Genetic Polymorphisms Involved in Mitochondrial Metabolism and Pancreatic Cancer Risk

Giulia Peduzzi; Manuel Gentiluomo; Francesca Tavano; Paolo Giorgio Arcidiacono; Stefano Ermini; Pavel Vodicka; Ugo Boggi; Giulia Martina Cavestro; Gabriele Capurso; Luca Morelli; Anna Caterina Milanetto; Raffaele Pezzilli; Rita T. Lawlor; Silvia Carrara; Martin Lovecek; Pavel Souc; Feng Guo; Thilo Hackert; Faik G. Uzunoglu; Maria Gazouli; Andrea Parniczky; Juozas Kupcinskas; Maarten F. Bijlsma; Bas Bueno-de-Mesquita; Roel Vermeulen; Casper H. J. van Eijck; Krzysztof Jamroziak; Renata Talar-Wojnarowska; William Greenhalf; Domenica Gioffreda; Maria C. Petrone; Stefano Landi; Livia Archibugi; Marta Puzzono; Niccola Funel; Cosimo Sperti; Maria L. Piredda; Beatrice Mohelnikova-Duchonova; Ye Lu; Viktor Hlavac; Xin Gao; Martin Schneider; Jakob R. Izbicki; George Theodoropoulos; Stefania Bunduc; Edita Kreivenaite; Olivier R. Busch; Ewa Malecka-Panas; Eithne Costello; Francesco Perri; Sabrina Gloria Giulia Testoni; Giuseppe Vanella; Claudio Pasquali; Martin Oliverius; Hermann Brenner; Martin Loos; Mara Gotz; Konstantinos Georgiou; Alint Eross; Evaristo Maiello; Andrea Szentesi; Francesca Bazzocchi; Daniela Basso; John P. Neoptolemos; P. Eter Hegyi; Vytautas Kiudelis; Federico Canzian; Daniele Campa

doi:10.1158/1055-9965.EPI-21-0353

Genetic Polymorphisms Involved in Mitochondrial Metabolism and Pancreatic Cancer Risk

Giulia Peduzzi, Manuel Gentiluomo, Francesca Tavano, Paolo Giorgio Arcidiacono, Stefano Ermini, Pavel Vodicka, Ugo Boggi, Giulia Martina Cavestro, Gabriele Capurso, Luca Morelli, Anna Caterina Milanetto, Raffaele Pezzilli, Rita T. Lawlor, Silvia Carrara, Martin Lovecek, Pavel Souc, Feng Guo, Thilo Hackert, Faik G. Uzunoglu, Maria GazouliAndrea Parniczky, Juozas Kupcinskas, Maarten F. Bijlsma, Bas Bueno-de-Mesquita, Roel Vermeulen, Casper H. J. van Eijck, Krzysztof Jamroziak, Renata Talar-Wojnarowska, William Greenhalf, Domenica Gioffreda, Maria C. Petrone, Stefano Landi, Livia Archibugi, Marta Puzzono, Niccola Funel, Cosimo Sperti, Maria L. Piredda, Beatrice Mohelnikova-Duchonova, Ye Lu, Viktor Hlavac, Xin Gao, Martin Schneider, Jakob R. Izbicki, George Theodoropoulos, Stefania Bunduc, Edita Kreivenaite, Olivier R. Busch, Ewa Malecka-Panas, Eithne Costello, Francesco Perri, Sabrina Gloria Giulia Testoni, Giuseppe Vanella, Claudio Pasquali, Martin Oliverius, Hermann Brenner, Martin Loos, Mara Gotz, Konstantinos Georgiou, Alint Eross, Evaristo Maiello, Andrea Szentesi, Francesca Bazzocchi, Daniela Basso, John P. Neoptolemos, P. Eter Hegyi, Vytautas Kiudelis, Federico Canzian, Daniele Campa

