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

Carvajal-Carmona LG, O'Mara TA, Painter JN, Lose FA, Dennis J, Michailidou K, Tyrer JP, Ahmed S, Ferguson K, Healey CS, Pooley K, Beesley J, Cheng T, Jones A, Howarth K, Martin L, Gorman M, Hodgson S, National Study of Endometrial Cancer Genetics Group (NSECG)Australian National Endometrial Cancer Study Group (ANECS)Wentzensen N, Fasching PA, Hein A, Beckmann MW, Renner SP, Dörk T, Hillemanns P, Dürst M, Runnebaum I, Lambrechts D, Coenegrachts L, Schrauwen S, Amant F, Winterhoff B, Dowdy SC, Goode EL, Teoman A, Salvesen HB, Trovik J, Njolstad TS, Werner HM, Scott RJ, Ashton K, Proietto T, Otton G, Wersäll O, Mints M, Tham E, RENDOCASHall P, Czene K, Liu J, Li J, Hopper JL, Southey MC, Australian Ovarian Cancer Study (AOCS)Ekici AB, Ruebner M, Johnson N, Peto J, Burwinkel B, Marme F, Brenner H, Dieffenbach AK, Meindl A, Brauch H, GENICA NetworkLindblom A, Depreeuw J, Moisse M, Chang-Claude J, Rudolph A, Couch FJ, Olson JE, Giles GG, Bruinsma F, Cunningham JM, Fridley BL, Børresen-Dale AL, Kristensen VN, Cox A, Swerdlow AJ, Orr N, Bolla MK, Wang Q, Weber RP, Chen Z, Shah M, Pharoah PD, Dunning AM, Tomlinson I, Easton DF, Spurdle AB, Thompson DJ - Hum. Genet. (2014)

Bottom Line: 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)).

View Article: PubMed Central - PubMed

Affiliation: Genome Center and Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, CA, 95616, USA, lgcarvajal@ucdavis.edu.

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.

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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. aTERT expression in endometrioid endometrial cancer (EEC) and non-endometrioid endometrial cancer (NEEC) tissue samples. bCLPTM1L expression in EEC and NEEC tissue samples. cTERT expression in endometrial cancer and normal endometrial tissue. dCLPTM1L expression in endometrial cancer and normal endometrial tissue
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Fig3: 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. aTERT expression in endometrioid endometrial cancer (EEC) and non-endometrioid endometrial cancer (NEEC) tissue samples. bCLPTM1L expression in EEC and NEEC tissue samples. cTERT expression in endometrial cancer and normal endometrial tissue. dCLPTM1L expression in endometrial cancer and normal endometrial tissue

Mentions: To identify possible mechanistic associations between TERT, CLPTM1L and endometrial cancer, we searched for information on endometrial gene expression and somatic variation in publically available datasets. Specifically, we looked at eight microarray datasets that have compared gene expression levels in endometrioid and non-endometrioid cancer (Fig. 2) and RNASeq data from The Cancer Genome Atlas (TCGA, Fig. 3). Analysis of microarray data found that TERT was overexpressed in non-endometrioid cancer (P = 0.0015, Fig. 2a), however, this was not observed in the larger TCGA RNASeq dataset (P = 1.0, Fig. 3a). Increased expression of CLPTM1L in non-endometrioid cancer was seen across five of the microarray datasets that also interrogated CLPTM1L expression (P < 0.0001, Fig. 2b), with a similar result also found by the TCGA RNASeq analysis (P = 4.1 × 10−8, Fig. 3b). Using TCGA RNASeq data we found significantly increased expression of both TERT (Fig. 3c) and CLPTM1L (Fig. 3d) in endometrial cancer tissue compared with normal tissue (TERTP = 1.5 × 10−18, CLPTM1LP = 1.5 × 10−19). TCGA endometrial cancer data analysis (http://www.cbioportal.org/public-portal/index.do) shows that the 5p15.33 region containing both TERT and CLPTM1L is significantly amplified in ~3 % of cases (Gistic Q value <0.00011, not shown), whilst TERT and CLPTM1L mutations have been identified in a small fraction of endometrial tumours (Kandoth et al. 2013).Fig. 2


