Finding Genes for Cancer Susceptibility and Growth Regulation

寻找癌症易感性和生长调节基因

基本信息

批准号：
8350000
负责人：
elaine ostrander
金额：
$ 299.87万
依托单位：
NATIONAL HUMAN GENOME RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8350000
关键词：
15q14 17q21 8q24 Affect African African American Age Alleles Architecture Biological Biological Markers Body Size Breast Breeding CXCL12 gene Cancer Family Cancer-Predisposing Gene Candidate Disease Gene Canis familiaris Case-Control Studies Caucasians Caucasoid Race Characteristics Chromosome Mapping Chromosomes Chromosomes, Human, Pair 2 Chromosomes, Human, Pair 3 Chromosomes, Human, Pair 4 Collaborations Colon Carcinoma Complex Coupling DNA Data Data Linkages Databases Development Digit structure Disease Disease susceptibility Ear Europe Exhibits Family First Degree Relative General Population Genes Genetic Genetic Variation Genets Genomics Genotype Growth Haplotypes Housing Human IL4 gene IL6 gene Individual Inflammation Inherited International Lead Leg Length Malignant - descriptor Malignant Neoplasms Malignant histiocytosis Malignant neoplasm of prostate Malignant neoplasm of urinary bladder Maps Measurement Morbidity - disease rate Morphology Museums Mutation Nature PTGS2 gene Paper Pathway interactions Phenotype Play Predisposition Printing Prostate Publications Publishing Quantitative Trait Loci Regulation Reporting Resources Risk Risk Estimate Role STAT3 gene Sampling Scanning Series Shapes Signal Transduction Single Nucleotide Polymorphism Site Specimen Squamous cell carcinoma System TNF gene Variant Washington Width Woman Work bladder transitional cell carcinoma cancer genetics cancer risk case control cranium density disorder risk dog genome follow-up genetic variant genome wide association study high risk human IL6ST protein interest male malignant breast neoplasm men middle age mortality population based positional cloning skeletal trait