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Abstract

Background: The mitochondrial metabolism has been associated with pancreatic ductal adenocarcinoma (PDAC) risk. Recent evidence also suggests the involvement of the genetic variability of the mitochondrial function in several traits involved in PDAC etiology. However, a systematic investigation of the genetic variability of mitochondrial genome (mtSNP) and of all the nuclear genes involved in its functioning (n-mtSNPs) has never been reported. Methods: We conducted a two-phase association study of mtSNPs and n-mtSNPs to assess their effect on PDAC risk. We analyzed 35,297 n-mtSNPs and 101 mtSNPs in up to 55,870 individuals (12,884 PDAC cases and 42,986 controls). In addition, we also conducted a gene-based analysis on 1,588 genes involved in mitochondrial metabolism using Multi-marker Analysis of GenoMic Annotation (MAGMA) software. Results: In the discovery phase, we identified 49 n-mtSNPs and no mtSNPs associated with PDAC risk (P < 0.05). In the second phase, none of the findings were replicated. In the gene-level analysis, we observed that three genes (TERT, SUGCT, and SURF1) involved in the mitochondrial metabolism showed an association below the Bonferroni-corrected threshold of statistical significance (P = 0.05/1588 = 3.1 × 10^–5). Conclusions: Even though the mitochondrial metabolism might be involved in PDAC etiology, our results, obtained in a study with one of the largest sample sizes to date, show that neither n-mtSNPs nor mtSNPs are associated with PDAC risk. Impact: This large case–control study does not support a role of the genetic variability of the mitochondrial function in PDAC risk.

Original language	English
Pages (from-to)	2342-2345
Number of pages	4
Journal	Cancer Epidemiology Biomarkers and Prevention
Volume	30
Issue number	12
DOIs	https://doi.org/10.1158/1055-9965.EPI-21-0353
Publication status	Published - Dec 2021

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Peduzzi, G., Gentiluomo, M., Tavano, F., Arcidiacono, P. G., Ermini, S., Vodicka, P., Boggi, U., Cavestro, G. M., Capurso, G., Morelli, L., Milanetto, A. C., Pezzilli, R., Lawlor, R. T., Carrara, S., Lovecek, M., Souc, P., Guo, F., Hackert, T., Uzunoglu, F. G., ... Campa, D. (2021). Genetic Polymorphisms Involved in Mitochondrial Metabolism and Pancreatic Cancer Risk. Cancer Epidemiology Biomarkers and Prevention, 30(12), 2342-2345. https://doi.org/10.1158/1055-9965.EPI-21-0353

@article{404eb31f33a64041bea646dcf35ceb60,

title = "Genetic Polymorphisms Involved in Mitochondrial Metabolism and Pancreatic Cancer Risk",

abstract = "Background: The mitochondrial metabolism has been associated with pancreatic ductal adenocarcinoma (PDAC) risk. Recent evidence also suggests the involvement of the genetic variability of the mitochondrial function in several traits involved in PDAC etiology. However, a systematic investigation of the genetic variability of mitochondrial genome (mtSNP) and of all the nuclear genes involved in its functioning (n-mtSNPs) has never been reported. Methods: We conducted a two-phase association study of mtSNPs and n-mtSNPs to assess their effect on PDAC risk. We analyzed 35,297 n-mtSNPs and 101 mtSNPs in up to 55,870 individuals (12,884 PDAC cases and 42,986 controls). In addition, we also conducted a gene-based analysis on 1,588 genes involved in mitochondrial metabolism using Multi-marker Analysis of GenoMic Annotation (MAGMA) software. Results: In the discovery phase, we identified 49 n-mtSNPs and no mtSNPs associated with PDAC risk (P < 0.05). In the second phase, none of the findings were replicated. In the gene-level analysis, we observed that three genes (TERT, SUGCT, and SURF1) involved in the mitochondrial metabolism showed an association below the Bonferroni-corrected threshold of statistical significance (P = 0.05/1588 = 3.1 × 10–5). Conclusions: Even though the mitochondrial metabolism might be involved in PDAC etiology, our results, obtained in a study with one of the largest sample sizes to date, show that neither n-mtSNPs nor mtSNPs are associated with PDAC risk. Impact: This large case–control study does not support a role of the genetic variability of the mitochondrial function in PDAC risk.",

