The goal of the laboratory is to develop new approaches to the study of the genetic basis of cancer and its outcomes. Previously, the major focus was the analysis of common genetic variation in candidate genes in cancer and its related outcomes, particularly in immunocompromised individuals. Emphasis was on conducting pilot association studies and annotating candidate genes drawn from key pathways in innate immunity and cancer biology, such as telomere stability or nutrient transport (i.e., Vitamin C sodium dependent transport). The laboratory has developed expertise in bio-informatics and advanced genetic analyses with new platforms designed to test dense sets of single nucleotide polymorphisms (SNPs), which are the most common genetic variants in the human genome. Specifically, the laboratory has integrated approaches to identify and validate common SNPs and ancestral haplotypes, which could be used to dissect the genetic basis of disease susceptibility. The laboratory utilizes programs and approaches in population genetics, epidemiology and molecular evolution, which assist in the choice and analysis of genetic variants under study. The same strategy has also been extended to pilot studies in solid tumors, such as osteogenic sarcoma, colorectal and prostate cancer. In addition, the laboratory has initiated study of the genetic events underlying development of Ewings Sarcoma. A population genetics approach has been employed to examine the possible contribution of genomic variation in the EWSR1 region and also to look at genetic variants on distant chromosomes that could increase or decrease risk for Ewings Sarcoma. Recently, the focus of the laboratory has shifted to dissect the genetic basis of SNP markers validated in large scale, genome-wide association studies (GWAS). This new approach can identify new regions to be studied in great detail and eventually applied to large molecular epidemiology studies to estimate the magnitude of the effect. It will also be possible to investigate the interaction between genes and environmental factors. Moreover, these markers may identify potential genotypic differences that could bear important predictive value for disease as well as highlight potential pathways related to both disease etiology and perhaps therapeutic intervention. We have developed a series of collaborations with leading epidemiologists and bio-statisticians in the Division of Cancer Epidemiology and Genetics (DCEG). Collaborative efforts have resulted in the development of new approaches to assess the false positive report probability (FPRP), a new tool intended to better assess the robustness of findings in genetic association studies. Lastly, the long-term goals of the laboratory are to identify and characterize genetic variants that could be used as prospective tools for early detection and intervention. the studies currently underway are directed at elucidating the biological basis of the susceptibility of risk alleles. At the same time, the current strategy continues to highlight genetic variants in key pathways in cancer susceptibility and outcome. In addition, the laboratory is closely related to the NCI Core Genotyping Facility of the NCI. The availability of high throughput sequence and genotype expertise is critical for conducting pilot studies as well as sufficiently powered, well-designed studies in molecular epidemiology and pharmacogenomics. Adaptation and integration of new informatic tools, such as Genewindow and ht-SNP selection have also been implemented. The laboratory has focused on a series of follow-up steps based on the results of the Cancer Genetic Markers of Susceptibility genome wide association studies of prostate and breast cancer. After extensive replication studies established strong statistical significance, the laboratory has begun to study the new loci, mapping the common and uncommon genetic variants in order to nominate suitable variants for functional studies, designed to provide plausibility to strong association signals. The laboratory will conduct a series of genetic analyses designed to dissect the genetic variants associated with disease risk also discovered in GWAS of other cancers, such pancreatic, bladder and lung cancers. These studies will include deep re-sequencing to develop a comprehensive catalogue of variants necessary to generate detailed haplotypes for subsequent genotyping large case controls. In turn, functional studies will be conducted to investigate the biological basis of the contribution of genetic variants to disease susceptibility. Collaboration with other laboratories will be sought to investigate the association between germ-line genetic variants and somatic changes in related tumor tissue.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIACP010201-01
Application #
8157948
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2010
Total Cost
$4,163,017
Indirect Cost
Name
Division of Cancer Epidemiology and Genetics
Department
Type
DUNS #
City
State
Country
Zip Code
Tang, Wei; Wallace, Tiffany A; Yi, Ming et al. (2018) IFNL4-?G Allele Is Associated with an Interferon Signature in Tumors and Survival of African-American Men with Prostate Cancer. Clin Cancer Res 24:5471-5481
Cobo, Isidoro; Martinelli, Paola; Flández, Marta et al. (2018) Transcriptional regulation by NR5A2 links differentiation and inflammation in the pancreas. Nature 554:533-537
Lou, Hong; Gharzouzi, Eduardo; Guerra, Sarita Polo et al. (2018) Low-cost HPV testing and the prevalence of cervical infection in asymptomatic populations in Guatemala. BMC Cancer 18:562
Klein, Alison P; Wolpin, Brian M; Risch, Harvey A et al. (2018) Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer. Nat Commun 9:556
Minas, Tsion Zewdu; Tang, Wei; Smith, Cheryl J et al. (2018) IFNL4-?G is associated with prostate cancer among men at increased risk of sexually transmitted infections. Commun Biol 1:191
Ricks-Santi, Luisel; McDonald, J Tyson; Gold, Bert et al. (2017) Next Generation Sequencing Reveals High Prevalence of BRCA1 and BRCA2 Variants of Unknown Significance in Early-Onset Breast Cancer in African American Women. Ethn Dis 27:169-178
Streicher, Samantha A; Klein, Alison P; Olson, Sara H et al. (2017) Impact of Sixteen Established Pancreatic Cancer Susceptibility Loci in American Jews. Cancer Epidemiol Biomarkers Prev 26:1540-1548
Samimi, Goli; Bernardini, Marcus Q; Brody, Lawrence C et al. (2017) Traceback: A Proposed Framework to Increase Identification and Genetic Counseling of BRCA1 and BRCA2 Mutation Carriers Through Family-Based Outreach. J Clin Oncol 35:2329-2337
Makowski, Matthew M; Willems, Esther; Fang, Jun et al. (2016) An interaction proteomics survey of transcription factor binding at recurrent TERT promoter mutations. Proteomics 16:417-26
Paquin, Ashley; Onabajo, Olusegun O; Tang, Wei et al. (2016) Comparative Functional Analysis of 12 Mammalian IFN-?4 Orthologs. J Interferon Cytokine Res 36:30-6

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