项目摘要

We are interested in genetic mapping of complex traits and genomics and focus on two main topics. First, we are mapping, studying, and identifying genetic variants that increase susceptibility to breast (BC) and prostate cancer (PC) in humans. Second, we are interested in the development of the canine system for understanding the role of genetic variation in complex traits. This year most of our efforts focused on prostate cancer and canine genetic variation. Prostate Cancer We observed previously that a large number of families with putative linkage to 15q11-14 also had colon cancer segregating in the families. We did an independent genome wide analysis of colon and prostate cancer (FitzGerald et al., Eur J Hum Genet. 2010 18:1141-7), using DNA from 96 Hereditary Prostate Cancer (HPC) families, each of which has one or more first-degree relatives with colon cancer (CCa), and further analyzed the subset of families with two or more CCa cases (n=27). The strongest linkage signal was identified at 15q14 when both PC and CCa phenotypes were considered to be affected in families with two or more CCa cases (recessive HLOD=3.88). We have worked with the International Consortium of Prostate Cancer Genetics (ICPCG) to identify loci associated with prostate cancer risk by combining linkage data from over 2000 families. We genotyped 762 families with the Illumina 6000 SNP linkage panel and identified loci on chromosomes 4 and 8. The locus on 8q24 has been previously implicated in other studies as being important for both susceptibility and somatic changes. The locus on 4q13-25 is new and appears to most strongly associated with later ages at onset (Lu et al., Prostate, Jul 11 Epub ahead of print). We have also collaborated with an addition international consortium termed the PRACTICAL to do GWAS studies aimed at finding prostate cancer loci. Our role has been to validate and extend the initial findings. The initial studies from the lead group were published in 2008 in Nature Genetics. In a subsequent study we validated these results showing that loci on chromosomes 3, 6, 7, 10, 11 19 and X contained SNPs strongly associated with prostate cancer (Kote-Jarai et al., Cancer Edpidemiol Biomarkers Prev. 2008, 17: 2901). We then sought to extend previous findings by additional analysis of more individual cases and controls and denser genotyping. In a paper published in Nature Genetics in 2009, that we were part of, the Consortium reported the identification of new prostate cancer susceptibility loci on chromosomes 2, 4, 8, 11, and 22 with P values of 1.6 X 10-8 to 2.7 X 10-33 (Eeles et al., Nat Genet. 2009, 41:1116-21). Seven additional loci were very recently identified by the PRACTICAL consortium and included our contributions (Kote-Jarai et al., Nat Genet, 2011 10: 875-791). The 40 loci identified by the GWAS approach explain about 25% of the familial risk of the disease. In an independent study we collaborated with Chris Haiman to study prostate cancer in African American men (AA) (Haiman et al., Nat Genet. 2011, 43: 570-3) AA men have the strongest morbidity and mortality associated with the disease. In search of common risk alleles we contributed to a GWAS with 1,047,986 SNP markers genpotyped in 3,425 African-Americans with PC (cases) and 3,290 African-American male controls. We followed up the most significant 17 new associations and identified a new risk variant on chromosome 17q21. Further studies are needed to investigate the biological contribution of this allele to prostate cancer risk. We completed a study of 100 candidate genes and over 1000 tag SNPs analyzed on a population based case-control study of men from Western Washington state (n = 1,458 cases and 1,351 controls). We recently completed a detailed study of the inflammation pathway. Ten SNPs in seven genes (CXCL12, IL4, IL6, IL6ST, PTGS2, STAT3, and TNF) were nominally associated (P < 0.05) with risk of PC in Caucasians. The most significant effect on risk was seen in the interleukin 6 signal transducer (IL6ST) gene (OR = 0.08, 95% CI: 0.01-0.63). Risk estimates for seven SNPs varied significantly according to disease aggressiveness (P(homogeneity) < 0.05), These results highlight the potential importance of the inflammation pathway in PC development and progression. Canines Our canine studies canine studies focus on finding genes important in disease susceptibility and growth regulation. This work is accomplished by collaboration with dog owners, breeders and kennel clubs and not by breeding or housing any dogs on site. Several high profile papers have resulted from these efforts to date. Domestic dogs exhibit tremendous phenotypic diversity. In a recent paper we generated a high density map of canine genetic variation by genotyping 915 dogs from 80 domestic dog breeds, 83 wild canids, and 10 outbred African dogs across 60,968 single-nucleotide polymorphisms (SNPs) (Boyko et al., Plos Biol 2010). Coupling this genomic resource with external measurements from breed standards and individuals as well as skeletal measurements from museum specimens, we identify 51 regions of the dog genome associated with phenotypic variation among breeds in 57 traits. In contrast to humans we find that for across dog breeds a small number of quantitative trait loci (less or = 3) explain the majority of phenotypic variation for most of the traits we studied. In addition, many genomic regions show signatures of recent selection, with most of the highly differentiated regions being associated with breed-defining traits such as body size, coat characteristics, and ear floppiness. Our results demonstrate the efficacy of mapping multiple traits in the domestic dog using a database of genotyped individuals and highlight the important role human-directed selection has played in altering the genetic architecture of key traits in this important species. We are also continuing our series of GWAS aimed at finding loci for cancer susceptibility in the dog. Ongoing studies include mapping loci for transitional cell carcinoma (TCC) of the bladder in the Scottish terrier and West Highland White terrier and very recently the Sheltie. We continued our studies of malignant histiocytosis (MH) in the Bernese mountain dog and squamous cell carcinoma (SCC) of the digit in the poodle and the giant schnauzer with a recent paper submitted on MH. We have found two loci for malignant histiocytosis and fine mapped both. We have also begun a similar study in Flat Coated Retrievers. Positional cloning efforts have been successful in the case of the SCC in the Poodle. Bladder cancer studies also reveal two loci. Fine mapping is completed, a small haplotype defines each locus. Mutation scanning is ongoing. In summary, our work is aimed at understanding the role of genetic variation in regulating phenotypes contributing to both morphology and disease susceptibility. As a result, the past year has been defined by significant progress on all fronts and publication of multiple papers.

