Genetic Epidemiology of Cancer

National Human Genome Research Institute

Investigators

Linked publications, trials & patents

Abstract

Dr. Bailey-Wilson has been working for over 40 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 genes that contribute to lung cancer susceptibility. In this fiscal year, family data have been collected in Louisiana under an NHGRI contract and at 4 other sites under an NCI R01. 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 tumor suppressor gene that is associated with LC risk; it may be involved in explaining part but not all of the 6q linkage signal. We also published additional sequencing studies of the region along with studies of a knock-out mouse model (in the lab of collaborator Ming You), suggesting that PARK2 may also harbor risk variants in some of our families. A new set of families was recently genotyped for a SNP marker linkage panel and were analyzed with novel linkages detected and published. A large GWAS on familial cases vs elderly, smoking controls was genotyped at the Center for Inherited Disease Research and the results were published in 2019. We have performed whole exome sequencing in collaboration with Dr. Margaret Spitz of Baylor University on 60 of our family-history-positive patients with several papers published. Dr. Anthony Musolf, a postdoc in Dr. Bailey-Wilsons Section published analyses of WES data in our WES data in families 2019. We analyzed targeted sequence data in the 6q region in our most strongly linked families and published a paper showing evidence for several rare causal variants in these families during this reporting period 2. These NHGRI analysis results helped the GELCC consortium obtain a successful grant review (1st percentile, funded starting 1/22/20, converted to U01 due to Dr. Bailey-Wilsons leadership role) for continuing the GELCC sequencing studies and performing functional studies on our best candidate genes. The GELCC published a paper in this reporting period presenting results of rare variant analyses in our data combined with data from other studies 1. Dr. Bailey-Wilson will continue to collaborate with GELCC investigators (as an unpaid collaborator). 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 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. on 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. We successfully competed for WES sequencing in these data and the data are currently being analyzed by us. In addition to the ongoing linkage studies, the ICPCG performing whole exome sequencing studies in our highly-aggregated prostate cancer families and results from the European American analyses were published in this reporting period 3. Dr. Deyana Lewis (a fellow in my group) is working on analysis of these data in the AAHPC families. She is also working with one of my former fellows, Dr. Cheryl Cropp, who is now an Assistant Professor at Samford University and a Guest Researcher at SGS, to co-lead the ICPCG WES and WGS analyses of AA families. Dr. Lewis successfully competed for a Coleman research award based on the AAHPC sequencing study and these funds have provided whole genome sequence data which she is now analyzing. In addition, Dr. Lewis published a paper on the impact of African-American descent on health disparities in prostate cancer in this reporting period 4. Dr. Bailey-Wilson is working on a collaborative study of Carcinoid tumor with Drs. Steven Wank of NIDDK. 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 paper presenting these results was published in 2015. We are now proceeding with additional linkage and whole genome sequence analysis of additional carcinoid tumor families. Dr. Qing Li in the Section has finished QC across WES and two sets of WGS data in the most informative family and is narrowing in on candidate causal variants. We continue our collaboration with Dr. M. Joe Casey and others in the Hereditary Cancer group founded by the late Henry Lynch at Creighton University on two projects. First, we successfully competed for WES sequencing at NISC to search for germline mutations in families with multiple individuals affected with melanoma or pancreatic cancers but with unknown mutational status. These samples have been sequenced and are being analyzed. In the second project, Dr. Candace Middlebrooks, a fellow in my group, is performing survival analyses on families with known germline mutations in high risk cancer genes to determine what additional cancers show increased risk in carriers of the mutations. One paper presenting the results in families with mutations in CDKN2A was published previously, a paper presenting our analyses of BRCA1 mutation families is under review and a manuscript presenting analyses of BRCA2 mutation families is in preparation. Drs. Lewis and Middlebrooks are collaborating with Dr. Athena Starlard-Davenport at University of Tennessee Health Sciences Center on breast cancer interactions. They recently successfully competed for centrally-funded whole genome sequencing of participants in this breast cancer study. These WGS data are being analyzed. This year, in analyses of the STAR study, they showed that shortened telomeres are associated with increased risk of breast cancer in this population.and BMI is associated with shortened telomere but not directly with breast cancer risk (manuscript in revision)