TERT gene harbors multiple variants associated with pancreatic cancer susceptibility

Daniele Campa, Cosmeri Rizzato, Rachael Stolzenberg-Solomon, Paola Pacetti, Pavel Vodicka, Sean P. Cleary, Gabriele Capurso, H. B. Bueno-De-Mesquita, Jens Werner, Maria Gazouli, Katja Butterbach, Audrius Ivanauskas, Nathalia Giese, Gloria M. Petersen, Paola Fogar, Zhaoming Wang, Claudio Bassi, Miroslav Ryska, George E. Theodoropoulos, Charles KooperbergDonghui Li, William Greenhalf, Claudio Pasquali, Thilo Hackert, Charles S. Fuchs, Beatrice Mohelnikova-Duchonova, Cosimo Sperti, Niccola Funel, Aida Karina Dieffenbach, Nicholas J. Wareham, Julie Buring, Ivana Holcátová, Eithne Costello, Carlo Federico Zambon, Juozas Kupcinskas, Harvey A. Risch, Peter Kraft, Paige M. Bracci, Raffaele Pezzilli, Sara H. Olson, Howard D. Sesso, Patricia Hartge, Oliver Strobel, Ewa Małecka-Panas, Kala Visvanathan, Alan A. Arslan, Sergio Pedrazzoli, Pavel Souček, Domenica Gioffreda, Timothy J. Key, Renata Talar-Wojnarowska, Aldo Scarpa, Andrea Mambrini, Eric J. Jacobs, Krzysztof Jamroziak, Alison Klein, Francesca Tavano, Franco Bambi, Stefano Landi, Melissa A. Austin, Ludmila Vodickova, Hermann Brenner, Stephen J. Chanock, Gianfranco Delle Fave, Ada Piepoli, Maurizio Cantore, Wei Zheng, Brian M. Wolpin, Laufey T. Amundadottir, Federico Canzian

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

A small number of common susceptibility loci have been identified for pancreatic cancer, one of which is marked by rs401681 in the TERT-CLPTM1L gene region on chromosome 5p15.33. Because this region is characterized by low linkage disequilibrium, we sought to identify whether additional single nucleotide polymorphisms (SNPs) could be related to pancreatic cancer risk, independently of rs401681. We performed an in-depth analysis of genetic variability of the telomerase reverse transcriptase (TERT) and the telomerase RNA component (TERC) genes, in 5,550 subjects with pancreatic cancer and 7,585 controls from the PANcreatic Disease ReseArch (PANDoRA) and the PanScan consortia. We identified a significant association between a variant in TERT and pancreatic cancer risk (rs2853677, odds ratio=0.85; 95% confidence interval=0.80-0.90, p=8.3 × 10-8). Additional analysis adjusting rs2853677 for rs401681 indicated that the two SNPs are independently associated with pancreatic cancer risk, as suggested by the low linkage disequilibrium between them (r2=0.07, D′=0.28). Three additional SNPs in TERT reached statistical significance after correction for multiple testing: rs2736100 (p=3.0 × 10-5), rs4583925 (p=4.0 × 10-5) and rs2735948 (p=5.0 × 10-5). In conclusion, we confirmed that the TERT locus is associated with pancreatic cancer risk, possibly through several independent variants. What's new? Most pancreatic cancer patients do not survive long after diagnosis, and, so far, there are not many genetic markers to help screen for the disease. In search of genetic predictors of pancreatic cancer, the authors zoomed in on a region linked to susceptibility to the disease. They measured the frequency of different variants of two genes, telomerase reverse transcriptase and telomerase RNA component, among thousands of pancreatic cancer patients and controls. They identified several variants of the TERT gene that indicate a boosted pancreatic cancer risk, and which may develop into useful prognostic tools.

