Finding Genes for Cancer Susceptibility and Growth Regulation

寻找癌症易感性和生长调节基因

• 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
• 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

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图谱感兴趣，并重点关注两个主要主题。 首先，我们正在绘制、研究和识别增加人类乳腺癌 (BC) 和前列腺癌 (PC) 易感性的基因变异。其次，我们对犬科动物系统的发展感兴趣，以了解遗传变异在复杂性状中的作用。 今年我们的大部分工作集中在前列腺癌和犬类遗传变异上。 前列腺癌 我们之前观察到，大量与 15q11-14 具有假定连锁的家族也患有结肠癌家族分离。 我们对结肠癌和前列腺癌进行了独立的全基因组分析（FitzGerald 等人，Eur J Hum Genet. 2010 18:1141-7），使用来自 96 个遗传性前列腺癌 (HPC) 家族的 DNA，每个家族都有一个或多个患有结肠癌 (CCa) 的一级亲属，并进一步分析了具有两个或多个 CCa 病例的家族子集 (n=27)。 当 PC 和 CCa 表型都被认为在有两个或更多 CCa 病例的家庭中受到影响时（隐性 HLOD=3.88），在 15q14 处确定了最强的连锁信号。 我们与国际前列腺癌遗传学联盟 (ICPCG) 合作，通过结合来自 2000 多个家庭的连锁数据来识别与前列腺癌风险相关的基因座。我们使用 Illumina 6000 SNP 连锁面板对 762 个家族进行了基因分型，并鉴定了 4 号和 8 号染色体上的位点。之前的其他研究表明 8q24 上的位点对于易感性和体细胞变化都很重要。 4q13-25 上的基因座是新的，似乎与发病年龄较晚密切相关（Lu et al., Prostate, Jul 11​​ Epub before print）。 我们还与另一个名为 PRACTICAL 的国际联盟合作开展 GWAS 研究，旨在寻找前列腺癌基因座。 我们的作用是验证和扩展最初的发现。 领导小组的初步研究发表于 2008 年《自然遗传学》杂志上。 在随后的研究中，我们验证了这些结果，表明染色体 3、6、7、10、11、19 和 X 上的基因座包含与前列腺癌密切相关的 SNP（Kote-Jarai 等人，Cancer Edpidemiol Biomarkers Prev. 2008, 17: 2901）。 然后，我们试图通过对更多个体病例和对照以及更密集的基因分型进行额外分析来扩展先前的发现。 在我们参与的 2009 年《自然遗传学》杂志上发表的一篇论文中，该联盟报告了在 2、4、8、11 和 22 号染色体上鉴定出新的前列腺癌易感位点，P 值为 1.6 X 10-8 至 2.7 X 10-33（Eeles 等人，Nat Genet. 2009, 41:1116-21）。 PRACTICAL 联盟最近确定了另外七个位点，其中包括我们的贡献（Kote-Jarai 等人，Nat Genet，2011 10：875-791）。 GWAS 方法确定的 40 个基因座解释了约 25% 的疾病家族风险。 在一项独立研究中，我们与 Chris Haiman 合作研究了非裔美国男性 (AA) 的前列腺癌（Haiman 等人，Nat Genet. 2011, 43: 570-3），AA 男性与该疾病相关的发病率和死亡率最高。 为了寻找常见的风险等位基因，我们对 3,425 名患有 PC 的非裔美国人（病例）和 3,290 名非裔美国男性对照组的 1,047,986 个 SNP 标记进行了基因型分析，完成了 GWAS。我们追踪了最重要的 17 个新关联，并在染色体 17q21 上发现了一个新的风险变异。需要进一步的研究来调查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 个候选基因和 1000 多个标签 SNP 进行分析的研究，该研究是对来自华盛顿州西部的男性进行的基于人群的病例对照研究（n = 1,458 例病例和 1,351 名对照）。我们最近完成了炎症途径的详细研究。 7 个基因（CXCL12、IL4、IL6、IL6ST、PTGS2、STAT3 和 TNF）中的 10 个 SNP 名义上与白种人 PC 风险相关（P < 0.05）。对风险影响最显着的是白细胞介素 6 信号转导器 (IL6ST) 基因（OR = 0.08，95% CI：0.01-0.63）。七个 SNP 的风险估计根据疾病侵袭性存在显着差异（P（同质性）< 0.05），这些结果强调了炎症途径在 PC 发生和进展中的潜在重要性。 犬科动物 我们的犬类研究专注于寻找在疾病易感性和生长调节中重要的基因。这项工作是通过与狗主人、饲养员和养犬俱乐部合作完成的，而不是通过在现场饲养或饲养任何狗来完成。迄今为止，这些努力已经产生了几篇备受瞩目的论文。 家养狗表现出巨大的表型多样性。在最近的一篇论文中，我们通过对来自 80 个家养犬种的 915 只狗、83 只野生犬科动物和 10 只近交非洲狗的 60,968 个单核苷酸多态性 (SNP) 进行基因分型，生成了犬类遗传变异的高密度图谱 (Boyko 等人，Plos Biol 2010)。将该基因组资源与品种标准和个体的外部测量以及博物馆标本的骨骼测量相结合，我们确定了狗基因组的 51 个区域，这些区域与品种间 57 个性状的表型变异相关。与人类相比，我们发现对于不同的狗品种来说，少数数量性状基因座（少于或= 3）解释了我们研究的大多数性状的大部分表型变异。此外，许多基因组区域显示出最近选择的特征，大多数高度分化的区域与品种定义性状相关，例如体型、皮毛特征和耳朵松弛度。我们的结果证明了使用基因型个体数据库绘制家犬多个性状的有效性，并强调了人类定向选择在改变这一重要物种关键性状遗传结构方面所发挥的重要作用。 我们还在继续开展全基因组关联分析（GWAS）系列，旨在寻找狗的癌症易感性位点。 正在进行的研究包括绘制苏格兰梗、西高地白梗以及最近的喜乐蒂膀胱移行细胞癌（TCC）的位点图谱。 我们继续研究伯尔尼山犬的恶性组织细胞增多症 (MH) 以及贵宾犬和巨型雪纳瑞的手指鳞状细胞癌 (SCC)，最近提交了一篇关于 MH 的论文。我们发现了两个恶性组织细胞增多症的位点，并对两者进行了精细定位。我们也在平毛寻回犬中开始了类似的研究。位置克隆的努力在贵宾犬的 SCC 案例中取得了成功。 膀胱癌研究还揭示了两个基因座。 精细作图完成后，一个小的单倍型定义了每个基因座。突变扫描正在进行中。 总之，我们的工作旨在了解遗传变异在调节表型中的作用，从而影响形态和疾病易感性。因此，过去的一年在各方面都取得了重大进展，并发表了多篇论文。