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

Carvajal-Carmona LG, O'Mara TA, Painter JN, Lose FA, Dennis J, Michailidou K, Tyrer JP, Ahmed S, Ferguson K, Healey CS, Pooley K, Beesley J, Cheng T, Jones A, Howarth K, Martin L, Gorman M, Hodgson S, National Study of Endometrial Cancer Genetics Group (NSECG)Australian National Endometrial Cancer Study Group (ANECS)Wentzensen N, Fasching PA, Hein A, Beckmann MW, Renner SP, Dörk T, Hillemanns P, Dürst M, Runnebaum I, Lambrechts D, Coenegrachts L, Schrauwen S, Amant F, Winterhoff B, Dowdy SC, Goode EL, Teoman A, Salvesen HB, Trovik J, Njolstad TS, Werner HM, Scott RJ, Ashton K, Proietto T, Otton G, Wersäll O, Mints M, Tham E, RENDOCASHall P, Czene K, Liu J, Li J, Hopper JL, Southey MC, Australian Ovarian Cancer Study (AOCS)Ekici AB, Ruebner M, Johnson N, Peto J, Burwinkel B, Marme F, Brenner H, Dieffenbach AK, Meindl A, Brauch H, GENICA NetworkLindblom A, Depreeuw J, Moisse M, Chang-Claude J, Rudolph A, Couch FJ, Olson JE, Giles GG, Bruinsma F, Cunningham JM, Fridley BL, Børresen-Dale AL, Kristensen VN, Cox A, Swerdlow AJ, Orr N, Bolla MK, Wang Q, Weber RP, Chen Z, Shah M, Pharoah PD, Dunning AM, Tomlinson I, Easton DF, Spurdle AB, Thompson DJ - Hum. Genet. (2014)

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. aTERT expression in endometrioid endometrial cancer (EEC) and non-endometrioid endometrial cancer (NEEC) tissue samples. bCLPTM1L expression in EEC and NEEC tissue samples. cTERT expression in endometrial cancer and normal endometrial tissue. dCLPTM1L expression in endometrial cancer and normal endometrial tissue
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Fig3: 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. aTERT expression in endometrioid endometrial cancer (EEC) and non-endometrioid endometrial cancer (NEEC) tissue samples. bCLPTM1L expression in EEC and NEEC tissue samples. cTERT expression in endometrial cancer and normal endometrial tissue. dCLPTM1L expression in endometrial cancer and normal endometrial tissue
Mentions: To identify possible mechanistic associations between TERT, CLPTM1L and endometrial cancer, we searched for information on endometrial gene expression and somatic variation in publically available datasets. Specifically, we looked at eight microarray datasets that have compared gene expression levels in endometrioid and non-endometrioid cancer (Fig. 2) and RNASeq data from The Cancer Genome Atlas (TCGA, Fig. 3). Analysis of microarray data found that TERT was overexpressed in non-endometrioid cancer (P = 0.0015, Fig. 2a), however, this was not observed in the larger TCGA RNASeq dataset (P = 1.0, Fig. 3a). Increased expression of CLPTM1L in non-endometrioid cancer was seen across five of the microarray datasets that also interrogated CLPTM1L expression (P < 0.0001, Fig. 2b), with a similar result also found by the TCGA RNASeq analysis (P = 4.1 × 10−8, Fig. 3b). Using TCGA RNASeq data we found significantly increased expression of both TERT (Fig. 3c) and CLPTM1L (Fig. 3d) in endometrial cancer tissue compared with normal tissue (TERTP = 1.5 × 10−18, CLPTM1LP = 1.5 × 10−19). TCGA endometrial cancer data analysis (http://www.cbioportal.org/public-portal/index.do) shows that the 5p15.33 region containing both TERT and CLPTM1L is significantly amplified in ~3 % of cases (Gistic Q value <0.00011, not shown), whilst TERT and CLPTM1L mutations have been identified in a small fraction of endometrial tumours (Kandoth et al. 2013).Fig. 2

Bottom Line: 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)).

View Article: PubMed Central - PubMed

Affiliation: Genome Center and Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, CA, 95616, USA, lgcarvajal@ucdavis.edu.

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.

Show MeSH
Related in: MedlinePlus