Dr. Bailey-Wilson has been working for over 30 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 is being genotyped for a SNP marker linkage panel and data are expected in the next year. A large GWAS on familial cases vs elderly, smoking controls was genotyped at the Center for Inherited Disease Research and analyses are ongoing. We are analyzing targeted sequence data in the 6q region in our most strongly linked families. We have performed whole exome sequencing in collaboration with Dr. Margaret Spitz of Baylor University on 60 of our family-history-positive patients and analyses are ongoing. A new paper suggesting an additional candidate locus for LC susceptibility based on all sequence data available to date is currently under review and more analyses are ongoing. Whole genome sequencing studies on about 100 affected relatives in our highly aggregated families has started in collaboration with Dr. Ramaswamy Govindan, Washington University. We expect to receive these data in the next year. 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. 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. 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. This year, we published a study confirming associations from population-based GWAS of PRCA as also being important risk loci for familial PRCA 1. Dr. Bailey-Wilson's group is analyzing fine-mapping and sequence 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. We are also collaborating with Dr. Diptasri Mandal on linkage studies of prostate cancer in African-American men from Louisiana. In addition to the ongoing linkage studies, the ICPCG is performing whole exome sequencing studies in our highly-aggregated prostate cancer families and we are starting to analyze these data in the AAHPC families and are leading the ICPCG analyses of AA 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 Translational 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. Data collection is now complete for this large prostate case-control study, with a sample of about 1000 each. Several papers on breast and prostate 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 and a manuscript is in press. We are analyzing 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 is working on a 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. In one of these families, our linkage analyses were used to localize a causal variant shared by all affecteds and cosegregating with disease in the large family. Dr. Wanks group has characterized this variant and shown that it is causal, and a manuscript is under review.

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Human Genome Research
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Byun, Jinyoung; Schwartz, Ann G; Lusk, Christine et al. (2018) Genome-wide association study of familial lung cancer. Carcinogenesis 39:1135-1140
Lynch, Henry T; Lanspa, Stephen; Shaw, Trudy et al. (2018) Phenotypic and genotypic heterogeneity of Lynch syndrome: a complex diagnostic challenge. Fam Cancer 17:403-414
Liu, Yanhong; Lusk, Christine M; Cho, Michael H et al. (2018) Rare Variants in Known Susceptibility Loci and Their Contribution to Risk of Lung Cancer. J Thorac Oncol 13:1483-1495
Musolf, Anthony M; Simpson, Claire L; de Andrade, Mariza et al. (2017) Familial Lung Cancer: A Brief History from the Earliest Work to the Most Recent Studies. Genes (Basel) 8:
Musolf, Anthony M; Simpson, Claire L; de Andrade, Mariza et al. (2016) Parametric Linkage Analysis Identifies Five Novel Genome-Wide Significant Loci for Familial Lung Cancer. Hum Hered 82:64-74
Middlebrooks, Candace D; Banday, A Rouf; Matsuda, Konichi et al. (2016) Association of germline variants in the APOBEC3 region with cancer risk and enrichment with APOBEC-signature mutations in tumors. Nat Genet 48:1330-1338
Figueroa, Jonine D; Middlebrooks, Candace D; Banday, A Rouf et al. (2016) Identification of a novel susceptibility locus at 13q34 and refinement of the 20p12.2 region as a multi-signal locus associated with bladder cancer risk in individuals of European ancestry. Hum Mol Genet 25:1203-14
Liu, Yanhong; Kheradmand, Farrah; Davis, Caleb F et al. (2016) Focused Analysis of Exome Sequencing Data for Rare Germline Mutations in Familial and Sporadic Lung Cancer. J Thorac Oncol 11:52-61
Larson, Nicholas B; McDonnell, Shannon; Albright, Lisa Cannon et al. (2016) Post hoc Analysis for Detecting Individual Rare Variant Risk Associations Using Probit Regression Bayesian Variable Selection Methods in Case-Control Sequencing Studies. Genet Epidemiol 40:461-9
Sei, Yoshitatsu; Zhao, Xilin; Forbes, Joanne et al. (2015) A Hereditary Form of Small Intestinal Carcinoid Associated With a Germline Mutation in Inositol Polyphosphate Multikinase. Gastroenterology 149:67-78

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