author = "Giulia Peduzzi and Manuel Gentiluomo and Francesca Tavano and Arcidiacono, {Paolo Giorgio} and Stefano Ermini and Pavel Vodicka and Ugo Boggi and Cavestro, {Giulia Martina} and Gabriele Capurso and Luca Morelli and Milanetto, {Anna Caterina} and Raffaele Pezzilli and Lawlor, {Rita T.} and Silvia Carrara and Martin Lovecek and Pavel Souc and Feng Guo and Thilo Hackert and Uzunoglu, {Faik G.} and Maria Gazouli and Andrea Parniczky and Juozas Kupcinskas and Bijlsma, {Maarten F.} and Bas Bueno-de-Mesquita and Roel Vermeulen and {van Eijck}, {Casper H. J.} and Krzysztof Jamroziak and Renata Talar-Wojnarowska and William Greenhalf and Domenica Gioffreda and Petrone, {Maria C.} and Stefano Landi and Livia Archibugi and Marta Puzzono and Niccola Funel and Cosimo Sperti and Piredda, {Maria L.} and Beatrice Mohelnikova-Duchonova and Ye Lu and Viktor Hlavac and Xin Gao and Martin Schneider and Izbicki, {Jakob R.} and George Theodoropoulos and Stefania Bunduc and Edita Kreivenaite and Busch, {Olivier R.} and Ewa Malecka-Panas and Eithne Costello and Francesco Perri and Testoni, {Sabrina Gloria Giulia} and Giuseppe Vanella and Claudio Pasquali and Martin Oliverius and Hermann Brenner and Martin Loos and Mara Gotz and Konstantinos Georgiou and Alint Eross and Evaristo Maiello and Andrea Szentesi and Francesca Bazzocchi and Daniela Basso and Neoptolemos, {John P.} and Hegyi, {P. Eter} and Vytautas Kiudelis and Federico Canzian and Daniele Campa",

year = "2021",

month = dec,

doi = "10.1158/1055-9965.EPI-21-0353",

language = "English",

volume = "30",

pages = "2342--2345",

journal = "Cancer Epidemiology Biomarkers and Prevention",

issn = "1055-9965",

publisher = "American Association for Cancer Research Inc.",

number = "12",

}

Peduzzi, G, Gentiluomo, M, Tavano, F, Arcidiacono, PG, Ermini, S, Vodicka, P, Boggi, U, Cavestro, GM, Capurso, G, Morelli, L, Milanetto, AC, Pezzilli, R, Lawlor, RT, Carrara, S, Lovecek, M, Souc, P, Guo, F, Hackert, T, Uzunoglu, FG, Gazouli, M, Parniczky, A, Kupcinskas, J, Bijlsma, MF, Bueno-de-Mesquita, B, Vermeulen, R, van Eijck, CHJ, Jamroziak, K, Talar-Wojnarowska, R, Greenhalf, W, Gioffreda, D, Petrone, MC, Landi, S, Archibugi, L, Puzzono, M, Funel, N, Sperti, C, Piredda, ML, Mohelnikova-Duchonova, B, Lu, Y, Hlavac, V, Gao, X, Schneider, M, Izbicki, JR, Theodoropoulos, G, Bunduc, S, Kreivenaite, E, Busch, OR, Malecka-Panas, E, Costello, E, Perri, F, Testoni, SGG, Vanella, G, Pasquali, C, Oliverius, M, Brenner, H, Loos, M, Gotz, M, Georgiou, K, Eross, A, Maiello, E, Szentesi, A, Bazzocchi, F, Basso, D, Neoptolemos, JP, Hegyi, PE, Kiudelis, V, Canzian, F & Campa, D 2021, 'Genetic Polymorphisms Involved in Mitochondrial Metabolism and Pancreatic Cancer Risk', Cancer Epidemiology Biomarkers and Prevention, vol. 30, no. 12, pp. 2342-2345. https://doi.org/10.1158/1055-9965.EPI-21-0353

TY - JOUR

T1 - Genetic Polymorphisms Involved in Mitochondrial Metabolism and Pancreatic Cancer Risk

AU - Peduzzi, Giulia

AU - Gentiluomo, Manuel

AU - Tavano, Francesca

AU - Arcidiacono, Paolo Giorgio

AU - Ermini, Stefano

AU - Vodicka, Pavel

AU - Boggi, Ugo

AU - Cavestro, Giulia Martina

AU - Capurso, Gabriele

AU - Morelli, Luca

AU - Milanetto, Anna Caterina

AU - Pezzilli, Raffaele

AU - Lawlor, Rita T.

