethal cancers?" BRCA1 mutation is one of the best-known genetic causes for breast cancer. In BRCA1+ families, up to 80% of the family members who inherited BRCA1 mutation will develop breast cancer by age of 70, whereas 20% of the family members who also inherited BRCA1 mutation (BRCA1+ carrier) are breast cancer-resistance in that they will never develop breast cancer in their lifetime. In this proposal, we plan to study the genetic basis of breast cancer-resistance. We plan to use exome sequencing method to compare the entire genes between the breast cancer-affected and breast cancer- unaffected pairs from the same BRCA1+ families to identify the genes mutated differently between the two types of family members and to determine their functional relevance to breast cancer. Our proposal directly addresses the PQD3 by identifying the genes that protect the BRCA1+ individuals from breast cancer.