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 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-Wilsons group is applying our new propensity score method for including environmental risk factor data into non-parametric analyses (in GenIBD) to these data. A large GWAS on familial cases vs elderly, smoking controls is being genotyped at the Center for Inherited Disease Research. 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 will receive those data shortly. We will also perform whole genome sequencing studies on about 100 affected relatives in our highly aggregated families has started in collaboration with Dr. Ramaswamy Govindan, Washington University. 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, this year follow-up in Finland and in the ICPCG families support this as a causal locus 2. 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. We have published a large meta-analysis of the ICPCG families in our chromosome X linkage region. We are also collaborating with Dr. Diptasri Mandal on linkage studies of prostate cancer in African-American men from Louisiana.This year we have published additional linkage studies using ordered subsets analyses in the Finnish study 1. 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. 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 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 preparation. Data collection was completed last year and we have just received revised 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. This work is ongoing. Dr. Cheryl Cropp has collaborated with her PhD advisor, Dr. Giacomini, on a pharmacogenomics study of a cancer treatment drug which has resulted in a publication this year 3.

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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
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
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
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
Xiong, Donghai; Wang, Yian; Kupert, Elena et al. (2015) A recurrent mutation in PARK2 is associated with familial lung cancer. Am J Hum Genet 96:301-8
Teerlink, Craig C; Thibodeau, Stephen N; McDonnell, Shannon K et al. (2014) Association analysis of 9,560 prostate cancer cases from the International Consortium of Prostate Cancer Genetics confirms the role of reported prostate cancer associated SNPs for familial disease. Hum Genet 133:347-56
Cropp, Cheryl D; Robbins, Christiane M; Sheng, Xin et al. (2014) 8q24 risk alleles and prostate cancer in African-Barbadian men. Prostate 74:1579-88

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