Massively Parallel Sequencing for Familial Colon Cancer Genes

家族性结肠癌基因的大规模并行测序

• 批准号: 9067321
• 负责人: Lisa Cannon Albright
• 金额: $ 57.89万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9067321
• 关键词: Affect; Age; Alleles; BMPR1A gene; Bioinformatics; CHEK2 gene; Cancer Family; Cancer-Predisposing Gene; Candidate Disease Gene; Cessation of life; Clinic; Clinical; Clinical Management; Colon Carcinoma; Colorectal Cancer; Counseling; DNA Sequence; Data; Deletion Mutation; Development; Diagnosis; Disease; Exons; Family; Family history of; First Degree Relative; Gene Mutation; Generations; Genes; Genetic; Genetic Heterogeneity; Genetic Predisposition to Disease; Germ-Line Mutation; Hereditary Malignant Neoplasm; Heritability; Human Genome; Individual; Inherited; Insertion Mutation; Lead; Life Style; MADH4 gene; MLH1 gene; MSH2 gene; MSH6 gene; Malignant Neoplasms; Massive Parallel Sequencing; Minority; Mismatch Repair; Mutation; NAT1 gene; NAT2 gene; Odds Ratio; Oncogenes; PMS2 gene; PTEN gene; Penetrance; Play; Population Database; Predisposition; Prevention program; Probability; Problem Solving; Recording of previous events; Relative Risks; Research; Resources; Risk; Risk Factors; Role; SNP genotyping; STK11 gene; Sampling; Sequence Analysis; Series; Susceptibility Gene; Technology; Testing; Translating; Utah; Variant; XRCC2 gene; anticancer research; base; cancer genetics; cancer risk; case control; clinical practice; clinically relevant; cost; design; exome sequencing; gene discovery; genetic linkage analysis; genetic pedigree; genetic resource; genetic risk factor; genetic variant; genome wide association study; genome-wide; high risk; improved; indexing; malignant breast neoplasm; member; multidisciplinary; mutation screening; next generation; non-genetic; segregation; skills

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.

描述（由申请人提供）：结直肠癌仍然是美国最常见的癌症之一，2009 年估计有 146,970 例新诊断病例和 49,920 例死亡病例（Jemal 2009）。结肠癌也是家族性最强的癌症之一。一级亲属患有结肠癌的个体的风险增加 2 至 3 倍，而那些有超过一名一级亲属患有结肠癌或单个一级亲属在 50 岁时患病的个体，其风险比没有家族史的个体高 3 至 6 倍。最重要的高危结直肠癌易感基因 APC、MLH1、MSH2、MSH6、PMS2 和 PTEN 均在十多年前发现。目前，对这些基因的突变筛查以及一小部分与极小部分结直肠癌有关的其他基因正在发挥作用。 在具有很强的疾病家族史或存在基因突变的综合征证据的个体的临床管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结直肠癌风险影响非常小的常见等位基因；它们的临床效用尚未确定。然而，总的来说，已知的遗传效应谱只能解释结直肠癌家族性高发的大约四分之一。应该强调的是，目前，绝大多数在家族癌症诊所就诊的个体仅根据其家族史接受咨询，因为他们的已知易感基因不存在突变。因此，该项目的长期目标是确定导致遗传性结直肠癌风险无法解释的大部分基因。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研究问题，对于这些问题，连锁分析会因广泛的遗传异质性而混淆。利用犹他州人口数据库提供的无与伦比的家族癌症遗传学资源，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）通过对一系列结直肠癌病例的人类基因组中的所有基因外显子进行测序来鉴定候选基因，这些结直肠癌病例具有非常强烈的结直肠癌家族史，而目前已知的高风险易感基因之一无法解释； 2) 结直肠癌易感基因将通过对步骤#1中的候选基因进行病例对照重新测序来验证，该病例对照是在一系列有结直肠癌家族史的结直肠癌病例中与一系列无癌对照进行比较。为该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，拥有分析大量重测序数据所需的统计和生物信息技能，并且能够将研究结果几乎直接转化为临床癌症遗传学。因此，这个团队和项目准备向解决结直肠癌遗传学中的“遗传性缺失问题”迈出一大步。

项目成果

Adding In Silico Assessment of Potential Splice Aberration to the Integrated Evaluation of BRCA Gene Unclassified Variants.

• DOI: 10.1002/humu.22973
• 发表时间: 2016-07
• 期刊: Human mutation
• 影响因子: 3.9
• 作者: Vallée MP;Di Sera TL;Nix DA;Paquette AM;Parsons MT;Bell R;Hoffman A;Hogervorst FB;Goldgar DE;Spurdle AB;Tavtigian SV
• 通讯作者: Tavtigian SV