Original languageEnglish
Pages (from-to)2175-2183
Number of pages9
JournalInternational Journal of Cancer
Volume137
Issue number9
DOIs
Publication statusPublished - Nov 1 2015

Fingerprint

Telomerase
Pancreatic Neoplasms
Genes
Single Nucleotide Polymorphism
Linkage Disequilibrium
Pancreatic Diseases
Disease Susceptibility
Genetic Markers
Chromosomes
Odds Ratio
Confidence Intervals

Keywords

  • pancreatic cancer
  • polymorphisms
  • susceptibility
  • telomerase

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Campa, D., Rizzato, C., Stolzenberg-Solomon, R., Pacetti, P., Vodicka, P., Cleary, S. P., ... Canzian, F. (2015). TERT gene harbors multiple variants associated with pancreatic cancer susceptibility. International Journal of Cancer, 137(9), 2175-2183. https://doi.org/10.1002/ijc.29590

TERT gene harbors multiple variants associated with pancreatic cancer susceptibility. / Campa, Daniele; Rizzato, Cosmeri; Stolzenberg-Solomon, Rachael; Pacetti, Paola; Vodicka, Pavel; Cleary, Sean P.; Capurso, Gabriele; Bueno-De-Mesquita, H. B.; Werner, Jens; Gazouli, Maria; Butterbach, Katja; Ivanauskas, Audrius; Giese, Nathalia; Petersen, Gloria M.; Fogar, Paola; Wang, Zhaoming; Bassi, Claudio; Ryska, Miroslav; Theodoropoulos, George E.; Kooperberg, Charles; Li, Donghui; Greenhalf, William; Pasquali, Claudio; Hackert, Thilo; Fuchs, Charles S.; Mohelnikova-Duchonova, Beatrice; Sperti, Cosimo; Funel, Niccola; Dieffenbach, Aida Karina; Wareham, Nicholas J.; Buring, Julie; Holcátová, Ivana; Costello, Eithne; Zambon, Carlo Federico; Kupcinskas, Juozas; Risch, Harvey A.; Kraft, Peter; Bracci, Paige M.; Pezzilli, Raffaele; Olson, Sara H.; Sesso, Howard D.; Hartge, Patricia; Strobel, Oliver; Małecka-Panas, Ewa; Visvanathan, Kala; Arslan, Alan A.; Pedrazzoli, Sergio; Souček, Pavel; Gioffreda, Domenica; Key, Timothy J.; Talar-Wojnarowska, Renata; Scarpa, Aldo; Mambrini, Andrea; Jacobs, Eric J.; Jamroziak, Krzysztof; Klein, Alison; Tavano, Francesca; Bambi, Franco; Landi, Stefano; Austin, Melissa A.; Vodickova, Ludmila; Brenner, Hermann; Chanock, Stephen J.; Delle Fave, Gianfranco; Piepoli, Ada; Cantore, Maurizio; Zheng, Wei; Wolpin, Brian M.; Amundadottir, Laufey T.; Canzian, Federico.

In: International Journal of Cancer, Vol. 137, No. 9, 01.11.2015, p. 2175-2183.

