Genetic variation in DNA repair pathway genes and melanoma risk.
Reduced DNA repair capacity has been proposed as a predisposing factor for melanoma. We comprehensively evaluated 1463 genetic variants across 60 DNA repair-related pathway genes in relation to melanoma risk in a nested case-control study of 218 melanoma cases (20% on head and neck) and 218 matched controls within the Nurses' Health Study (NHS). We then genotyped the two variants with the smallest P value in two replication sets: 184 melanoma cases (28% on head and neck) and 184 matched controls in the Health Professionals Follow-Up Study (HPFS); and 183 melanoma cases (10% on head and neck) and 183 matched controls in the NHS. The SNP rs3219125 in the PARP1 gene was significantly associated with melanoma risk in the discovery set (odds ratio (OR) 3.14; 95% confidence interval (CI) 1.70-5.80) and in the HPFS replication set (OR, 1.92; 95% CI, 1.05-3.54) but not in the NHS replication set (OR, 1.07; 95% CI, 0.58-1.97). In the joint analysis, the OR was 1.89 (95% CI, 1.34-2.68) for this polymorphism, and this increased risk was more pronounced among patients with lesions in head/neck (OR, 3.19; 95% CI, 1.77-5.73 for head/neck, and OR, 1.54; 95% CI, 1.03-2.30 for other sites, P value for heterogeneity test=0.036). Our findings suggest the possible involvement of the PARP1 variant in melanoma development, especially for sites with high sun exposure. Further work on fine-mapping and on the functional characterization of this and linked SNPs in this region is required.
Zhang
Mingfeng
M
Clinical Research Program, Department of Dermatology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA.
Qureshi
Abrar A
AA
Guo
Qun
Q
Han
Jiali
J
D000328:Adult; D000368:Aged; D064007:Ataxia Telangiectasia Mutated Proteins; D016022:Case-Control Studies; D018797:Cell Cycle Proteins / Q000235:genetics; D016001:Confidence Intervals; D004260:DNA Repair; D004273:DNA, Neoplasm; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000473:pathology; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D012307:Risk Factors; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology; D013472:Sunlight / Q000009:adverse effects; D014481:United States
D018797:Cell Cycle Proteins; D004273:DNA, Neoplasm; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases