Genetic determinants of telomere length and risk of pancreatic cancer: A PANDoRA study: International Journal of Cancer

D Campa; M Matarazzi; W Greenhalf; M Bijlsma; KU Saum; C Pasquali; H van Laarhoven; A Szentesi; F Federici; P Vodicka; N Funel; R Pezzilli; HB Bueno-de-Mesquita; L Vodickova; D Basso; O Obazee; T Hackert; P Soucek; K Cuk; J Kaiser; C Sperti; M Lovecek; G Capurso; B Mohelnikova-Duchonova; KT Khaw; AK König; J Kupcinskas; R Kaaks; F Bambi; L Archibugi; A Mambrini; GM Cavestro; S Landi; P Hegyi; JR Izbicki; D Gioffreda; CF Zambon; F Tavano; R Talar-Wojnarowska; K Jamroziak; TJ Key; G Delle Fave; O Strobel; L Jonaitis; A Andriulli; RT Lawlor; F Pirozzi; V Katzke; C Valsuani; YK Vashist; H Brenner; F Canzian

doi:10.1002/ijc.31928

Genetic determinants of telomere length and risk of pancreatic cancer: A PANDoRA study: International Journal of Cancer

D Campa, M Matarazzi, W Greenhalf, M Bijlsma, KU Saum, C Pasquali, H van Laarhoven, A Szentesi, F Federici, P Vodicka, N Funel, R Pezzilli, HB Bueno-de-Mesquita, L Vodickova, D Basso, O Obazee, T Hackert, P Soucek, K Cuk, J KaiserC Sperti, M Lovecek, G Capurso, B Mohelnikova-Duchonova, KT Khaw, AK König, J Kupcinskas, R Kaaks, F Bambi, L Archibugi, A Mambrini, GM Cavestro, S Landi, P Hegyi, JR Izbicki, D Gioffreda, CF Zambon, F Tavano, R Talar-Wojnarowska, K Jamroziak, TJ Key, G Delle Fave, O Strobel, L Jonaitis, A Andriulli, RT Lawlor, F Pirozzi, V Katzke, C Valsuani, YK Vashist, H Brenner, F Canzian

IRCCS Ospedale San Raffaele

Research output: Contribution to journal › Article

Abstract

Telomere deregulation is a hallmark of cancer. Telomere length measured in lymphocytes (LTL) has been shown to be a risk marker for several cancers. For pancreatic ductal adenocarcinoma (PDAC) consensus is lacking whether risk is associated with long or short telomeres. Mendelian randomization approaches have shown that a score built from SNPs associated with LTL could be used as a robust risk marker. We explored this approach in a large scale study within the PANcreatic Disease ReseArch (PANDoRA) consortium. We analyzed 10 SNPs (ZNF676-rs409627, TERT-rs2736100, CTC1-rs3027234, DHX35-rs6028466, PXK-rs6772228, NAF1-rs7675998, ZNF208-rs8105767, OBFC1-rs9420907, ACYP2-rs11125529 and TERC-rs10936599) alone and combined in a LTL genetic score (“teloscore”, which explains 2.2% of the telomere variability) in relation to PDAC risk in 2,374 cases and 4,326 controls. We identified several associations with PDAC risk, among which the strongest were with the TERT-rs2736100 SNP (OR = 1.54; 95%CI 1.35–1.76; p = 1.54 × 10−10) and a novel one with the NAF1-rs7675998 SNP (OR = 0.80; 95%CI 0.73–0.88; p = 1.87 × 10−6, ptrend = 3.27 × 10−7). The association of short LTL, measured by the teloscore, with PDAC risk reached genome-wide significance (p = 2.98 × 10−9 for highest vs. lowest quintile; p = 1.82 × 10−10 as a continuous variable). In conclusion, we present a novel genome-wide candidate SNP for PDAC risk (TERT-rs2736100), a completely new signal (NAF1-rs7675998) approaching genome-wide significance and we report a strong association between the teloscore and risk of pancreatic cancer, suggesting that telomeres are a potential risk factor for pancreatic cancer. © 2018 UICC

Original language	English
Pages (from-to)	1275-1283
Number of pages	9
Journal	Int. J. Cancer
Volume	144
Issue number	6
DOIs	https://doi.org/10.1002/ijc.31928
Publication status	Published - 2019

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Campa, D., Matarazzi, M., Greenhalf, W., Bijlsma, M., Saum, KU., Pasquali, C., van Laarhoven, H., Szentesi, A., Federici, F., Vodicka, P., Funel, N., Pezzilli, R., Bueno-de-Mesquita, HB., Vodickova, L., Basso, D., Obazee, O., Hackert, T., Soucek, P., Cuk, K., ... Canzian, F. (2019). Genetic determinants of telomere length and risk of pancreatic cancer: A PANDoRA study: International Journal of Cancer. Int. J. Cancer, 144(6), 1275-1283. https://doi.org/10.1002/ijc.31928

Genetic determinants of telomere length and risk of pancreatic cancer: A PANDoRA study : International Journal of Cancer. / Campa, D; Matarazzi, M; Greenhalf, W; Bijlsma, M; Saum, KU; Pasquali, C; van Laarhoven, H; Szentesi, A; Federici, F; Vodicka, P; Funel, N; Pezzilli, R; Bueno-de-Mesquita, HB; Vodickova, L; Basso, D; Obazee, O; Hackert, T; Soucek, P; Cuk, K; Kaiser, J; Sperti, C; Lovecek, M; Capurso, G; Mohelnikova-Duchonova, B; Khaw, KT; König, AK; Kupcinskas, J; Kaaks, R; Bambi, F; Archibugi, L; Mambrini, A; Cavestro, GM; Landi, S; Hegyi, P; Izbicki, JR; Gioffreda, D; Zambon, CF; Tavano, F; Talar-Wojnarowska, R; Jamroziak, K; Key, TJ; Delle Fave, G; Strobel, O; Jonaitis, L; Andriulli, A; Lawlor, RT; Pirozzi, F; Katzke, V; Valsuani, C; Vashist, YK; Brenner, H; Canzian, F.

In: Int. J. Cancer, Vol. 144, No. 6, 2019, p. 1275-1283.

Research output: Contribution to journal › Article

Campa, D, Matarazzi, M, Greenhalf, W, Bijlsma, M, Saum, KU, Pasquali, C, van Laarhoven, H, Szentesi, A, Federici, F, Vodicka, P, Funel, N, Pezzilli, R, Bueno-de-Mesquita, HB, Vodickova, L, Basso, D, Obazee, O, Hackert, T, Soucek, P, Cuk, K, Kaiser, J, Sperti, C, Lovecek, M, Capurso, G, Mohelnikova-Duchonova, B, Khaw, KT, König, AK, Kupcinskas, J, Kaaks, R, Bambi, F, Archibugi, L, Mambrini, A, Cavestro, GM, Landi, S, Hegyi, P, Izbicki, JR, Gioffreda, D, Zambon, CF, Tavano, F, Talar-Wojnarowska, R, Jamroziak, K, Key, TJ, Delle Fave, G, Strobel, O, Jonaitis, L, Andriulli, A, Lawlor, RT, Pirozzi, F, Katzke, V, Valsuani, C, Vashist, YK, Brenner, H & Canzian, F 2019, 'Genetic determinants of telomere length and risk of pancreatic cancer: A PANDoRA study: International Journal of Cancer', Int. J. Cancer, vol. 144, no. 6, pp. 1275-1283. https://doi.org/10.1002/ijc.31928

Campa, D ; Matarazzi, M ; Greenhalf, W ; Bijlsma, M ; Saum, KU ; Pasquali, C ; van Laarhoven, H ; Szentesi, A ; Federici, F ; Vodicka, P ; Funel, N ; Pezzilli, R ; Bueno-de-Mesquita, HB ; Vodickova, L ; Basso, D ; Obazee, O ; Hackert, T ; Soucek, P ; Cuk, K ; Kaiser, J ; Sperti, C ; Lovecek, M ; Capurso, G ; Mohelnikova-Duchonova, B ; Khaw, KT ; König, AK ; Kupcinskas, J ; Kaaks, R ; Bambi, F ; Archibugi, L ; Mambrini, A ; Cavestro, GM ; Landi, S ; Hegyi, P ; Izbicki, JR ; Gioffreda, D ; Zambon, CF ; Tavano, F ; Talar-Wojnarowska, R ; Jamroziak, K ; Key, TJ ; Delle Fave, G ; Strobel, O ; Jonaitis, L ; Andriulli, A ; Lawlor, RT ; Pirozzi, F ; Katzke, V ; Valsuani, C ; Vashist, YK ; Brenner, H ; Canzian, F. / Genetic determinants of telomere length and risk of pancreatic cancer: A PANDoRA study : International Journal of Cancer. In: Int. J. Cancer. 2019 ; Vol. 144, No. 6. pp. 1275-1283.

