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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
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 reg...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Berlin Heidelberg
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4291520/ https://www.ncbi.nlm.nih.gov/pubmed/25487306 http://dx.doi.org/10.1007/s00439-014-1515-4 |
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author | Carvajal-Carmona, Luis G. O’Mara, Tracy A. Painter, Jodie N. Lose, Felicity A. Dennis, Joe Michailidou, Kyriaki Tyrer, Jonathan P. Ahmed, Shahana Ferguson, Kaltin Healey, Catherine S. Pooley, Karen Beesley, Jonathan Cheng, Timothy Jones, Angela Howarth, Kimberley Martin, Lynn Gorman, Maggie Hodgson, Shirley Wentzensen, Nicholas Fasching, Peter A. Hein, Alexander Beckmann, Matthias W. Renner, Stefan P. Dörk, Thilo Hillemanns, Peter Dürst, Matthias Runnebaum, Ingo Lambrechts, Diether Coenegrachts, Lieve Schrauwen, Stefanie Amant, Frederic Winterhoff, Boris Dowdy, Sean C. Goode, Ellen L. Teoman, Attila Salvesen, Helga B. Trovik, Jone Njolstad, Tormund S. Werner, Henrica M. J. Scott, Rodney J. Ashton, Katie Proietto, Tony Otton, Geoffrey Wersäll, Ofra Mints, Miriam Tham, Emma Hall, Per Czene, Kamila Liu, Jianjun Li, Jingmei Hopper, John L. Southey, Melissa C. Ekici, Arif B. Ruebner, Matthias Johnson, Nichola Peto, Julian Burwinkel, Barbara Marme, Frederik Brenner, Hermann Dieffenbach, Aida K. Meindl, Alfons Brauch, Hiltrud Lindblom, Annika Depreeuw, Jeroen Moisse, Matthieu Chang-Claude, Jenny Rudolph, Anja Couch, Fergus J. Olson, Janet E. Giles, Graham G. Bruinsma, Fiona Cunningham, Julie M. Fridley, Brooke L. Børresen-Dale, Anne-Lise Kristensen, Vessela N. Cox, Angela Swerdlow, Anthony J. Orr, Nicholas Bolla, Manjeet K. Wang, Qin Weber, Rachel Palmieri Chen, Zhihua Shah, Mitul Pharoah, Paul D. P. Dunning, Alison M. Tomlinson, Ian Easton, Douglas F. Spurdle, Amanda B. Thompson, Deborah J. |
author_facet | Carvajal-Carmona, Luis G. O’Mara, Tracy A. Painter, Jodie N. Lose, Felicity A. Dennis, Joe Michailidou, Kyriaki Tyrer, Jonathan P. Ahmed, Shahana Ferguson, Kaltin Healey, Catherine S. Pooley, Karen Beesley, Jonathan Cheng, Timothy Jones, Angela Howarth, Kimberley Martin, Lynn Gorman, Maggie Hodgson, Shirley Wentzensen, Nicholas Fasching, Peter A. Hein, Alexander Beckmann, Matthias W. Renner, Stefan P. Dörk, Thilo Hillemanns, Peter Dürst, Matthias Runnebaum, Ingo Lambrechts, Diether Coenegrachts, Lieve Schrauwen, Stefanie Amant, Frederic Winterhoff, Boris Dowdy, Sean C. Goode, Ellen L. Teoman, Attila Salvesen, Helga B. Trovik, Jone Njolstad, Tormund S. Werner, Henrica M. J. Scott, Rodney J. Ashton, Katie Proietto, Tony Otton, Geoffrey Wersäll, Ofra Mints, Miriam Tham, Emma Hall, Per Czene, Kamila Liu, Jianjun Li, Jingmei Hopper, John L. Southey, Melissa C. Ekici, Arif B. Ruebner, Matthias Johnson, Nichola Peto, Julian Burwinkel, Barbara Marme, Frederik Brenner, Hermann Dieffenbach, Aida K. Meindl, Alfons Brauch, Hiltrud Lindblom, Annika Depreeuw, Jeroen Moisse, Matthieu Chang-Claude, Jenny Rudolph, Anja Couch, Fergus J. Olson, Janet E. Giles, Graham G. Bruinsma, Fiona Cunningham, Julie M. Fridley, Brooke L. Børresen-Dale, Anne-Lise Kristensen, Vessela N. Cox, Angela Swerdlow, Anthony J. Orr, Nicholas Bolla, Manjeet K. Wang, Qin Weber, Rachel Palmieri Chen, Zhihua Shah, Mitul Pharoah, Paul D. P. Dunning, Alison M. Tomlinson, Ian Easton, Douglas F. Spurdle, Amanda B. Thompson, Deborah J. |
author_sort | Carvajal-Carmona, Luis G. |
collection | PubMed |
description | 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00439-014-1515-4) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-4291520 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Springer Berlin Heidelberg |
record_format | MEDLINE/PubMed |
spelling | pubmed-42915202015-01-16 Candidate locus analysis of the TERT–CLPTM1L cancer risk region on chromosome 5p15 identifies multiple independent variants associated with endometrial cancer risk Carvajal-Carmona, Luis G. O’Mara, Tracy A. Painter, Jodie N. Lose, Felicity A. Dennis, Joe Michailidou, Kyriaki Tyrer, Jonathan P. Ahmed, Shahana Ferguson, Kaltin Healey, Catherine S. Pooley, Karen Beesley, Jonathan Cheng, Timothy Jones, Angela Howarth, Kimberley Martin, Lynn Gorman, Maggie Hodgson, Shirley Wentzensen, Nicholas Fasching, Peter A. Hein, Alexander Beckmann, Matthias W. Renner, Stefan P. Dörk, Thilo Hillemanns, Peter Dürst, Matthias Runnebaum, Ingo Lambrechts, Diether Coenegrachts, Lieve