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 (TERTP = 1.5 × 10−18, CLPTM1LP = 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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00439-014-1515-4) contains supplementary material, which is available to authorized users.

Comprehensive genetic assessment of the ESR1 locus identifies a risk region for endometrial cancer

“…This SNP set was defined as the SNPs which were in LD (r 2 > 0.2) and had a likelihood of association with endometrial cancer < 100:1 with the relevant lead SNP (Carvajal-Carmona et al 2015; Glubb, et al 2015). …”

“…Lead SNP, rs79575945 is also reported to be associated with expression of SYNE1 , adjacent to ESR1 . Given SNPs at this locus have previously been identified as predisposing to breast cancer, also a hormonally driven cancer, this study adds weight to the rationale for performing informed candidate fine-scale genetic studies across cancer types (Carvajal-Carmona et al 2015). …”

“…There were 290 TCGA patients (221 endometrioid histology) with complete genotype, RNA-Seq and copy-number data included in the analysis. Quality control was performed on the germline SNP genotypes as previously described (Carvajal-Carmona, et al 2015). To increase the number of SNPs in the analysis, we imputed genotypes for SNPs present in the 1000 Genomes dataset v3 in the ESR1 region (chr6: 150,125,000–152,650,000, April 2012 release) which were not genotyped by the Affymetrix 6.0 platform using minimac (Fuchsberger, et al 2014; Howie, et al 2012) software.…”

Genome-wide analysis of gynecologic cancer: The Cancer Genome Atlas in ovarian and endometrial cancer

“…A recent CGA analysis demonstrated high expression levels of TERT and cleft lip and palate transmembrane protein 1-like protein in endometrial cancer (67). TERT is highly expressed in DNA copy number-stable cancers, including thyroid carcinoma (68), and in endometrial cancer with a low genome copy number (69).…”

Fine mapping in TERT‐CLPTM1L region identified three independent lung cancer susceptibility signals: A large‐scale multi‐ethnic population study

“…Up till now, fine mapping studies have identified multiple independent cancer susceptibility loci in TERT-CLPTM1L region for a specific cancer type, such as breast, ovarian, and prostate cancer. [16][17][18][19] Much more efforts were also performed in lung cancer, and several novel genetic variants were identified as lung cancer risk loci. 18,20,21 In 2013, Walsh et al 9 conducted a fine mapping study in 5p15.…”