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title = "Genetic determinants of telomere length and risk of pancreatic cancer: A PANDoRA study: International Journal of Cancer",

abstract = "Telomere deregulation is a hallmark of cancer. Telomere length measured in lymphocytes (LTL) has been shown to be a risk marker for several cancers. For pancreatic ductal adenocarcinoma (PDAC) consensus is lacking whether risk is associated with long or short telomeres. Mendelian randomization approaches have shown that a score built from SNPs associated with LTL could be used as a robust risk marker. We explored this approach in a large scale study within the PANcreatic Disease ReseArch (PANDoRA) consortium. We analyzed 10 SNPs (ZNF676-rs409627, TERT-rs2736100, CTC1-rs3027234, DHX35-rs6028466, PXK-rs6772228, NAF1-rs7675998, ZNF208-rs8105767, OBFC1-rs9420907, ACYP2-rs11125529 and TERC-rs10936599) alone and combined in a LTL genetic score (“teloscore”, which explains 2.2% of the telomere variability) in relation to PDAC risk in 2,374 cases and 4,326 controls. We identified several associations with PDAC risk, among which the strongest were with the TERT-rs2736100 SNP (OR = 1.54; 95%CI 1.35–1.76; p = 1.54 × 10−10) and a novel one with the NAF1-rs7675998 SNP (OR = 0.80; 95%CI 0.73–0.88; p = 1.87 × 10−6, ptrend = 3.27 × 10−7). The association of short LTL, measured by the teloscore, with PDAC risk reached genome-wide significance (p = 2.98 × 10−9 for highest vs. lowest quintile; p = 1.82 × 10−10 as a continuous variable). In conclusion, we present a novel genome-wide candidate SNP for PDAC risk (TERT-rs2736100), a completely new signal (NAF1-rs7675998) approaching genome-wide significance and we report a strong association between the teloscore and risk of pancreatic cancer, suggesting that telomeres are a potential risk factor for pancreatic cancer. {\textcopyright} 2018 UICC",

author = "D Campa and M Matarazzi and W Greenhalf and M Bijlsma and KU Saum and C Pasquali and {van Laarhoven}, H and A Szentesi and F Federici and P Vodicka and N Funel and R Pezzilli and HB Bueno-de-Mesquita and L Vodickova and D Basso and O Obazee and T Hackert and P Soucek and K Cuk and J Kaiser and C Sperti and M Lovecek and G Capurso and B Mohelnikova-Duchonova and KT Khaw and AK K{\"o}nig and J Kupcinskas and R Kaaks and F Bambi and L Archibugi and A Mambrini and GM Cavestro and S Landi and P Hegyi and JR Izbicki and D Gioffreda and CF Zambon and F Tavano and R Talar-Wojnarowska and K Jamroziak and TJ Key and {Delle Fave}, G and O Strobel and L Jonaitis and A Andriulli and RT Lawlor and F Pirozzi and V Katzke and C Valsuani and YK Vashist and H Brenner and F Canzian",

year = "2019",

doi = "10.1002/ijc.31928",

language = "English",

volume = "144",

pages = "1275--1283",

journal = "Int. J. Cancer",

issn = "0020-7136",

publisher = "Wiley-Liss Inc.",

number = "6",

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TY - JOUR

T1 - Genetic determinants of telomere length and risk of pancreatic cancer: A PANDoRA study

