Sequence variants at the TERT-CLPTM1L locus associate with many cancer types

Abstract

The common sequence variants that have recently been associated with cancer risk are particular to a single, or at most two, cancer types. Following up on our genome-wide scan of basal cell carcinoma1, we identified rs401681(C) on chromosome 5p15.33 satisfying our threshold for genome-wide significance (OR=1.25, P=3.7×10−12). We tested rs401681 for association with sixteen additional cancer types in over 30,000 cancer cases and 45,000 controls and found association with lung cancer (OR=1.15, P=7.2×10−8) and urinary bladder, prostate and cervix cancer (ORs 1.07–1.31, all P<4×10−4). However, rs401681(C) appears to confer protection against cutaneous melanoma (OR=0.88, P=8.0×10−4). Interestingly, most of these cancer types have a strong environmental component to their risk. Investigation of the region led us to rs2736098(A), that showed stronger association with some cancer types. However, neither variant could fully account for the association of the other. Rs2736098 corresponds to A305A in the telomerase reverse transcriptase (TERT) protein while rs401681 is in an intron of the CLPTM1L gene.

CHEK2*1100delC homozygosity in the Netherlands—prevalence and risk of breast and lung cancer

“…36,37 The lung cancer cohort of 457 lung cancer patients was collected as an extension of the POLYGENE project. 38 Patients with lung cancer were identified through the population-based cancer registry of the Comprehensive Cancer Center IKO, Nijmegen, the Netherlands. Patients diagnosed in one of the three hospitals from the east of the Netherlands (Radboud University Medical Center and Canisius Wilhelmina Hospital in Nijmegen and Rijnstate Hospital in Arnhem) who were still alive on 15 April 2008 were recruited for a study on gene-environment interactions in lung cancer.…”

Meta-analysis of telomere length in 19 713 subjects reveals high heritability, stronger maternal inheritance and a paternal age effect

“…11 Genetic association studies have revealed associations between single-nucleotide polymorphisms (SNPs) in the TERC and TERT genes and TL. [11][12][13][14][15][16][17] Other studies reported associations between SNPs in TERC and POT1 with human longevity, 11,17,18 suggesting that genes regulating TL may influence human longevity.…”

The pursuit of genome-wide association studies: where are we now?

“…91 The 5p15.33 locus contains two genes, TERT and CLPTM1L, and interestingly the sequence variants at this locus were found to be associated with several cancers. 92 Although these studies firmly identified the 15q25 locus for lung cancer, the underlying associations were different between the studies. Two studies found that the 15q25 association was primarily with lung cancer and not with smoking, but the other study concluded that the link with lung cancer is mediated through smoking and nicotine dependence.…”

“…138 This approach should also be workable for the GWAS of cancers, as studies have shown that the 8q24 locus was linked to several cancers 59 and the sequence variants at the TERT-CLPTM1L locus were also found to be associated with a number of cancers. 92 SNPs in PSCA gene were also found to be associated with diffuse-type gastric cancer and urinary bladder cancer. 139,140 Likewise for neuropsychiatric diseases, the evidence of shared genetic liability for schizophrenia and bipolar disorder has also been increasing.…”