Research output: Contribution to journalArticle

Campa, D, Rizzato, C, Stolzenberg-Solomon, R, Pacetti, P, Vodicka, P, Cleary, SP, Capurso, G, Bueno-De-Mesquita, HB, Werner, J, Gazouli, M, Butterbach, K, Ivanauskas, A, Giese, N, Petersen, GM, Fogar, P, Wang, Z, Bassi, C, Ryska, M, Theodoropoulos, GE, Kooperberg, C, Li, D, Greenhalf, W, Pasquali, C, Hackert, T, Fuchs, CS, Mohelnikova-Duchonova, B, Sperti, C, Funel, N, Dieffenbach, AK, Wareham, NJ, Buring, J, Holcátová, I, Costello, E, Zambon, CF, Kupcinskas, J, Risch, HA, Kraft, P, Bracci, PM, Pezzilli, R, Olson, SH, Sesso, HD, Hartge, P, Strobel, O, Małecka-Panas, E, Visvanathan, K, Arslan, AA, Pedrazzoli, S, Souček, P, Gioffreda, D, Key, TJ, Talar-Wojnarowska, R, Scarpa, A, Mambrini, A, Jacobs, EJ, Jamroziak, K, Klein, A, Tavano, F, Bambi, F, Landi, S, Austin, MA, Vodickova, L, Brenner, H, Chanock, SJ, Delle Fave, G, Piepoli, A, Cantore, M, Zheng, W, Wolpin, BM, Amundadottir, LT & Canzian, F 2015, 'TERT gene harbors multiple variants associated with pancreatic cancer susceptibility', International Journal of Cancer, vol. 137, no. 9, pp. 2175-2183. https://doi.org/10.1002/ijc.29590
Campa D, Rizzato C, Stolzenberg-Solomon R, Pacetti P, Vodicka P, Cleary SP et al. TERT gene harbors multiple variants associated with pancreatic cancer susceptibility. International Journal of Cancer. 2015 Nov 1;137(9):2175-2183. https://doi.org/10.1002/ijc.29590
Campa, Daniele ; Rizzato, Cosmeri ; Stolzenberg-Solomon, Rachael ; Pacetti, Paola ; Vodicka, Pavel ; Cleary, Sean P. ; Capurso, Gabriele ; Bueno-De-Mesquita, H. B. ; Werner, Jens ; Gazouli, Maria ; Butterbach, Katja ; Ivanauskas, Audrius ; Giese, Nathalia ; Petersen, Gloria M. ; Fogar, Paola ; Wang, Zhaoming ; Bassi, Claudio ; Ryska, Miroslav ; Theodoropoulos, George E. ; Kooperberg, Charles ; Li, Donghui ; Greenhalf, William ; Pasquali, Claudio ; Hackert, Thilo ; Fuchs, Charles S. ; Mohelnikova-Duchonova, Beatrice ; Sperti, Cosimo ; Funel, Niccola ; Dieffenbach, Aida Karina ; Wareham, Nicholas J. ; Buring, Julie ; Holcátová, Ivana ; Costello, Eithne ; Zambon, Carlo Federico ; Kupcinskas, Juozas ; Risch, Harvey A. ; Kraft, Peter ; Bracci, Paige M. ; Pezzilli, Raffaele ; Olson, Sara H. ; Sesso, Howard D. ; Hartge, Patricia ; Strobel, Oliver ; Małecka-Panas, Ewa ; Visvanathan, Kala ; Arslan, Alan A. ; Pedrazzoli, Sergio ; Souček, Pavel ; Gioffreda, Domenica ; Key, Timothy J. ; Talar-Wojnarowska, Renata ; Scarpa, Aldo ; Mambrini, Andrea ; Jacobs, Eric J. ; Jamroziak, Krzysztof ; Klein, Alison ; Tavano, Francesca ; Bambi, Franco ; Landi, Stefano ; Austin, Melissa A. ; Vodickova, Ludmila ; Brenner, Hermann ; Chanock, Stephen J. ; Delle Fave, Gianfranco ; Piepoli, Ada ; Cantore, Maurizio ; Zheng, Wei ; Wolpin, Brian M. ; Amundadottir, Laufey T. ; Canzian, Federico. / TERT gene harbors multiple variants associated with pancreatic cancer susceptibility. In: International Journal of Cancer. 2015 ; Vol. 137, No. 9. pp. 2175-2183.
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abstract = "A small number of common susceptibility loci have been identified for pancreatic cancer, one of which is marked by rs401681 in the TERT-CLPTM1L gene region on chromosome 5p15.33. Because this region is characterized by low linkage disequilibrium, we sought to identify whether additional single nucleotide polymorphisms (SNPs) could be related to pancreatic cancer risk, independently of rs401681. We performed an in-depth analysis of genetic variability of the telomerase reverse transcriptase (TERT) and the telomerase RNA component (TERC) genes, in 5,550 subjects with pancreatic cancer and 7,585 controls from the PANcreatic Disease ReseArch (PANDoRA) and the PanScan consortia. We identified a significant association between a variant in TERT and pancreatic cancer risk (rs2853677, odds ratio=0.85; 95{\%} confidence interval=0.80-0.90, p=8.3 × 10-8). Additional analysis adjusting rs2853677 for rs401681 indicated that the two SNPs are independently associated with pancreatic cancer risk, as suggested by the low linkage disequilibrium between them (r2=0.07, D′=0.28). Three additional SNPs in TERT reached statistical significance after correction for multiple testing: rs2736100 (p=3.0 × 10-5), rs4583925 (p=4.0 × 10-5) and rs2735948 (p=5.0 × 10-5). In conclusion, we confirmed that the TERT locus is associated with pancreatic cancer risk, possibly through several independent variants. What's new? Most pancreatic cancer patients do not survive long after diagnosis, and, so far, there are not many genetic markers to help screen for the disease. In search of genetic predictors of pancreatic cancer, the authors zoomed in on a region linked to susceptibility to the disease. They measured the frequency of different variants of two genes, telomerase reverse transcriptase and telomerase RNA component, among thousands of pancreatic cancer patients and controls. They identified several variants of the TERT gene that indicate a boosted pancreatic cancer risk, and which may develop into useful prognostic tools.",
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author = "Daniele Campa and Cosmeri Rizzato and Rachael Stolzenberg-Solomon and Paola Pacetti and Pavel Vodicka and Cleary, {Sean P.} and Gabriele Capurso and Bueno-De-Mesquita, {H. B.} and Jens Werner and Maria Gazouli and Katja Butterbach and Audrius Ivanauskas and Nathalia Giese and Petersen, {Gloria M.} and Paola Fogar and Zhaoming Wang and Claudio Bassi and Miroslav Ryska and Theodoropoulos, {George E.} and Charles Kooperberg and Donghui Li and William Greenhalf and Claudio Pasquali and Thilo Hackert and Fuchs, {Charles S.} and Beatrice Mohelnikova-Duchonova and Cosimo Sperti and Niccola Funel and Dieffenbach, {Aida Karina} and Wareham, {Nicholas J.} and Julie Buring and Ivana Holc{\'a}tov{\'a} and Eithne Costello and Zambon, {Carlo Federico} and Juozas Kupcinskas and Risch, {Harvey A.} and Peter Kraft and Bracci, {Paige M.} and Raffaele Pezzilli and Olson, {Sara H.} and Sesso, {Howard D.} and Patricia Hartge and Oliver Strobel and Ewa Małecka-Panas and Kala Visvanathan and Arslan, {Alan A.} and Sergio Pedrazzoli and Pavel Souček and Domenica Gioffreda and Key, {Timothy J.} and Renata Talar-Wojnarowska and Aldo Scarpa and Andrea Mambrini and Jacobs, {Eric J.} and Krzysztof Jamroziak and Alison Klein and Francesca Tavano and Franco Bambi and Stefano Landi and Austin, {Melissa A.} and Ludmila Vodickova and Hermann Brenner and Chanock, {Stephen J.} and {Delle Fave}, Gianfranco and Ada Piepoli and Maurizio Cantore and Wei Zheng and Wolpin, {Brian M.} and Amundadottir, {Laufey T.} and Federico Canzian",
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T1 - TERT gene harbors multiple variants associated with pancreatic cancer susceptibility

