A personal history of non-melanoma skin cancer (NMSC) is associated with an increased subsequent risk of both non-cutaneous malignancies and cutaneous and mucosal cancers. The basis for this observation remains unclear, but the risk of subsequent non-skin cancers suggests a high cancer-risk phenotype. A likely candidate underlying this susceptibility to both cutaneous and non-cutaneous malignancies is inter-individual differences in DNA repair. Because of the strong link between Nucleotide Excision Repair (NER) and NMSC, and because of the importance of bulky DNA adducts to all cancers, the NER pathway is the most relevant DNA repair pathway. We hypothesize that polymorphisms in genes in the NER pathway may be the underlying susceptibility factor. We will test this hypothesis in a prospective cohort study (CLUE II) of 28,594 persons who will have been followed-up for 19 years (through 2009) for the occurrence of cancer. The cohort will be genotyped (using blood collected at baseline in 1989) for 75 polymorphisms in 26 NER genes.
The specific aim addresses the joint role of genetic alterations in the NER pathway and history of NMSC on subsequent non-NMSC cancer. Using time-to-event analyses, the influence of NER genotypes on cancer risk will be assessed in those with and without a personal history of NMSC. In addition to haplotype analysis, a novel statistical approach, logic regression, will be used to comprehensively assess the potential interactions within the NER pathway. The proposed study builds on pilot data from a subset of individuals in the cohort indicating an increased risk of subsequent cancer in persons with a history of NMSC who had ERCC2./XPD Lys751GIn Lys/GIn or Gin/Gin genotypes. Based on a strong scientific rationale, the hypothesis links an epidemiologic observation of a high cancer-risk NMSC phenotype with genetic variation in the NER pathway. The approach of using a prospective cohort study holds distinct advantages over case-control studies. Translation of the expected results will lead to better identification of at risk populations who should be considered for prevention interventions.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA105069-05
Application #
7595257
Study Section
Epidemiology of Cancer Study Section (EPIC)
Program Officer
Martin, Damali
Project Start
2005-05-25
Project End
2011-08-31
Budget Start
2009-04-01
Budget End
2011-08-31
Support Year
5
Fiscal Year
2009
Total Cost
$395,550
Indirect Cost
Name
Medical University of South Carolina
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
Genkinger, J M; Kitahara, C M; Bernstein, L et al. (2015) Central adiposity, obesity during early adulthood, and pancreatic cancer mortality in a pooled analysis of cohort studies. Ann Oncol 26:2257-66
Arem, Hannah; Moore, Steven C; Patel, Alpa et al. (2015) Leisure time physical activity and mortality: a detailed pooled analysis of the dose-response relationship. JAMA Intern Med 175:959-67
Wu, Chen; Kraft, Peter; Stolzenberg-Solomon, Rachael et al. (2014) Genome-wide association study of survival in patients with pancreatic adenocarcinoma. Gut 63:152-60
Alberg, Anthony J; Fischer, Alexander H (2014) Is a personal history of nonmelanoma skin cancer associated with increased or decreased risk of other cancers? Cancer Epidemiol Biomarkers Prev 23:433-6
Klein, Alison P; Lindström, Sara; Mendelsohn, Julie B et al. (2013) An absolute risk model to identify individuals at elevated risk for pancreatic cancer in the general population. PLoS One 8:e72311
Alberg, Anthony J; Jorgensen, Timothy J; Ruczinski, Ingo et al. (2013) DNA repair gene variants in relation to overall cancer risk: a population-based study. Carcinogenesis 34:86-92
Li, Donghui; Duell, Eric J; Yu, Kai et al. (2012) Pathway analysis of genome-wide association study data highlights pancreatic development genes as susceptibility factors for pancreatic cancer. Carcinogenesis 33:1384-90
Ruczinski, Ingo; Jorgensen, Timothy J; Shugart, Yin Yao et al. (2012) A population-based study of DNA repair gene variants in relation to non-melanoma skin cancer as a marker of a cancer-prone phenotype. Carcinogenesis 33:1692-8
Wheless, Lee; Kistner-Griffin, Emily; Jorgensen, Timothy J et al. (2012) A community-based study of nucleotide excision repair polymorphisms in relation to the risk of non-melanoma skin cancer. J Invest Dermatol 132:1354-62
Moore, Steven C; Patel, Alpa V; Matthews, Charles E et al. (2012) Leisure time physical activity of moderate to vigorous intensity and mortality: a large pooled cohort analysis. PLoS Med 9:e1001335

Showing the most recent 10 out of 43 publications