Massively Parallel Sequencing for Familial Colon Cancer Genes

描述(申请人提供)：结直肠癌仍然是美国最常见的癌症之一，2009年估计有146,970例新诊断和49,920例死亡(2009年1月)。结肠癌也是家族性最强的癌症之一。有结肠癌一级亲属的人的风险增加2到3倍，而那些有一个以上的一级亲属患有结肠癌或50岁时有一个一级亲属受到影响的人比没有家族史的人风险高3到6倍。最突出的高危结直肠癌易感基因APC、MLH1、MSH2、MSH6、PMS2和PTEN都是十多年前发现的。目前，对这些基因的突变筛查，加上一小部分导致结直肠癌的额外基因的简短清单，发挥了作用。 在有强烈家族病史或存在基因突变的综合征证据的个人的临床管理中发挥重要作用。在风险谱的另一端，全基因组关联研究已经确定了一些对结直肠癌风险影响非常小的常见等位基因；它们的临床实用价值尚未确定。然而，综上所述，已知的遗传效应谱只能解释大约四分之一的结直肠癌家族史。应该强调的是，目前在家族性癌症诊所就诊的绝大多数人只根据他们的家族病史进行咨询，因为他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结直肠癌风险的未解释部分的大多数基因。在过去的几年里，新的DNA测序技术--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，对于遗传易感性的连锁分析被广泛的遗传异质性搞混了。利用犹他州人口数据库提供的无与伦比的家族性癌症遗传学资源，将使用两种大规模并行测序策略来追求该项目的长期目标：1)将通过对一系列结直肠癌病例的人类基因组中所有基因外显子进行测序来识别候选基因，这些病例具有非常强的结直肠癌家族史，但目前已知的高危易感基因之一无法解释这些基因；2)在有结直肠癌家族史的结直肠癌病例中，与一系列非癌症对照相比，将通过从步骤1开始对候选基因进行病例对照重新测序来验证结直肠癌易感基因。为这个项目组建的多学科团队可以获得研究癌症遗传学的无与伦比的资源，拥有分析大量重新测序数据所需的统计和生物信息学技能，并有能力几乎直接将发现转化为临床癌症遗传学。因此，这个团队和项目正准备向解决结直肠癌遗传学中的“缺失遗传性问题”迈出一大步。

DESCRIPTION (provided by applicant): Colorectal cancer remains one of the most common cancers in the US with 146,970 new diagnoses and 49,920 deaths estimated for 2009 (Jemal 2009). Colon cancer is also one of the most familial of cancers. Individuals with a first-degree relative with colon cancer have a 2- to 3-fold increased risk, and those with more than one first-degree relative with colon cancer or a single first-degree relative affected at age d 50 years have a 3- to 6-fold greater risk than those with no family history. The most prominent high-risk colorectal cancer susceptibility genes, APC, MLH1, MSH2, MSH6, PMS2, and PTEN, were all discovered more than a decade ago. Currently, mutation screening of these genes, plus a short list of additional genes that are responsible for a very small fraction of colorectal cancer, plays an important role in the clinical management of individuals 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 colorectal cancer risk; their clinical utility has yet to be established. However, taken together, the known spectrum of genetic effects only explain about one quarter of the overall familial excess of colorectal cancer. It should be emphasized that, at present, the vast majority of individuals 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 colorectal cancer risk. Over the last few years, new DNA sequencing technologies - referred to as "next generation" or "massively parallel" sequencing - have matured rapidly. They are now ripe for application to research questions in genetic susceptibility for which linkage analysis is confounded by extensive genetic heterogeneity. Taking advantage of unparalleled familial cancer genetics resources available through the Utah Population Database, two massively parallel sequencing strategies will be used to pursue the long term objective of this project: 1) candidate genes will be identified by sequencing all of the gene exons in the human genome from a series of colorectal cancer cases who have a very strong family history of colorectal cancer that is not explained by one of the currently known high-risk susceptibility genes; and 2) colorectal cancer susceptibility genes will be validated by case-control re-sequencing of the candidate genes from step #1 in a much larger series of colorectal cancer cases who have family history of colorectal cancer in comparison with a series of cancer-free controls. The multidisciplinary team assembled for this project has access to an unparalleled resource for studying cancer genetics, has statistical and bioinformatic skills required to analyze massive re-sequencing data, and has the ability to translate findings almost directly to clinical cancer genetics. Thus this team and project are poised to take a huge step towards solving the "problem of missing heritability" in colorectal cancer genetics.