Comparison of address-based sampling and random-digit dialing methods for recruiting young men as controls in a case-control study of testicular cancer susceptibility.

Random-digit dialing (RDD) using landline telephone numbers is the historical gold standard for control recruitment in population-based epidemiologic research. However, increasing cell-phone usage and diminishing response rates suggest that the effectiveness of RDD in recruiting a random sample of the general population, particularly for younger target populations, is decreasing. In this study, we compared landline RDD with alternative methods of control recruitment, including RDD using cell-phone numbers and address-based sampling (ABS), to recruit primarily white men aged 18-55 years into a study of testicular cancer susceptibility conducted in the Philadelphia, Pennsylvania, metropolitan area between 2009 and 2012. With few exceptions, eligible and enrolled controls recruited by means of RDD and ABS were similar with regard to characteristics for which data were collected on the screening survey. While we find ABS to be a comparably effective method of recruiting young males compared with landline RDD, we acknowledge the potential impact that selection bias may have had on our results because of poor overall response rates, which ranged from 11.4% for landline RDD to 1.7% for ABS.

A second independent locus within DMRT1 is associated with testicular germ cell tumor susceptibility.

Susceptibility to testicular germ cell tumors (TGCT) has a significant heritable component, and genome-wide association studies (GWASs) have identified association with variants in several genes, including KITLG, SPRY4, BAK1, TERT, DMRT1 and ATF7IP. In our GWAS, we genotyped 349 TGCT cases and 919 controls and replicated top hits in an independent set of 439 cases and 960 controls in an attempt to find novel TGCT susceptibility loci. We identified a second marker (rs7040024) in the doublesex and mab-3-related transcription factor 1 (DMRT1) gene that is independent of the previously described risk allele (rs755383) at this locus. In combined analysis that mutually conditions on both DMRT1 single nucleotide polymorphism markers, TGCT cases had elevated odds of carriage of the rs7040024 major A allele [per-allele odds ratio (OR) = 1.48, 95% confidence interval (CI) 1.23, 1.78; P = 2.52 × 10(-5)] compared with controls, while the association with rs755383 persisted (per allele OR = 1.26, 95% CI 1.08, 1.47, P = 0.0036). In similar analyses, the association of rs7040024 among men with seminomatous tumors did not differ from that among men with non-seminomatous tumors. In combination with KITLG, the strongest TGCT susceptibility locus found to date, men with TGCT had greatly elevated odds (OR = 14.1, 95% CI 5.12, 38.6; P = 2.98 × 10(-7)) of being double homozygotes for the risk (major) alleles at DMRT (rs7040024) and KITLG (rs4474514) when compared with men without TGCT. Our findings continue to corroborate that genes influencing male germ cell development and differentiation have emerged as the major players in inherited TGCT susceptibility.

Chemotherapy refractory testicular germ cell tumor is associated with a variant in Armadillo Repeat gene deleted in Velco-Cardio-Facial syndrome (ARVCF).

INTRODUCTION: There is evidence that inherited genetic variation affects both testicular germ cell tumor (TGCT) treatment outcome and risks of late-complications arising from cisplatin-based chemotherapy. Using a candidate gene approach, we examined associations of three genes involved in the cisplatin metabolism pathway, GSTP1, COMT, and TPMT, with TGCT outcome and cisplatin-induced neurotoxicity. MATERIALS AND METHODS: Our study population includes a subset of patients (n = 137) from a genome-wide association study at the University of Pennsylvania that evaluates inherited genetic susceptibility to TGCT. All patients in our study had at least one course of cisplatin-based chemotherapy with at least 1 year of follow-up. A total of 90 markers in GSTP1, COMT, and TPMT and their adjacent genomic regions (±20 kb) were analyzed for associations with refractory TGCT after first course of chemotherapy, progression-free survival (PFS), overall survival (OS), peripheral neuropathy, and ototoxicity. RESULTS: After adjustment for multiple comparisons, one Single nucleotide polymorphism (SNP), rs2073743, in the flanking region (±20 kb) of COMT was associated with refractory TGCT after initial chemotherapy. This SNP lies within the intron region of the Armadillo Repeat gene deleted in Velco-Cardio-Facial syndrome (ARVCF). The G allele of rs2073743 predisposed patients to refractory disease with a relative risk of 2.6 (95% CI 1.1, 6.3; P = 0.03). Assuming recessive inheritance, patients with the GG genotype had 22.7 times higher risk (95% CI 3.3, 155.8; P = 0.04) of developing refractory disease when compared to those with the GC or CC genotypes. We found no association of our candidate genes with peripheral neuropathy, ototoxicity, PFS and OS. DISCUSSION: This is the first study to suggest that germline genetic variants of ARVCF may affect TGCT outcome. The result of this study is hypothesis generating and should be validated in future studies.

Common variation in KITLG and at 5q31.3 predisposes to testicular germ cell cancer.

Testicular germ cell tumors (TGCT) have been expected to have a strong underlying genetic component. We conducted a genome-wide scan among 277 TGCT cases and 919 controls and found that seven markers at 12p22 within KITLG (c-KIT ligand) reached genome-wide significance (P < 5.0 x 10(-8) in discovery). In independent replication, TGCT risk was increased threefold per copy of the major allele at rs3782179 and rs4474514 (OR = 3.08, 95% CI = 2.29-4.13; OR = 3.07, 95% CI = 2.29-4.13, respectively). We found associations with rs4324715 and rs6897876 at 5q31.3 near SPRY4 (sprouty 4; P < 5.0 x 10(-6) in discovery). In independent replication, risk of TGCT was increased nearly 40% per copy of the major allele (OR = 1.37, 95% CI = 1.14-1.64; OR = 1.39, 95% CI = 1.16-1.66, respectively). All of the genotypes were associated with both seminoma and nonseminoma TGCT subtypes. These results demonstrate that common genetic variants affect TGCT risk and implicate KITLG and SPRY4 as genes involved in TGCT susceptibility.