Dr. Bailey-Wilson has been working for over 20 years to detect genetic risk factors for lung cancer and possible gene-gene and/or gene-environment interactions. The purpose of this study 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 is in preparation. In this fiscal year, we have continued sequencing candidate loci in this region and follow-up of these results is ongoing. A paper has been submitted describing evidence for a novel tumor suppressor locus discovered in our data. A second set of families has been genotyped for the same GWS markers and analyses are ongoing. Dr. Bailey-Wilson and Dr. Doan have also applied their new propensity score method for including environmental risk factor data into non-parametric analyses (in LODPAL) to the original GWS data and a paper is in preparation. ? ? 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, 3p, 11q, 8 and X. 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 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. Dr. Bailey-Wilson's group is analyzing African-American Hereditary Prostate Cancer (AAHPC) families, and a paper is in press for the AAHPC linkage study. We work with the International Prostate Cancer Genetics Consortium (ICPCG) to try to localize prostate cancer loci more rapidly. A meta-analysis paper was published by this group this year showing an interaction effect in two-locus analyses and another manuscript following up published linkage on chr17 is in preparation. Dr. Bailey-Wilson is in charge of the Chromosome X meta-analysis. 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. Schleutker in Finland. Fine mapping markers were genotyped for the Finnish dataset to follow up suggestive linkages, resulting in a paper published last year presenting strong evidence for a locus on chromosome 3p. We are currently analyzing SNPs in this region in these families. A new set of 43 extended Finnish prostate cancer pedigrees have been genotyped for a genome wide scan and analyses are ongoing. An association analysis of prostate cancer cases and controls from Finland has been published for candidate genes in the androgen pathway, another association paper is in preparation and a new candidate gene is being evaluated. In a collaboration with Dr. Cooney in Michigan, evidence for linkage at 15q21 in men with aggressive prostate cancer was also published this year.? ? A collaborative linkage study of breast cancer families that are not segregating mutations at either the BRCA1 or BRCA2 loci is ongoing. We are working with collaborators in Finland to follow-up candidate regions from our previous genome-wide linkage studies. Additional genotyping of SNP markers in several of these regions has been performed and association analyses have been completed. A new dataset, in collaboration with Dr. Rachel Ellsworth of the Windber Research Institute, and Drs. Henry Lynch and Patrice Watson of Creighton University, is now being studied. We are examining families with known mutations in BRCA1 and BRCA2 loci to attempt to detect modifier loci and gene-gene interactions. Genotyping for GWS markers has been completed for several families in this fiscal year and these data are being analyzed.? ? As an adjunct to the family-based studies of prostate and breast cancer described above, Dr. Bailey-Wilson is collaborating with Drs. Trent and Carpten of Tranlational Genomics, Drs. Cristina Leske and 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. The pilot phase of a large case-control study is underway funded by a contract from NHGRI, to be followed by the very large study. Dr. Bailey-Wilson is now the Project Officer for the data collection pilot study contract. Data collection is proceeding on schedule. ? ? A collaborative linkage study of melanoma families that are not linked to known melanoma loci is ongoing. A genome wide scan of these samples yielded significant evidence of linkage of early-onset melanoma to one region of the genome at chromosome 1p22. Approximately 150 additional families from the Melanoma Consortium have been collected and are being typed for a genome wide scan by CIDR and data will be merged with the data from the original scan to identify novel regions of interest. We continue to do follow up work in the 1p22 region identified in early onset cutaneous melanoma families. We have selected ~ 400 SNP markers to be genotyped in this region for a fine-mapping study. These data will be analyzed by Dr. Bailey-Wilson's group, using both linkage and association methods. In families that segregate both ocular and cutaneous melanoma we have typed 50 microsatellite and 1500 SNP markers in 3 regions. These data have been analyzed in this fiscal year and a manuscript is in preparation. Genotyping for a genome wide association study is being performed by the Melanoma Consortium and Dr. Gillanders from Dr. Bailey-Wilson?s group will be involved in some of the analyses of these data. A description of features associated with CDKN2A mutations in the consortium data is in press. ?
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