GENOMIC ANALYSIS OF INHERITED BREAST AND OVARIAN CANCER

遗传性乳腺癌和卵巢癌的基因组分析

• 批准号: 10222586
• 负责人: MARY-CLAIRE KING
• 金额: $ 92.7万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-10 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10222586
• 关键词: Address; Affect; Alleles; BRCA1 gene; BRCA2 gene; Biology; Breast Cancer Patient; Breast Cancer Risk Factor; Cancer Family; Candidate Disease Gene; Characteristics; Code; DNA; Development; Diagnosis; Distant; Family; Frequencies; Genes; Genetic; Genetic Predisposition to Disease; Genomics; Germ-Line Mutation; Goals; Individual; Inherited; Life; Malignant Neoplasms; Malignant neoplasm of ovary; Mammalian Oviducts; Medicine; Molecular; Mutation; Nucleic Acid Regulatory Sequences; Oncogenes; Ovarian; Patients; Population Control; RNA; Recording of previous events; Relative Risks; Research Personnel; Risk; Risk Factors; Sampling; Somatic Mutation; Specimen; Surgical Oncologist; Translations; Woman; Wrestling; actionable mutation; bioinformatics tool; clinical care; clinical practice; clinically actionable; college; follower of religion Jewish; founder mutation; gene discovery; genome sequencing; homologous recombination; human genome sequencing; kindred; malignant breast neoplasm; peritoneal cancer; public health relevance; tumor; whole genome

 DESCRIPTION (provided by applicant): Each year in the U.S., 230,000 women are diagnosed with breast cancer and 40,000 women die of it; 21,000 women are diagnosed with ovarian cancer and 14,000 women die of it; family history is one of the most important risk factors for each of these cancers, yet most of that risk remains unexplained. I have been wrestling with this problem my entire scientific life. The discoveries of BRCA1 and BRCA2, their characterization, and the translation of these discoveries to clinical practice have unquestionably made a difference. This proposal is my plan to identify the genetic causes of inherited breast cancer in those families that remain unsolved. My hypothesis is that the remaining genetic predisposition to breast and ovarian cancer is due to many different, individually rare mutations of severe effect. I suggest that some of these mutations lie in distant regulatory regions of known breast and ovarian cancer genes: the coding sequences and the close-in regions having already been thoroughly screened in our studies. I further suggest that other mutations likely alter genes not yet known to be involved in inherited predisposition to these cancers. I propose to identify these mutations, the genes that harbor them, and the mechanisms by which they act. My approach will be to integrate whole genome sequencing with application and development of bioinformatics tools and with experimental biology. I propose to address the problem from three directions simultaneously: * Discovery of new mutational mechanisms and new genes in extended kindreds severely affected by breast or ovarian cancer with normal sequences of all known breast and ovarian cancer genes * Discovery of founder mutations in young-onset breast cancer patients of Ashkenazi Jewish ancestry who have normal sequences of all known breast and ovarian cancer genes, then comparing the frequencies of potentially critical founder alleles in independent AJ cases and AJ population controls * Discovery of new candidate genes revealed by somatic mutation signatures characteristic of BRCA1, BRCA2, and perhaps other genes involved in homologous recombination, in ovarian, fallopian tube, and peritoneal cancer specimens from patients already evaluated for germline mutations in known ovarian cancer genes In addition to me, the investigators undertaking this effort are young geneticists, bioinformaticists, molecular biologists, and surgical oncologists. Our partners in whole genome sequencing are the Baylor College of Medicine Human Genome Sequencing Center. Our shared goal is to provide the information necessary to enable all genes with mutations responsible for inherited breast and ovarian cancer to be integrated into clinical practice



项目成果

Lasker Award winner Mary-Claire King.

拉斯克奖得主玛丽·克莱尔·金。

• DOI: 10.1038/nm.3696
• 发表时间: 2014
• 期刊: Nature medicine
• 影响因子: 82.9
• 作者: King,Mary-Claire

Essential Role of BRCA2 in Ovarian Development and Function.

• DOI: 10.1056/nejmoa1800024
• 发表时间: 2018-09-13
• 期刊: The New England journal of medicine
• 作者: Weinberg-Shukron A;Rachmiel M;Renbaum P;Gulsuner S;Walsh T;Lobel O;Dreifuss A;Ben-Moshe A;Zeligson S;Segel R;Shore T;Kalifa R;Goldberg M;King MC;Gerlitz O;Levy-Lahad E;Zangen D
• 通讯作者: Zangen D

Helicase-inactivating BRIP1 mutation yields Fanconi anemia with microcephaly and other congenital abnormalities.

• DOI: 10.1101/mcs.a005652
• 发表时间: 2020-10
• 期刊: Cold Spring Harbor molecular case studies
• 影响因子: 1.8
• 作者: Kamal L;Pierce SB;Canavati C;Rayyan AA;Jaraysa T;Lobel O;Lolas S;Norquist BM;Rabie G;Zahdeh F;Levy-Lahad E;King MC;Kanaan MN
• 通讯作者: Kanaan MN

Contribution of inherited mutations in the BRCA2-interacting protein PALB2 to familial breast cancer.

• DOI: 10.1158/0008-5472.can-10-3958
• 发表时间: 2011-03-15
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Casadei S;Norquist BM;Walsh T;Stray S;Mandell JB;Lee MK;Stamatoyannopoulos JA;King MC
• 通讯作者: King MC

Germline mutations of inhibins in early-onset ovarian epithelial tumors.

• DOI: 10.1002/humu.22489
• 发表时间: 2014-03
• 期刊: HUMAN MUTATION
• 影响因子: 3.9
• 作者: Tournier, Isabelle;Marlin, Regine;Walton, Kelly;Charbonnier, Francoise;Coutant, Sophie;Thery, Jean-Christophe;Charbonnier, Camille;Spurrell, Cailyn;Vezain, Myriam;Ippolito, Lorena;Bougeard, Gaelle;Roman, Horace;Tinat, Julie;Sabourin, Jean-Christophe;Stoppa-Lyonnet, Dominique;Caron, Olivier;Bressac-de Paillerets, Brigitte;Vaur, Dominique;King, Mary-Claire;Harrison, Craig;Frebourg, Thierry
• 通讯作者: Frebourg, Thierry