Abstract 1346: Investigation of six testicular germ cell tumor susceptibility genes reveals a parent-of-origin effect in SPRY4.
Authors: Grotmol Tom , Karlsson Robert , Andreassen Kristine , Kristiansen Wenche , Aschim Elin , Bremnes Roy , Dahl Olav , Fosså Sophie , Klepp Olbjørn , Langberg Carl , Solberg Arne , Tretli Steinar , Magnusson Patrik , Adami Hans-Olov , Haugen Trine , Wiklund Fredrik 
Published: August 2014

Abstract
BACKGROUND: Testicular germ cell tumor (TGCT) is the most common malignancy in young men. Genetic components and conditions during pregnancy are known to play an etiologic role. Recent genome-wide association studies have identified single nucleotide polymorphisms (SNPs) associated with TGCT risk in the genes ATF7IP, BAK1, DMRT1, KITLG, SPRY4, and TERT. In the present study we validate these associations in a Scandinavian population, and explore effect modification by parental sex and differences in associations between the two major histological subtypes, seminoma and nonseminoma.
METHODS: A total of 118 SNPs in the six genes were genotyped in a population-based Swedish-Norwegian sample comprising 831 TGCT case-parent triads, 474 dyads, 712 singletons and 3922 population controls. 734 additional SNPs were imputed using reference haplotypes from the 1000 genomes project. SNP-TGCT association was investigated using a likelihood-based association test for nuclear families and unrelated subjects implemented in the software package UNPHASED. Forward stepwise regression within each gene was applied to determine independent association signals. Effect modification by parent-of-origin and effect differences between histological subtypes were explored.
RESULTS: We observed strong association between SNPs in all six genes and TGCT (lowest P-value per gene: ATF7IP 6.2×10−6; BAK1 2.1×10−10; DMRT1 6.7×10−25; KITLG 2.1×10−48; SPRY4 1.4×10−29; TERT 1.8×10−18). Stepwise regression indicated three independent signals for BAK1 and TERT, two independent signals for SPRY4, and one independent signal for DMRT1, ATF7IP and KITLG. A significant parent-of-origin effect was observed for rs10463352 in SPRY4 (maternal odds ratio=1.72, paternal odds ratio=0.99, interaction P=0.0013). No significant effect differences were found between seminoma and nonseminoma.
CONCLUSION: Previously reported genetic associations with TGCT were validated in a Scandinavian population. A genetic variant in SPRY4 only influenced TGCT risk when inherited maternally. The simplest interpretation of this parent-of-origin effect is that the SPRY4 (tumor suppressor) gene is silenced, by imprinting or some other epigenetic mechanism, in the fathers of TGCT cases. Parent-of-origin effects have to our knowledge not been reported before in the development of this cancer form.
Citation Format: Tom Grotmol, Robert Karlsson, Kristine Andreassen, Wenche Kristiansen, Elin Aschim, Roy Bremnes, Olav Dahl, Sophie Fosså, Olbjørn Klepp, Carl Langberg, Arne Solberg, Steinar Tretli, Patrik Magnusson, Hans-Olov Adami, Trine Haugen, Fredrik Wiklund. Investigation of six testicular germ cell tumor susceptibility genes reveals a parent-of-origin effect in SPRY4. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1346. doi:10.1158/1538-7445.AM2013-1346