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, summarized in a recent review article that she co-authored this year (1). 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 effect of smoking in individuals predicted to be carriers of this 6q locus was published this year (5). This work showed that non-smoking and light-smoking individuals carrying a rare risk haplotype in our 6q linkage region are at particularly increased risk compared to non-carriers with the same smoking exposures. This has major implications for targeting smoking cessation, early-detection screening and chemoprevention efforts to carriers of this risk allele if the responsible gene can be identified. 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). This would represent the first major gene ever discovered for this cancer and is an exciting result. A pilot genome-wide association study has confirmed evidence of association to SNPs in the nicotinic receptor subunit genes on 15q seen in 3 large population-based case-control studies (2,3,4). 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 much larger GWAS on familial cases vs elderly, smoking controls is under development. 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. This year, in collaboration with Dr. Robert Burks group, we published analyses evaluating the contribution of risk alleles at HPC1 and HPCX to prostate cancer risk in an Ashkenazi Jewish founder population (7). 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 a large meta-analysis of the ICPCG families was published (6). 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. Johanna Schleutker in Finland and have analyzed a genome-wide linkage scan of a new set of 43 extended Finnish prostate cancer pedigrees combined with the existing, previously analyzed Finnish families. A manuscript presenting these results is under review and another is in preparation. Another linkage metaanalysis of the Finnish families with the ICPCG families is also underway. 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 starting several 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. We plan to carry out genome-wide association studies and other candidate gene studies in this population once sample accrual is completed. 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. We have also begun a new collaboration with Dr. Constantine Stratakis of NICHD on a linkage study of bilateral adrenal tumors. We have begun processing the genotype data and will begin the linkage analyses during the next year.

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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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