AU - Campa, Daniele

AU - Rizzato, Cosmeri

AU - Stolzenberg-Solomon, Rachael

AU - Pacetti, Paola

AU - Vodicka, Pavel

AU - Cleary, Sean P.

AU - Capurso, Gabriele

AU - Bueno-De-Mesquita, H. B.

AU - Werner, Jens

AU - Gazouli, Maria

AU - Butterbach, Katja

AU - Ivanauskas, Audrius

AU - Giese, Nathalia

AU - Petersen, Gloria M.

AU - Fogar, Paola

AU - Wang, Zhaoming

AU - Bassi, Claudio

AU - Ryska, Miroslav

AU - Theodoropoulos, George E.

AU - Kooperberg, Charles

AU - Li, Donghui

AU - Greenhalf, William

AU - Pasquali, Claudio

AU - Hackert, Thilo

AU - Fuchs, Charles S.

AU - Mohelnikova-Duchonova, Beatrice

AU - Sperti, Cosimo

AU - Funel, Niccola

AU - Dieffenbach, Aida Karina

AU - Wareham, Nicholas J.

AU - Buring, Julie

AU - Holcátová, Ivana

AU - Costello, Eithne

AU - Zambon, Carlo Federico

AU - Kupcinskas, Juozas

AU - Risch, Harvey A.

AU - Kraft, Peter

AU - Bracci, Paige M.

AU - Pezzilli, Raffaele

AU - Olson, Sara H.

AU - Sesso, Howard D.

AU - Hartge, Patricia

AU - Strobel, Oliver

AU - Małecka-Panas, Ewa

AU - Visvanathan, Kala

AU - Arslan, Alan A.

AU - Pedrazzoli, Sergio

AU - Souček, Pavel

AU - Gioffreda, Domenica

AU - Key, Timothy J.

AU - Talar-Wojnarowska, Renata

AU - Scarpa, Aldo

AU - Mambrini, Andrea

AU - Jacobs, Eric J.

AU - Jamroziak, Krzysztof

AU - Klein, Alison

AU - Tavano, Francesca

AU - Bambi, Franco

AU - Landi, Stefano

AU - Austin, Melissa A.

