Variants near DMRT1, TERT and ATF7IP are associated with testicular germ cell cancer

Abstract

We conducted a genome-wide association study for testicular germ cell tumor, genotyping 298,782 SNPs in 979 affected individuals and 4,947 controls from the UK and replicating associations in a further 664 cases and 3,456 controls. We identified three new susceptibility loci, two of which include genes that are involved in telomere regulation. We identified two independent signals within the TERT-CLPTM1L locus on chromosome 5, which has previously been associated with multiple other cancers (rs4635969, OR=1.54, P=1.14x10(-23); rs2736100, OR=1.33, P=7.55x10(-15)). We also identified a locus on chromosome 12 (rs2900333, OR=1.27, P=6.16x10(-10)) that contains ATF7IP, a regulator of TERT expression. Finally, we identified a locus on chromosome 9 (rs755383, OR=1.37, P=1.12x10(-23)), containing the sex determination gene DMRT1, which has been linked to teratoma susceptibility in mice.

Hotspot TERT promoter mutations are rare events in testicular germ cell tumors

“…Recently, a GWAS study reported an association of TGCT and genetic variants on the TERT locus, on chromosome 5, suggesting the role of TERT gene on TGCT tumorigenesis [15]. However, the molecular mechanism associated with telomerase activation in different types of germ cell tumors are complex and remain unclear.…”

Risk of multiple myeloma is associated with polymorphisms within telomerase genes and telomere length

“…2,[5][6][7][8][9][10][11] The genetic variability of the telomerase reverse transcriptase (TERT) and the telomerase RNA component (TERC) gene regions could play a role in MM etiology for two reasons: first the two genes are responsible for crucial cellular processes, namely telomere homeostasis, second their polymorphic variants have been found to be associated with multiple cancer types and other human phenotypes. [12][13][14][15][16][17][18][19][20][21][22][23][24] TERT and TERC constitute the telomerase complex, 25 whose correct functioning is fundamental for the accurate de novo synthesis of telomeric ends. Even moderate changes in TERT and TERC activity could profoundly affect telomere homeostasis.…”

“…30 It is not, therefore, surprising that it harbors multiple variants associated with risk of different diseases and in particular with various cancer types. For example the rs2736100 SNP is associated with glioma, testicular and lung cancer, 16,18,20 while rs401681 is associated with lung, bladder and pancreatic cancer, 17,19,21 rs10069690 with estrogen receptor-negative breast cancer 12,13 and rs2242652 with breast, prostate and ovarian cancer. 12,14,15 In addition, TERT polymorphisms are associated with other human phenotypes such as pulmonary fibrosis and PSA levels.…”

Transgenerational epigenetic effects of theApobec1cytidine deaminase deficiency on testicular germ cell tumor susceptibility and embryonic viability

“…Testicular cancer is the most common malignancy affecting young men (3), more than 90% of testicular cancers result from TGCTs (4), TGCTs rank third in heritability among all cancers (5), and family history is the strongest known risk factor with a two-to sixfold increase among sons and a 5-to 19-fold increase among brothers of affected individuals (6)(7)(8)(9). Despite the strong evidence for heritability, the only TGCT susceptibility factors identified in genome-wide association studies are the gr/gr deletion on the Y chromosome and autosomal variants in KITLG, SPRY4, BAK1, and DMRT1, which together account for less than 10% of risk (10)(11)(12)(13)(14). The substantial difference in prevalence between sons and brothers of cases and the epidemiological evidence for maternal estrogens, birth order, birth weight, and other factors (15)(16)(17) together raise the possibility that maternal conditions, epigenetic effects, and perhaps unconventional modes of inheritance also contribute to TGCT risk (18).…”