T2 - International Journal of Cancer

AU - Campa, D

AU - Matarazzi, M

AU - Greenhalf, W

AU - Bijlsma, M

AU - Saum, KU

AU - Pasquali, C

AU - van Laarhoven, H

AU - Szentesi, A

AU - Federici, F

AU - Vodicka, P

AU - Funel, N

AU - Pezzilli, R

AU - Bueno-de-Mesquita, HB

AU - Vodickova, L

AU - Basso, D

AU - Obazee, O

AU - Hackert, T

AU - Soucek, P

AU - Cuk, K

AU - Kaiser, J

AU - Sperti, C

AU - Lovecek, M

AU - Capurso, G

AU - Mohelnikova-Duchonova, B

AU - Khaw, KT

AU - König, AK

AU - Kupcinskas, J

AU - Kaaks, R

AU - Bambi, F

AU - Archibugi, L

AU - Mambrini, A

AU - Cavestro, GM

AU - Landi, S

AU - Hegyi, P

AU - Izbicki, JR

AU - Gioffreda, D

AU - Zambon, CF

AU - Tavano, F

AU - Talar-Wojnarowska, R

AU - Jamroziak, K

AU - Key, TJ

AU - Delle Fave, G

AU - Strobel, O

AU - Jonaitis, L

AU - Andriulli, A

AU - Lawlor, RT

AU - Pirozzi, F

AU - Katzke, V

AU - Valsuani, C

AU - Vashist, YK

AU - Brenner, H

AU - Canzian, F

PY - 2019

Y1 - 2019

N2 - Telomere deregulation is a hallmark of cancer. Telomere length measured in lymphocytes (LTL) has been shown to be a risk marker for several cancers. For pancreatic ductal adenocarcinoma (PDAC) consensus is lacking whether risk is associated with long or short telomeres. Mendelian randomization approaches have shown that a score built from SNPs associated with LTL could be used as a robust risk marker. We explored this approach in a large scale study within the PANcreatic Disease ReseArch (PANDoRA) consortium. We analyzed 10 SNPs (ZNF676-rs409627, TERT-rs2736100, CTC1-rs3027234, DHX35-rs6028466, PXK-rs6772228, NAF1-rs7675998, ZNF208-rs8105767, OBFC1-rs9420907, ACYP2-rs11125529 and TERC-rs10936599) alone and combined in a LTL genetic score (“teloscore”, which explains 2.2% of the telomere variability) in relation to PDAC risk in 2,374 cases and 4,326 controls. We identified several associations with PDAC risk, among which the strongest were with the TERT-rs2736100 SNP (OR = 1.54; 95%CI 1.35–1.76; p = 1.54 × 10−10) and a novel one with the NAF1-rs7675998 SNP (OR = 0.80; 95%CI 0.73–0.88; p = 1.87 × 10−6, ptrend = 3.27 × 10−7). The association of short LTL, measured by the teloscore, with PDAC risk reached genome-wide significance (p = 2.98 × 10−9 for highest vs. lowest quintile; p = 1.82 × 10−10 as a continuous variable). In conclusion, we present a novel genome-wide candidate SNP for PDAC risk (TERT-rs2736100), a completely new signal (NAF1-rs7675998) approaching genome-wide significance and we report a strong association between the teloscore and risk of pancreatic cancer, suggesting that telomeres are a potential risk factor for pancreatic cancer. © 2018 UICC

AB - Telomere deregulation is a hallmark of cancer. Telomere length measured in lymphocytes (LTL) has been shown to be a risk marker for several cancers. For pancreatic ductal adenocarcinoma (PDAC) consensus is lacking whether risk is associated with long or short telomeres. Mendelian randomization approaches have shown that a score built from SNPs associated with LTL could be used as a robust risk marker. We explored this approach in a large scale study within the PANcreatic Disease ReseArch (PANDoRA) consortium. We analyzed 10 SNPs (ZNF676-rs409627, TERT-rs2736100, CTC1-rs3027234, DHX35-rs6028466, PXK-rs6772228, NAF1-rs7675998, ZNF208-rs8105767, OBFC1-rs9420907, ACYP2-rs11125529 and TERC-rs10936599) alone and combined in a LTL genetic score (“teloscore”, which explains 2.2% of the telomere variability) in relation to PDAC risk in 2,374 cases and 4,326 controls. We identified several associations with PDAC risk, among which the strongest were with the TERT-rs2736100 SNP (OR = 1.54; 95%CI 1.35–1.76; p = 1.54 × 10−10) and a novel one with the NAF1-rs7675998 SNP (OR = 0.80; 95%CI 0.73–0.88; p = 1.87 × 10−6, ptrend = 3.27 × 10−7). The association of short LTL, measured by the teloscore, with PDAC risk reached genome-wide significance (p = 2.98 × 10−9 for highest vs. lowest quintile; p = 1.82 × 10−10 as a continuous variable). In conclusion, we present a novel genome-wide candidate SNP for PDAC risk (TERT-rs2736100), a completely new signal (NAF1-rs7675998) approaching genome-wide significance and we report a strong association between the teloscore and risk of pancreatic cancer, suggesting that telomeres are a potential risk factor for pancreatic cancer. © 2018 UICC

U2 - 10.1002/ijc.31928

DO - 10.1002/ijc.31928

M3 - Article

VL - 144

SP - 1275

EP - 1283

JO - Int. J. Cancer

JF - Int. J. Cancer

SN - 0020-7136

IS - 6

ER -