A comprehensive approach to breast cancer susceptibility across the risk spectrum

跨风险范围的乳腺癌易感性综合方法

基本信息

批准号：
8187594
负责人：
David E. Goldgar
金额：
$ 57.3万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-05 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8187594
关键词：
Accounting Affect Age Alleles American BRCA1 Mutation BRCA1 gene BRCA2 Mutation BRCA2 gene Base Sequence Biochemical Pathway Bioinformatics Breast Breast Cancer Genetics CHEK2 gene Cancer-Predisposing Gene Candidate Disease Gene Cell Cycle Checkpoint Clinic Clinical Clinical Management Counseling DNA DNA Double Strand Break DNA Resequencing DNA Sequence Data Development Diagnosis Disease Double Strand Break Repair Exhibits Exons Family Family history of Family member Frequencies Gene Mutation Genes Genetic Genetic Heterogeneity Genetic Predisposition to Disease Genotype Germ-Line Mutation Growth Hereditary Breast Carcinoma Hereditary Malignant Neoplasm Heritability Human Genome Incidence Inherited International Lead Malignant neoplasm of ovary Minority Mutation PTEN gene Pathway interactions Pattern Penetrance Play Predisposition Prevention program Probability Problem Solving Recording of previous events Relative (related person)Relative Risks Research Resources Risk Risk Factors Role Sampling Screening procedure Series Susceptibility Gene TP53 gene Technology Testing Translating Validation Variant Woman Work anticancer research base breast cancer diagnosis breast cancer family burden of illness cancer genetics cancer risk case control clinical practice clinically relevant cost design disease transmission early onset exome experience follow-up gene discovery genetic linkage analysis genetic resource genetic risk factor genetic variant genome wide association study genome-wide high risk improved knowledge base malignant breast neoplasm meetings next generation non-genetic outcome forecast population based repaired segregation skills

项目摘要

DESCRIPTION (provided by applicant): Based on data from 2002-2006, SEER estimated that in 2009, 192,370 American women were diagnosed with breast cancer and 40,170 died of the disease (Horner 2009). Although familial and/or early onset breast cancer does not represent the majority of the disease, these cases are often associated with poor prognosis. Further, because of their early age at diagnosis, these cases have a disproportionately large impact in terms of years of life lost to the disease. The high-risk breast cancer susceptibility genes BRCA1, BRCA2, PTEN, and TP53 were all discovered more than a decade ago. Currently, mutation screening of these genes plays an important role in the clinical management of women with a strong family history of the disease or syndromic evidence for the presence of a gene mutation. At the other end of the risk spectrum, genome-wide association studies have identified a number of common alleles with very modest effects on breast cancer; their clinical utility has yet to be established. However, taken together, the known spectrum of genetic effects only explain about a third of the overall familial excess of breast cancer. It should be emphasized that, at present, the vast majority of women seen at familial cancer clinics are counseled on the basis of their family history alone because they do not have mutations in the known susceptibility genes. Accordingly, the long-term objective of this project is to identify the majority of genes responsible for the unexplained component of inherited breast cancer risk. Over the last few years, new DNA sequencing technologies - often referred to as "next generation" or "massively parallel" sequencing - have been maturing rapidly. They are now ripe for application to research questions in genetic susceptibility, for which linkage analysis is confounded by extensive genetic heterogeneity and candidate gene studies technologically limited to small numbers of genes. Taking advantage of breast cancer genetics resources that have been gathered by international consortia over the last 15-plus years, two massively parallel sequencing strategies will be used to pursue the long term objective of this project: 1) resequencing all of the gene exons in the human genome from a series of breast cancer cases who have strong family history that is not explained by one of the currently known high-risk susceptibility genes; and 2) resequencing the gene exons of all of the genes in biochemical pathways that have been implicated in breast cancer susceptibility from a series of 2,400 early onset breast cancer cases and frequency-matched controls. The collaborative team assembled for this project has collected the largest breast cancer family resource extant, has unique expertise in breast cancer genetics, has the statistical and bioinformatic skills required to analyze massive resequencing data, and has the experience required to build wider consortia as necessary. Thus this team and project are poised to meet their long-term breast cancer susceptibility gene identification objective and thereby solve the "problem of missing heritability" in breast cancer genetics. PUBLIC HEALTH RELEVANCE: Currently, clinical cancer genetics applied to families with a history of breast and/ or ovarian cancer is only useful to the minority of families in which there is a BRCA1, BRCA2, TP53, or PTEN mutation; unfortunately, mutations in these genes only explain a minority of such families. This project will apply new DNA sequencing technologies to an outstanding resource of breast cancer cases and families to identify the majority of genes that contribute early onset and familial breast cancer. In the long term, discovery of these genes will lead to more effective prevention programs and, potentially, improved treatments.

描述（由申请人提供）：基于2002 - 2006年的数据，SEER估计在2009年，192,370名美国妇女被诊断出患有乳腺癌，40,170人死于该疾病（Horner 2009）。尽管家族性和/或早期发作乳腺癌并不代表大多数疾病，但这些病例通常与预后不良有关。此外，由于诊断时很小的年龄，这些病例就疾病失去了生命的岁月而产生的影响不成比例。十多年前发现了高危乳腺癌易感性基因BRCA1，BRCA2，PTEN和TP53。当前，这些基因的突变筛查在具有较强家族史的疾病或综合症证据的女性的临床管理中起着重要作用。在风险范围的另一端，全基因组关联研究已经确定了许多对乳腺癌产生非常适中的常见等位基因。他们的临床效用尚未建立。然而，综上所述，遗传效应的已知范围仅解释了总体家族过度过度的三分之一。应该强调的是，目前，仅根据家族史而在家族癌症诊所看到的绝大多数妇女都受到咨询，因为她们在已知的敏感性基因中没有突变。因此，该项目的长期目标是确定导致遗传性乳腺癌风险无法解释的组成部分的大多数基因。在过去的几年中，新的DNA测序技术（通常称为“下一代”或“大规模平行”测序）一直在迅速成熟。现在，它们已经成熟地用于研究遗传易感性中的问题，为此，连锁分析被广泛的遗传异质性和候选基因研究在技术上限于少量基因。利用国际财团在过去15年以上收集的乳腺癌遗传学资源，将使用两种大规模平行的测序策略来追求该项目的长期目标：1）重新陈述所有基因外显子中的所有基因外显子来自一系列乳腺癌病例的人类基因组，这些病例具有很强的家族史，而目前已知的高风险易感基因之一并未解释。 2）重新陈述生化途径中所有基因的基因外显子，这些基因与乳腺癌的敏感性有关，这与一系列2400个早期发作乳腺癌病例和频率匹配的对照组相反。为该项目组装的合作团队已收集了最大的乳腺癌家庭资源，具有独特的乳腺癌遗传学专业知识，具有分析大量重新定价数据所需的统计和生物信息技能，并且具有必要的建立更广泛的财团所需的经验。因此，该团队和项目有望满足其长期的乳腺癌易感性基因鉴定目标，从而解决了乳腺癌遗传学中“缺少遗传力的问题”。公共卫生相关性：目前，适用于具有乳腺癌和/或卵巢癌史的家庭的临床癌症遗传学仅对少数有BRCA1，BRCA2，TP53或PTEN突变的家庭有用；不幸的是，这些基因的突变只能解释少数此类家庭。该项目将将新的DNA测序技术应用于乳腺癌病例和家庭的杰出资源，以识别大多数促进早期发作和家族性乳腺癌的基因。从长远来看，这些基因的发现将导致更有效的预防计划，并可能改善治疗方法。