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.
Keywords: GSTP1, COMT, TPMT, ARVCF, testicular germ cell tumor, refractory disease, neuropathy, ototoxicity
Citation: Fung C, Vaughn DJ, Mitra N, Ciosek SL, Vardhanabhuti S, Nathanson KL and Kanetsky PA (2012) Chemotherapy refractory testicular germ cell tumor is associated with a variant in Armadillo Repeat gene deleted in Velco-Cardio-Facial syndrome (ARVCF). Front. Endocrin. 3:163. doi: 10.3389/fendo.2012.00163
Received: 06 September 2012; Paper pending published: 04 October 2012;
Accepted: 28 November 2012; Published online: 13 December 2012.
Edited by:Alberto Ferlin, University of Padova, Italy
Reviewed by:Daniela Pasquali, Seconda Università degli Studi Napoli, Italy
Copyright © 2012 Fung, Vaughn, Mitra, Ciosek, Vardhanabhuti, Nathanson and Kanetsky. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.
*Correspondence: Chunkit Fung, Department of Hematology and Oncology, Wilmot Cancer Center, University of Rochester Medical Center, 601 Elmwood Avenue, Box 704, Rochester, NY 14642, USA. e-mail: email@example.com