Candidate locus analysis of the TERT-CLPTM1L cancer risk region on chromosome 5p15 identifies multiple independent variants associated with endometrial cancer risk

Abstract

Several studies have reported associations between multiple cancer types and single-nucleotide polymorphisms (SNPs) on chromosome 5p15, which harbours TERT and CLPTM1L, but no such association has been reported with endometrial cancer. To evaluate the role of genetic variants at the TERT-CLPTM1L region in endometrial cancer risk, we carried out comprehensive fine-mapping analyses of genotyped and imputed SNPs using a custom Illumina iSelect array which includes dense SNP coverage of this region. We examined 396 SNPs (113 genotyped, 283 imputed) in 4,401 endometrial cancer cases and 28,758 controls. Single-SNP and forward/backward logistic regression models suggested evidence for three variants independently associated with endometrial cancer risk (P = 4.9 × 10(-6) to P = 7.7 × 10(-5)). Only one falls into a haplotype previously associated with other cancer types (rs7705526, in TERT intron 1), and this SNP has been shown to alter TERT promoter activity. One of the novel associations (rs13174814) maps to a second region in the TERT promoter and the other (rs62329728) is in the promoter region of CLPTM1L; neither are correlated with previously reported cancer-associated SNPs. Using TCGA RNASeq data, we found significantly increased expression of both TERT and CLPTM1L in endometrial cancer tissue compared with normal tissue (TERT P = 1.5 × 10(-18), CLPTM1L P = 1.5 × 10(-19)). Our study thus reports a novel endometrial cancer risk locus and expands the spectrum of cancer types associated with genetic variation at 5p15, further highlighting the importance of this region for cancer susceptibility.

Fig. 1

Association between SNPs in the 5p15 region and endometrial cancer. SNPs in SNP sets 1–3 are shown by circles, squares and triangles, respectively, with the filled symbols denoting the most significant SNP in that set. Only SNPs with MAF >0.02 and imputation information score >0.8 are shown

Fig. 2

Forest plot showing the differential expression of a TERT and b CLPTM1L by endometrial cancer histological subtype using collated datasets of endometrial cancer microarray gene expression. The solid vertical line represents no change in gene expression between the two histological subtypes and the dashed line indicates the overall standardized mean difference (SMD) in expression across all studies analysed. SMD is a unit-free measurement of gene expression. A positive SMD value represents increased gene expression in non-endometrioid endometrial cancer (NEEC) compared with endometrioid endometrial cancer (EEC). Heterogeneity P value was calculated by Q-statistic

Fig. 3

Boxplots of endometrial tissue normalized gene expression levels using RNASeq data generated by The Cancer Genome Atlas. Boxplots depict the median and first and third quartiles. a TERT expression in endometrioid endometrial cancer (EEC) and non-endometrioid endometrial cancer (NEEC) tissue samples. b CLPTM1L expression in EEC and NEEC tissue samples. c TERT expression in endometrial cancer and normal endometrial tissue. d CLPTM1L expression in endometrial cancer and normal endometrial tissue