Genome-wide association studies (GWAS) have been successful in identifying common genetic variation involved in susceptibility to etiologically complex disease. We conducted a GWAS to identify common genetic variation involved in susceptibility to upper aero-digestive tract (UADT) cancers. Genome-wide genotyping was carried out using the Illumina HumanHap300 beadchips in 2,091 UADT cancer cases and 3,513 controls from two large European multi-centre UADT cancer studies, as well as 4,821 generic controls. The 19 top-ranked variants were investigated further in an additional 6,514 UADT cancer cases and 7,892 controls of European descent from an additional 13 UADT cancer studies participating in the INHANCE consortium. Five common variants presented evidence for significant association in the combined analysis (p≤5×10−7). Two novel variants were identified, a 4q21 variant (rs1494961, p = 1×10−8) located near DNA repair related genes HEL308 and FAM175A (or Abraxas) and a 12q24 variant (rs4767364, p = 2×10−8) located in an extended linkage disequilibrium region that contains multiple genes including the aldehyde dehydrogenase 2 (ALDH2) gene. Three remaining variants are located in the ADH gene cluster and were identified previously in a candidate gene study involving some of these samples. The association between these three variants and UADT cancers was independently replicated in 5,092 UADT cancer cases and 6,794 controls non-overlapping samples presented here (rs1573496-ADH7, p = 5×10−8; rs1229984-ADH1B, p = 7×10−9; and rs698-ADH1C, p = 0.02). These results implicate two variants at 4q21 and 12q24 and further highlight three ADH variants in UADT cancer susceptibility.

Testicular germ cell carcinoma (TGCC) is the most common malignancy among men ages 20 to 34 years. Although the pathogenesis of TGCC is poorly understood, suboptimal androgen levels or impaired androgen signaling may play a role. Some persistent organochlorine pesticides commonly found in human tissue possess antiandrogenic properties. We examined whether the risk of TGCC is associated with serum levels of 11 organochlorine pesticides, including p,p ¶-DDE, and whether the p,p ¶-DDE-TGCC association is modified by CAG or GGN repeat polymorphisms in the androgen receptor gene. We conducted a population-based case-control study among 18-to 44-year-old male residents of three Washington State counties. Cases (n = 246) were diagnosed during 1999 to 2003 with a first, primary TGCC. Controls (n = 630) were men of similar age with no history of TGCC from the same population identified through random-digit telephone dialing. Questionnaires elicited information on demographic, medical, and lifestyle factors. A blood specimen provided serum for gas chromatographyhigh-resolution mass spectrometry analysis of organochlorine pesticide residues and DNA for genotyping. We observed no clear patterns between TGCC risk and concentrations of any of the organochlorines measured, nor did we observe that the risk associated with p,p ¶-DDE was modified by androgen receptor CAG (<23 versus z23 repeats) or GGN (<17 versus z17 repeats) genotype. This study does not provide support for the hypothesis that adult exposure to organochlorine pesticides is associated with risk of TGCC. Due to uncertainty regarding how well organochlorine levels measured in adulthood reflect exposures during early life, further research is needed using exposure measurements collected in utero or during infancy. (Cancer Epidemiol Biomarkers Prev 2008;17(8):2012 -8)

Background Exposure to estrogens increases the risk of endometrial cancer. Certain estrogen metabolites can form bulky DNA adducts, which are removed via nucleotide excision repair (NER), and the ability to perform this repair might be related to endometrial cancer risk. Methods We examined 64 tag- and functional SNPs in the NER genes ERCC1, ERCC2 (XPD), ERCC3 (XPB), ERCC4 (XPF), ERCC5 (XPG), LIG1, XPA, and XPC in a population-based case-control study in Washington State, with 783 endometrial cancer cases and 795 controls. Results The presence of ERCC5 rs4150386 C, LIG1 rs3730865 C, XPA rs2808667 T, or XPC rs3731127 T alleles was associated with risk of endometrial cancer, with respective age-, county- and reference year-adjusted per-allele odds ratios (ORs) and 95% confidence intervals (CIs) of 0.68 (0.53–0.87, p=0.002), 1.46 (1.02–2.10, p=0.04), 0.71 (0.52–0.97, p=0.03) and 1.57 (1.13–2.17, p=0.007). Conclusions Certain ERCC5, LIG1, XPA and XPC genotypes might influence endometrial cancer risk. Impact Because of multiple redundancies in DNA repair pathways (and therefore a low prior probability), and the large number of associations examined, false positive findings are likely. Further characterization of the relation between variation in NER genes and endometrial cancer risk is warranted.

A total of 485 patients with a proven or suspected diagnosis of soft tissue sarcoma were referred over a 3-year period. Of these, 61 were referred for opinion only and 424 for definitive treatment. Overall there were 223 patients with primary soft tissue sarcoma and 84 with recurrent sarcoma, 84 with benign soft tissue tumours and 22 with non-soft tissue sarcoma malignancy; 11 patients were referred with known metastatic disease. The commonest benign tumours mimicking soft tissue sarcoma were fibromatosis and benign intermuscular or intramuscular lipoma. The malignant tumours suspected clinically of being soft tissue sarcoma were bone tumours, lymphoma and metastatic carcinoma. Of the 172 patients with primary soft tissue sarcoma referred with a proven diagnosis this had been established by excision biopsy in 94 and open incision biopsy in 48. By contrast, of those undiagnosed at referral, 44 of 51 patients with soft tissue sarcoma had the diagnosis made by Tru-cut core biopsy. Amputation was performed in four of 165 patients with primary extremity soft tissue sarcoma and in five of 54 with recurrent extremity sarcoma, giving an overall amputation rate of 4 per cent. It is proposed that the amputation rate for extremity soft tissue sarcoma can be reduced by the use of reconstructive procedures, particularly myocutaneous flaps to the proximal limbs and limb girdles, and free vascularized flaps to sites distal to the midthigh and midarm.