Schrauwen, Stefanie Amant, Frederic Winterhoff, Boris Dowdy, Sean C. Goode, Ellen L. Teoman, Attila Salvesen, Helga B. Trovik, Jone Njolstad, Tormund S. Werner, Henrica M. J. Scott, Rodney J. Ashton, Katie Proietto, Tony Otton, Geoffrey Wersäll, Ofra Mints, Miriam Tham, Emma Hall, Per Czene, Kamila Liu, Jianjun Li, Jingmei Hopper, John L. Southey, Melissa C. Ekici, Arif B. Ruebner, Matthias Johnson, Nichola Peto, Julian Burwinkel, Barbara Marme, Frederik Brenner, Hermann Dieffenbach, Aida K. Meindl, Alfons Brauch, Hiltrud Lindblom, Annika Depreeuw, Jeroen Moisse, Matthieu Chang-Claude, Jenny Rudolph, Anja Couch, Fergus J. Olson, Janet E. Giles, Graham G. Bruinsma, Fiona Cunningham, Julie M. Fridley, Brooke L. Børresen-Dale, Anne-Lise Kristensen, Vessela N. Cox, Angela Swerdlow, Anthony J. Orr, Nicholas Bolla, Manjeet K. Wang, Qin Weber, Rachel Palmieri Chen, Zhihua Shah, Mitul Pharoah, Paul D. P. Dunning, Alison M. Tomlinson, Ian Easton, Douglas F. Spurdle, Amanda B. Thompson, Deborah J. Hum Genet Original Investigation 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00439-014-1515-4) contains supplementary material, which is available to authorized users. Springer Berlin Heidelberg 2014-12-09 2015 /pmc/articles/PMC4291520/ /pubmed/25487306 http://dx.doi.org/10.1007/s00439-014-1515-4 Text en © The Author(s) 2014 https://creativecommons.org/licenses/by/4.0/ Open AccessThis article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited. |
spellingShingle | Original Investigation Carvajal-Carmona, Luis G. O’Mara, Tracy A. Painter, Jodie N. Lose, Felicity A. Dennis, Joe Michailidou, Kyriaki Tyrer, Jonathan P. Ahmed, Shahana Ferguson, Kaltin Healey, Catherine S. Pooley, Karen Beesley, Jonathan Cheng, Timothy Jones, Angela Howarth, Kimberley Martin, Lynn Gorman, Maggie Hodgson, Shirley Wentzensen, Nicholas Fasching, Peter A. Hein, Alexander Beckmann, Matthias W. Renner, Stefan P. Dörk, Thilo Hillemanns, Peter Dürst, Matthias Runnebaum, Ingo Lambrechts, Diether Coenegrachts, Lieve Schrauwen, Stefanie Amant, Frederic Winterhoff, Boris Dowdy, Sean C. Goode, Ellen L. Teoman, Attila Salvesen, Helga B. Trovik, Jone Njolstad, Tormund S. Werner, Henrica M. J. Scott, Rodney J. Ashton, Katie Proietto, Tony Otton, Geoffrey Wersäll, Ofra Mints, Miriam Tham, Emma Hall, Per Czene, Kamila Liu, Jianjun Li, Jingmei Hopper, John L. Southey, Melissa C. Ekici, Arif B. Ruebner, Matthias Johnson, Nichola Peto, Julian Burwinkel, Barbara Marme, Frederik Brenner, Hermann Dieffenbach, Aida K. Meindl, Alfons Brauch, Hiltrud Lindblom, Annika Depreeuw, Jeroen Moisse, Matthieu Chang-Claude, Jenny Rudolph, Anja Couch, Fergus J. Olson, Janet E. Giles, Graham G. Bruinsma, Fiona Cunningham, Julie M. Fridley, Brooke L. Børresen-Dale, Anne-Lise Kristensen, Vessela N. Cox, Angela Swerdlow, Anthony J. Orr, Nicholas Bolla, Manjeet K. Wang, Qin Weber, Rachel Palmieri Chen, Zhihua Shah, Mitul Pharoah, Paul D. P. Dunning, Alison M. Tomlinson, Ian Easton, Douglas F. Spurdle, Amanda B. Thompson, Deborah J. Candidate locus analysis of the TERT–CLPTM1L cancer risk region on chromosome 5p15 identifies multiple independent variants associated with endometrial cancer risk |
title | Candidate locus analysis of the TERT–CLPTM1L cancer risk region on chromosome 5p15 identifies multiple independent variants associated with endometrial cancer risk |
title_full | Candidate locus analysis of the TERT–CLPTM1L cancer risk region on chromosome 5p15 identifies multiple independent variants associated with endometrial cancer risk |
title_fullStr | Candidate locus analysis of the TERT–CLPTM1L cancer risk region on chromosome 5p15 identifies multiple independent variants associated with endometrial cancer risk |
title_full_unstemmed | Candidate locus analysis of the TERT–CLPTM1L cancer risk region on chromosome 5p15 identifies multiple independent variants associated with endometrial cancer risk |
title_short | Candidate locus analysis of the TERT–CLPTM1L cancer risk region on chromosome 5p15 identifies multiple independent variants associated with endometrial cancer risk |
title_sort | candidate locus analysis of the tert–clptm1l cancer risk region on chromosome 5p15 identifies multiple independent variants associated with endometrial cancer risk |
topic | Original Investigation |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4291520/ https://www.ncbi.nlm.nih.gov/pubmed/25487306 http://dx.doi.org/10.1007/s00439-014-1515-4 |
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