Evaluation of xeroderma pigmentosum XPA, XPC, XPD, XPF, XPB, XPG and DDB2 genes in familial early-onset lung cancer predisposition.

Epidemiological data has implicated heterozygosity for xeroderma pigmentosum (XP) as a risk factor for lung cancer. XP has 8 known complementation groups, 7 of which are caused by mutations in genes encoding components of the nucleotide excision repair (NER) pathway. To formally investigate the role of XP-related NER genes in lung cancer susceptibility, we screened germline DNA from 92 familial early-onset lung cancer patients for mutations in all coding regions and intron-exon boundaries of XPA, XPC, XPD, XPF, XPB, XPG and DDB2. Forty-one exonic variants were identified. Twenty-four were nonsynonymous, of which 14 were previously documented polymorphisms. Ten missense variants had not been previously described; none of which were detected in germline DNA from 278 cancer-free controls. Two of the novel missense changes are predicted to be functionally deleterious. Our findings are compatible with XP heterozygosity being a risk factor for lung cancer susceptibility.