AU - Vodickova, Ludmila

AU - Brenner, Hermann

AU - Chanock, Stephen J.

AU - Delle Fave, Gianfranco

AU - Piepoli, Ada

AU - Cantore, Maurizio

AU - Zheng, Wei

AU - Wolpin, Brian M.

AU - Amundadottir, Laufey T.

AU - Canzian, Federico

PY - 2015/11/1

Y1 - 2015/11/1

N2 - A small number of common susceptibility loci have been identified for pancreatic cancer, one of which is marked by rs401681 in the TERT-CLPTM1L gene region on chromosome 5p15.33. Because this region is characterized by low linkage disequilibrium, we sought to identify whether additional single nucleotide polymorphisms (SNPs) could be related to pancreatic cancer risk, independently of rs401681. We performed an in-depth analysis of genetic variability of the telomerase reverse transcriptase (TERT) and the telomerase RNA component (TERC) genes, in 5,550 subjects with pancreatic cancer and 7,585 controls from the PANcreatic Disease ReseArch (PANDoRA) and the PanScan consortia. We identified a significant association between a variant in TERT and pancreatic cancer risk (rs2853677, odds ratio=0.85; 95% confidence interval=0.80-0.90, p=8.3 × 10-8). Additional analysis adjusting rs2853677 for rs401681 indicated that the two SNPs are independently associated with pancreatic cancer risk, as suggested by the low linkage disequilibrium between them (r2=0.07, D′=0.28). Three additional SNPs in TERT reached statistical significance after correction for multiple testing: rs2736100 (p=3.0 × 10-5), rs4583925 (p=4.0 × 10-5) and rs2735948 (p=5.0 × 10-5). In conclusion, we confirmed that the TERT locus is associated with pancreatic cancer risk, possibly through several independent variants. What's new? Most pancreatic cancer patients do not survive long after diagnosis, and, so far, there are not many genetic markers to help screen for the disease. In search of genetic predictors of pancreatic cancer, the authors zoomed in on a region linked to susceptibility to the disease. They measured the frequency of different variants of two genes, telomerase reverse transcriptase and telomerase RNA component, among thousands of pancreatic cancer patients and controls. They identified several variants of the TERT gene that indicate a boosted pancreatic cancer risk, and which may develop into useful prognostic tools.

AB - A small number of common susceptibility loci have been identified for pancreatic cancer, one of which is marked by rs401681 in the TERT-CLPTM1L gene region on chromosome 5p15.33. Because this region is characterized by low linkage disequilibrium, we sought to identify whether additional single nucleotide polymorphisms (SNPs) could be related to pancreatic cancer risk, independently of rs401681. We performed an in-depth analysis of genetic variability of the telomerase reverse transcriptase (TERT) and the telomerase RNA component (TERC) genes, in 5,550 subjects with pancreatic cancer and 7,585 controls from the PANcreatic Disease ReseArch (PANDoRA) and the PanScan consortia. We identified a significant association between a variant in TERT and pancreatic cancer risk (rs2853677, odds ratio=0.85; 95% confidence interval=0.80-0.90, p=8.3 × 10-8). Additional analysis adjusting rs2853677 for rs401681 indicated that the two SNPs are independently associated with pancreatic cancer risk, as suggested by the low linkage disequilibrium between them (r2=0.07, D′=0.28). Three additional SNPs in TERT reached statistical significance after correction for multiple testing: rs2736100 (p=3.0 × 10-5), rs4583925 (p=4.0 × 10-5) and rs2735948 (p=5.0 × 10-5). In conclusion, we confirmed that the TERT locus is associated with pancreatic cancer risk, possibly through several independent variants. What's new? Most pancreatic cancer patients do not survive long after diagnosis, and, so far, there are not many genetic markers to help screen for the disease. In search of genetic predictors of pancreatic cancer, the authors zoomed in on a region linked to susceptibility to the disease. They measured the frequency of different variants of two genes, telomerase reverse transcriptase and telomerase RNA component, among thousands of pancreatic cancer patients and controls. They identified several variants of the TERT gene that indicate a boosted pancreatic cancer risk, and which may develop into useful prognostic tools.

KW - pancreatic cancer

KW - polymorphisms

KW - susceptibility

KW - telomerase

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