Genetic Epidemiology of Cancer

Bailey-Wilson博士在检测肺癌的遗传风险因素和可能的基因-基因和/或基因-环境相互作用方面已经工作了超过25年。她研究肺癌的目的是确定一个或多个导致肺癌易感性的基因。本财政年度，路易斯安那州已经收集了家庭数据。预计数据收集工作还将持续数年。Bailey-Wilson博士是肺癌遗传流行病学联盟（GELCC）的创始人，该联盟旨在从一大批合作研究人员那里获得更多的家庭数据。我们首次在染色体6q上发现了肺癌易感位点的全基因组显著连锁。我们还发表了一篇利用有序子集分析表征连锁证据的论文，将吸烟和其他连锁区域作为有序变量。这项研究表明，在这些高度聚集的家族中，一些额外的变异可能会增加患肺癌的风险。我们之前发表的证据表明RGS17是这个基因的一个很好的候选者，但这还没有得到明确的证明。对该区域的进一步测序研究正在进行中，同时还在研究一种基因敲除小鼠模型（在合作者Ming You的实验室中）。我们也在评估这个连锁区域的其他几个候选基因。这将是迄今为止发现的第一个与这种癌症有关的主要基因，这是一个令人兴奋的结果。对同一微卫星标记连锁面板进行了一组新家庭的基因分型，并对所有家庭的SNP标记连锁面板进行了基因分型。目前正在对微卫星和SNP联合数据进行分析。Bailey-Wilson博士正在应用我们的新倾向评分方法，将环境风险因素数据纳入对这些数据的非参数分析（在LODPAL中）。遗传疾病研究中心正在进行一项关于家族病例与老年人吸烟控制的大型GWAS基因分型。在接下来的一年里，我们将对我们高度聚集的家庭中受影响的亲属进行全外显子组和全基因组测序研究。

Dr. Bailey-Wilson has been working for over 25 years to detect genetic risk factors for lung cancer and possible gene-gene and/or gene-environment interactions. The purpose of her study of lung cancer is to identify a gene or genes that contribute to lung cancer susceptibility. In this fiscal year, family data have been collected in Louisiana. Data collection is expected to continue for several more years. Dr. Bailey-Wilson is a founder of the Genetic Epidemiology of Lung Cancer Consortium (GELCC) for the purpose of obtaining additional family data from a large group of collaborative investigators. The first genome-wide significant linkage of a lung cancer susceptibility locus on chromosome 6q was published by us. A paper characterizing the linkage evidence after using ordered subset analysis was also published by us using smoking and other linkage regions as the ordering variable. This work suggested that several additional variants may increase risk for lung cancer in these highly aggregated families. We have previously published evidence that RGS17 is a good candidate for this gene but this has not been proven definitively. Additional sequencing studies of the region are underway along with studies of a knock-out mouse model (in the lab of collaborator Ming You). We are also evaluating several other candidate genes in this linkage region. This would represent the first major gene ever discovered for this cancer and is an exciting result. A new set of families has been genotyped for the same microsatellite linkage panel of markers and a SNP marker linkage panel was genotyped in all families. Analyses are ongoing of the combined microsatellite and SNP data. Dr. Bailey-Wilson is applying our new propensity score method for including environmental risk factor data into non-parametric analyses (in LODPAL) to these data. A large GWAS on familial cases vs elderly, smoking controls is being genotyped at the Center for Inherited Disease Research. Over the next year we will be performing whole exome and whole genome sequencing studies on affected relatives in our highly aggregated families. Another major aim of Dr. Bailey-Wilson's research is to determine genetic risk factors in families with human prostate cancer. Papers published previously by our large group of collaborators have shown evidence of PRCA susceptibility genes in regions of chromosomes 1 (HPC1), 3p, 11q, 8 and Xq (HPCX). These results have been followed up by intensive linkage analyses of additional families to markers in these regions and in other regions that showed some mild evidence of linkage in the initial genome scans. Previously, our group identified mutations in the ribonuclease-L (RNASEL) gene as being the locus in our chromosome 1 linkage region (HPC1) causing increased risk to prostate cancer and showed evidence that mutations in the MSR1 gene on chromosome 8 plays a role in prostate cancer risk. Last year, in collaboration with Dr. Johanna Schleutker's group, we published new linkage analyses confirming linkage on chromosome 17 in a set of highly aggregated Finnish prostate cancer families. This year, some of our collaborators in the International Consortium for Prostate Cancer Genetics showed that HOXB13 is a good candidate for this locus and follow-up in Finland and in the ICPCG families support this as a causal locus. Dr. Bailey-Wilson's group is analyzing fine-mapping data in the African-American Hereditary Prostate Cancer (AAHPC) families. We work with the International Prostate Cancer Genetics Consortium (ICPCG) to try to localize prostate cancer loci more rapidly. This year we published a large meta-analysis of the ICPCG families in our chromosome X linkage region. A linkage meta-analysis is now underway to combine our African-American families from the AAHPC with those available from the ICPCG in order to increase power to detect loci that are of particular importance in this racial group. We are also collaborating with Dr. Diptasri Mandal on linkage studies of prostate cancer in African-American men from Louisiana and published a paper presenting our results this year. In addition to the ongoing linkage studies, the ICPCG is performing whole exome sequencing studies in our highly-aggregated prostate cancer families. As an adjunct to the family-based studies of prostate cancer described above, Dr. Bailey-Wilson is collaborating with Drs. Trent and Carpten of Tranlational Genomics, Dr. Barbara Nemesure of State University of New York at Stony Brook and Drs. Anselm Hennis and Lyndon Waterman of the University of the West Indies, in Barbados, on a study of the genetic epidemiology of prostate cancer and breast cancer in Barbados. These cancers occur at very high rates in the Barbadian population. Dr. Hennis' joint appointments in New York and Barbados have expedited this study. Data collection is underway for a large prostate case-control study, aiming for a sample of 1000 each. Several papers on breast cancer risk factors in this population have been published. We are analyzing fine-mapping SNPs on chromosome 8 to follow-up previous reports of linkage and association to prostate cancer in this region in other studies. Data collection was completed this year and we have just received genome-wide association data on a subset of the study participants. We plan to analyze these data accounting for local admixture and plan to expand to a GWAS of the entire dataset in the future. Dr. Bailey-Wilson has begun a new collaborative study of Carcinoid tumor with Drs. Steven Wank of NIDDK and Drs. Alejandro Schaffer and Richa Agarwala of CIT/NIH. In this study of this rare familial tumor, we are comparing linkage results in several large, highly aggregated families with whole-exome sequence data to attempt to localize genes responsible for this highly-penetrant familial tumor. This work is ongoing. Dr. Cheryl Cropp has collaborated with Dr. Sissung at NCI on meta-analysis of studies of the association of genetic variants at 8q24 with prostate cancer and published a paper this year.