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: 8373141
• 负责人: Lisa Cannon Albright
• 金额: $ 59.86万
• 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 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8373141
• 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; Minority; Mismatch Repair; Mutation; NAT2 gene; Odds Ratio; Oncogenes; PMS2 gene; PTEN gene; Penetrance; Play; Population Database; Predisposition; Prevention program; Probability; Problem Solving; Recording of previous events; Relative (related person); Relative Risks; Research; Resources; Risk; Risk Factors; Role; SNP genotyping; STK11 gene; Sampling; Screening procedure; 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; 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; 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. PUBLIC HEALTH RELEVANCE: Currently, clinical cancer genetics applied to families with a history of colorectal cancer is only useful to the minority of families in which there is an APC1, mismatch repair gene, BMPR1A, MUTYH, PTEN, SMAD4, or STK11 mutation; unfortunately, mutations in these genes only explain a minority of such families. This project will apply new DNA sequencing technologies to an unparalleled resource of colon cancer cases and families to identify the majority of genes that contribute to familial colon cancer. In the long term, discover of these genes will lead to more effective prevention programs and, potentially, improved treatments.

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例新诊断和49，920例死亡（Jemal 2009）。结肠癌也是家族性最强的癌症之一。有一级亲属患结肠癌的个体风险增加2- 3倍，有一个以上一级亲属患结肠癌或一个一级亲属在50岁时患结肠癌的个体风险比没有家族史的个体高3- 6倍。最突出的高危结直肠癌易感基因APC、MLH 1、MSH 2、MSH 6、PMS 2和PTEN都是在十多年前发现的。目前，这些基因的突变筛查，加上一个简短的名单，额外的基因是负责一个非常小的比例结直肠癌，发挥 在临床管理中的重要作用的个人与强大的家族病史的疾病或综合征的证据存在的基因突变。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温和的常见等位基因;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总体家族性过剩的四分之一。应该强调的是，目前，绝大多数在家族性癌症诊所就诊的个体仅根据其家族史进行咨询，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负责遗传性结直肠癌风险的不明成分的大多数基因。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，其中连锁分析被广泛的遗传异质性所混淆。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，将使用两种大规模平行测序策略来实现本项目的长期目标：第一章候选基因将通过对来自一系列结肠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，这些病例具有非常强的结肠直肠癌家族史，目前已知的高风险易感基因;和2）结直肠癌易感基因将通过对来自步骤#1的候选基因进行病例对照重新测序来验证，与一系列无癌症对照相比，在更大系列的具有结直肠癌家族史的结直肠癌病例中。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，具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朝着解决结直肠癌遗传学中的“缺失遗传性问题”迈出一大步。 公共卫生关系：目前，应用于有结直肠癌病史的家族的临床癌症遗传学仅适用于少数存在APC 1、错配修复基因、BMPR 1A、MUTYH、PTEN、SMAD 4或STK 11突变的家族;不幸的是，这些基因的突变只能解释少数此类家族。该项目将把新的DNA测序技术应用于无与伦比的结肠癌病例和家族资源，以确定导致家族性结肠癌的大多数基因。从长远来看，这些基因的发现将导致更有效的预防计划，并可能改善治疗。