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名美国女性被诊断患有乳腺癌，40,170人死于该疾病（Horner 2009）。虽然家族性和/或早发性乳腺癌并不占该疾病的大多数，但这些病例往往与预后不良有关。此外，由于诊断时年龄较早，这些病例在因该疾病而丧失的生命年数方面产生了不成比例的巨大影响。乳腺癌高危易感基因BRCA1、BRCA2、PTEN和TP53都是在十多年前发现的。目前，这些基因的突变筛查在具有强烈疾病家族史或存在基因突变的综合征证据的妇女的临床管理中起着重要作用。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很小的常见等位基因；它们的临床用途尚未确定。然而，总的来说，已知的遗传影响范围只能解释三分之一的家族性乳腺癌。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仅根据其家族史接受咨询，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解释成分的大部分基因。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——已经迅速成熟。它们现在已经成熟，可以应用于遗传易感性的研究问题，在遗传易感性中，连锁分析被广泛的遗传异质性和候选基因研究所混淆，技术上仅限于少数基因。利用国际联盟在过去15年收集的乳腺癌遗传资源，将采用两种大规模平行测序策略来实现该项目的长期目标：1)对一系列具有强烈家族史且目前已知的高危易感基因之一无法解释的乳腺癌病例的人类基因组中所有基因外显子进行重测序；2)从2400例早期乳腺癌病例和频率匹配的对照中，对所有与乳腺癌易感性相关的生化途径中所有基因的外显子进行重测序。为该项目组建的合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，拥有分析大量重测序数据所需的统计和生物信息学技能，并具有必要时建立更广泛联盟所需的经验。因此，该团队和项目有望实现其乳腺癌易感基因鉴定的长期目标，从而解决乳腺癌遗传学中的“缺失遗传性问题”。

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.