我们对复杂性状和基因组学的遗传学映射感兴趣，并专注于两个主要主题。首先，我们正在绘制，研究和鉴定人类中对乳腺癌（BC）和前列腺癌（PC）的易感性的遗传变异。其次，我们对犬类系统的发展感兴趣，以理解遗传变异在复杂性状中的作用。今年，我们大多数努力都集中在前列腺癌和犬类遗传变异上。前列腺癌我们以前观察到，与15q11-14的假定联系的大量家庭在家庭中也隔离了结肠癌。我们使用96个遗传前列腺癌（HPC）家族的DNA对结肠和前列腺癌进行了独立的基因组广泛分析（Fitzgerald等，Eur J HumGenet。201018：1141-7），每个DNA都有一个或多个。具有结肠癌（CCA）的一级亲戚，并进一步分析了两个或更多CCA病例的家庭（n = 27）。当PC和CCA表型都被认为在两个或多个CCA病例的家族中都受到影响（隐性HLOD = 3.88）时，在15q14识别了最强的连锁信号。我们与前列腺癌遗传学（ICPCG）的国际联盟合作，通过结合了2000多家家庭的连锁数据来识别与前列腺癌风险相关的基因座。我们对762个具有Illumina 6000 SNP连锁面板的家族进行了基因分型，并在染色体4和8上鉴定了基因座。先前在其他研究中涉及8q24的基因座对易感性和躯体变化都很重要。 4Q13-25的基因座是新的，并且在发作时似乎与后来的年龄最密切相关（Lu等人，前列腺，7月11日EPUB在印刷前）。我们还与一个额外的国际财团合作，该联盟称其为旨在寻找前列腺癌基因座的GWAS研究。我们的作用是验证和扩展初始发现。铅组的初步研究于2008年发表在自然遗传学上。在随后的研究中，我们验证了这些结果表明，染色体上的基因座3、6、7、10、11 19和X含有与前列腺癌密切相关的SNP（Kote-Jarai等人，癌症Edpidemiol Biomarkers Prev。2008，1008，17：2901 ）。然后，我们试图通过对更多个体病例和对照和密集的基因分型的进一步分析来扩展以前的发现。在2009年，我们是自然遗传学发表的一篇论文中，该财团报告了在染色体2、4、8、11和22上鉴定新的前列腺癌易感基因座，P值为1.6 x 10-8至2.7 x 10-33（Eeles等人，Nat Genet。2009，41：1116-21）。实际上，该联盟最近确定了另外七个基因座，并包括我们的贡献（Kote-Jarai等，Nat Genet，2011年10：875-791）。 GWAS鉴定的40个基因座解释了大约25％的疾病家族风险。在一项独立的研究中，我们与克里斯·海曼（Chris Haiman）合作研究了非洲裔美国男性（AA）（Haiman等人，Nat Genet。2011，43：570-3）AA男性的发病率和死亡率最强。为了寻找常见的风险等位基因，我们在3,425名具有PC（病例）和3,290名非裔美国人男性对照组的非裔美国人中造成了1,047,986个SNP标记的GWA。我们跟进了最重要的17个新关联，并在17q21染色体上确定了新的风险变体。需要进一步的研究来研究该等位基因对前列腺癌风险的生物学贡献。我们完成了一项对100个候选基因的研究和1000多个TAG SNP，该研究对来自西部华盛顿州的男性的基于人群的病例对照研究（n = 1,458例病例和1,351个对照）。我们最近完成了炎症途径的详细研究。七个基因（CXCL12，IL4，IL6，IL6ST，PTGS2，STAT3和TNF）中的十个SNP名义上相关（P <0.05）与高加索人的PC风险。在白介素6信号传感器（IL6ST）基因（OR = 0.08，95％CI：0.01-0.63）中，对风险的最显着影响。七个SNP的风险估计根据疾病的侵略性（P（同质性）<0.05）差异很大，这些结果突显了炎症途径在PC发育和进展中的潜在重要性。犬我们的犬类研究犬类研究集中于寻找对疾病易感性和生长调控重要的基因。这项工作是通过与狗的主人，育种者和狗窝俱乐部的合作来完成的，而不是通过现场繁殖或安置任何狗来完成的。迄今为止，这些努力造成了一些知名论文。家犬表现出巨大的表型多样性。在最近的一篇论文中，我们通过在60,968个单核苷酸多态性（SNP）中从80种家用狗品种，83种野生犬种和10只杂种非洲犬（SNP）中产生了犬遗传变异的高密度图（Boyko et al。，Plos Biol Biol。 2010）。将这种基因组资源与来自品种标准和个体的外部测量以及博物馆标本的骨骼测量结合在一起，我们确定了57种特征中品种之间与表型变异相关的51个狗基因组区域。与人类相反，我们发现，对于整个狗，少数定量性状基因座（较少或= 3）解释了我们研究的大多数性状的大多数表型变化。此外，许多基因组区域都显示出最近选择的特征，其中大多数高度分化的区域都与定义品种特征（例如体型，外套特征和耳朵柔软度）相关。我们的结果表明，使用基因分型个体数据库在家犬中绘制多个特征的功效，并强调了人为指导选择在改变该重要物种中关键特征的遗传结构方面起着重要作用。我们还继续进行一系列GWA，旨在寻找狗的癌症易感性的基因座。正在进行的研究包括在苏格兰梗和西高地白梗和最近的Sheltie的膀胱中的过渡细胞癌（TCC）映射基因座。我们继续研究了贵宾犬的数字和巨型Schnauzer的伯尔尼山犬和鳞状细胞癌（SCC）中的恶性组织细胞增多症（MH）的研究，最近在MH上提交了一份论文。我们发现了两个用于恶性组织细胞增多症的基因座，并绘制了两者。我们还开始在扁平涂层猎犬中进行类似的研究。在贵宾犬的SCC中，位置克隆工作已经成功。膀胱癌研究还显示了两个基因座。精细映射已完成，一个小单倍型定义了每个基因座。突变扫描正在进行中。总而言之，我们的工作旨在了解遗传变异在调节形态和疾病易感性促进表型中的作用。结果，过去一年的定义是由各个方面的重大进展和多篇论文的出版所定义的。