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 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 are examining various aspects of the method in these data. We have published one paper this fiscal year presenting evidence of a novel tumor suppressor gene, p34, on chromosome 6, although we do not believe that this locus accounts for the linkage results in our families. We have also published an evaluation of the EGFR-T790M allele in our data, concluding it is a rare lung cancer susceptibility allele with enhanced kinase activity. ? ? Another major aim of Dr. Bailey-Wilsons 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-Wilsons group is analyzing African-American Hereditary Prostate Cancer (AAHPC) families, and a paper was published this year 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 on linkage analysis of aggressive cancers and another paper following up prior linkage on chr17 was also published by Dr. Elizabeth Gillanders in this section. Another meta-analysis paper presented strong evidence for a PRCA susceptibility locus on chromosome 22q12.3. 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. We are currently analyzing SNPs in the 3p region in these families and a genome-wide linkage scan of a new set of 43 extended Finnish prostate cancer pedigrees. An association analysis of prostate cancer cases and controls from Finland has been published for the a variant in the KLF6 gene. Association analysis of ARLTS1 variants was also completed this year and a paper is under review. A segregation analysis of 1546 Finnish PRCA families was also published by our group this year.? ? A collaborative linkage study of breast cancer families that are segregating mutations at either the BRCA1 or BRCA2 loci is ongoing, in collaboration with Dr. Rachel Ellsworth of the Windber Research Institute, and Drs. Henry Lynch and Patrice Watson of Creighton University. We are examining large 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 and two-point linkage analyses have been completed this year, with multipoint analyses ongoing.? ? 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 has concluded successfully and funding has been obtained to continue the data collection of prostate cancer cases and controls, aiming for a sample of 1000 each. This second phase is now ongoing.? ? 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. Analysis of a new 6000 SNP genome-wide linkage data set is underway for 174 multiplex melanoma families collected from the consortium. 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-Wilsons group, using both linkage and association methods. Genotyping for a genome wide association study is being performed by the Melanoma Consortium and Dr. Gillanders from Dr. Bailey-Wilsons group will be involved in some of the analyses of these data. Results from the ongoing genome-wide linkage analysis will be incorporated into the analsis of thi genome-wide association study of 1000 melanoma cases and 1000 controls using the weighted falkse discovery rate method of Roeder et al. P-values in regions of the genome with evidence of linakage will be upweighted and conversely p-values for association in regions with evidence against linkage will be down-weighted. This strategy is expected to improve power. A description of features associated with CDKN2A mutations in the consortium data was published this year, as was a paper describing the results of a linkage study of atypical nevi in p16-Leiden melanoma families, and a paper describing the relationship between high-risk melanoma susceptibility genes and pancreatic cancer, neural system tumors, and uveal melanoma across the data available in the GenoMEL international melanoma genetics consortium.
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