A comprehensive approach to breast cancer susceptibility across the risk spectrum

描述(由申请人提供)：根据2002-2006年的数据，SEER估计在2009年，192,370名美国妇女被诊断患有乳腺癌，40,170人死于这种疾病(Horner，2009)。虽然家族性和/或早发性乳腺癌并不代表大多数疾病，但这些病例往往与预后不良有关。此外，由于确诊时年龄较早，这些病例在因该病失去的生命年数方面具有不成比例的巨大影响。高危乳腺癌易感基因BRCA1、BRCA2、PTEN和TP53都是十多年前发现的。目前，这些基因的突变筛查在有强烈家族病史或存在基因突变的综合征证据的妇女的临床处理中发挥着重要作用。在风险谱的另一端，全基因组关联研究已经确定了一些对乳腺癌影响非常小的常见等位基因；它们的临床应用尚未确定。然而，总而言之，已知的遗传效应谱只能解释大约三分之一的乳腺癌家族史。应该强调的是，目前在家族性癌症诊所就诊的绝大多数妇女只根据她们的家族病史进行咨询，因为她们在已知的易感基因中没有突变。因此，该项目的长期目标是确定导致遗传性乳腺癌风险的未知部分的大多数基因。在过去的几年里，新的DNA测序技术--通常被称为“下一代”或“大规模并行”测序--正在迅速成熟。它们现在已经成熟，可以应用于遗传易感性的研究问题，对于遗传易感性的连锁分析被广泛的遗传异质性和候选基因研究技术限制在少数基因所混淆。利用国际联合会在过去15年多时间里收集的乳腺癌遗传学资源，将使用两种大规模并行测序策略来实现该项目的长期目标：1)对一系列乳腺癌患者的人类基因组中的所有基因外显子进行重新测序，这些患者具有较强的家族史，但目前已知的高危易感基因之一无法解释这些基因外显子；以及2)从2400例早发性乳腺癌患者和频率匹配的对照组中对所有与乳腺癌易感性有关的生化途径中的基因外显子进行重新测序。为该项目组建的协作团队收集了现存最大的乳腺癌家族资源，在乳腺癌遗传学方面拥有独特的专业知识，拥有分析海量重测序数据所需的统计和生物信息学技能，并拥有必要时建立更广泛财团所需的经验。因此，这个团队和项目准备实现他们长期的乳腺癌易感基因鉴定目标，从而解决乳腺癌遗传学中的“遗传缺失问题”。 公共卫生相关性：目前，临床癌症遗传学应用于有乳腺癌和/或卵巢癌病史的家庭只对少数有BRCA1、BRCA2、TP53或PTEN突变的家庭有用；不幸的是，这些基因的突变只解释了这些家庭中的一小部分。该项目将把新的DNA测序技术应用于乳腺癌病例和家族的杰出资源，以确定导致早发性和家族性乳腺癌的大多数基因。从长远来看，这些基因的发现将导致更有效的预防计划，并有可能改进治疗。

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.