AU - Carrara, Silvia

AU - Lovecek, Martin

AU - Souc, Pavel

AU - Guo, Feng

AU - Hackert, Thilo

AU - Uzunoglu, Faik G.

AU - Gazouli, Maria

AU - Parniczky, Andrea

AU - Kupcinskas, Juozas

AU - Bijlsma, Maarten F.

AU - Bueno-de-Mesquita, Bas

AU - Vermeulen, Roel

AU - van Eijck, Casper H. J.

AU - Jamroziak, Krzysztof

AU - Talar-Wojnarowska, Renata

AU - Greenhalf, William

AU - Gioffreda, Domenica

AU - Petrone, Maria C.

AU - Landi, Stefano

AU - Archibugi, Livia

AU - Puzzono, Marta

AU - Funel, Niccola

AU - Sperti, Cosimo

AU - Piredda, Maria L.

AU - Mohelnikova-Duchonova, Beatrice

AU - Lu, Ye

AU - Hlavac, Viktor

AU - Gao, Xin

AU - Schneider, Martin

AU - Izbicki, Jakob R.

AU - Theodoropoulos, George

AU - Bunduc, Stefania

AU - Kreivenaite, Edita

AU - Busch, Olivier R.

AU - Malecka-Panas, Ewa

AU - Costello, Eithne

AU - Perri, Francesco

AU - Testoni, Sabrina Gloria Giulia

AU - Vanella, Giuseppe

AU - Pasquali, Claudio

AU - Oliverius, Martin

AU - Brenner, Hermann

AU - Loos, Martin

AU - Gotz, Mara

AU - Georgiou, Konstantinos

AU - Eross, Alint

AU - Maiello, Evaristo

AU - Szentesi, Andrea

AU - Bazzocchi, Francesca

AU - Basso, Daniela

AU - Neoptolemos, John P.

AU - Hegyi, P. Eter

AU - Kiudelis, Vytautas

AU - Canzian, Federico

AU - Campa, Daniele

PY - 2021/12

Y1 - 2021/12

N2 - Background: The mitochondrial metabolism has been associated with pancreatic ductal adenocarcinoma (PDAC) risk. Recent evidence also suggests the involvement of the genetic variability of the mitochondrial function in several traits involved in PDAC etiology. However, a systematic investigation of the genetic variability of mitochondrial genome (mtSNP) and of all the nuclear genes involved in its functioning (n-mtSNPs) has never been reported. Methods: We conducted a two-phase association study of mtSNPs and n-mtSNPs to assess their effect on PDAC risk. We analyzed 35,297 n-mtSNPs and 101 mtSNPs in up to 55,870 individuals (12,884 PDAC cases and 42,986 controls). In addition, we also conducted a gene-based analysis on 1,588 genes involved in mitochondrial metabolism using Multi-marker Analysis of GenoMic Annotation (MAGMA) software. Results: In the discovery phase, we identified 49 n-mtSNPs and no mtSNPs associated with PDAC risk (P < 0.05). In the second phase, none of the findings were replicated. In the gene-level analysis, we observed that three genes (TERT, SUGCT, and SURF1) involved in the mitochondrial metabolism showed an association below the Bonferroni-corrected threshold of statistical significance (P = 0.05/1588 = 3.1 × 10–5). Conclusions: Even though the mitochondrial metabolism might be involved in PDAC etiology, our results, obtained in a study with one of the largest sample sizes to date, show that neither n-mtSNPs nor mtSNPs are associated with PDAC risk. Impact: This large case–control study does not support a role of the genetic variability of the mitochondrial function in PDAC risk.

AB - Background: The mitochondrial metabolism has been associated with pancreatic ductal adenocarcinoma (PDAC) risk. Recent evidence also suggests the involvement of the genetic variability of the mitochondrial function in several traits involved in PDAC etiology. However, a systematic investigation of the genetic variability of mitochondrial genome (mtSNP) and of all the nuclear genes involved in its functioning (n-mtSNPs) has never been reported. Methods: We conducted a two-phase association study of mtSNPs and n-mtSNPs to assess their effect on PDAC risk. We analyzed 35,297 n-mtSNPs and 101 mtSNPs in up to 55,870 individuals (12,884 PDAC cases and 42,986 controls). In addition, we also conducted a gene-based analysis on 1,588 genes involved in mitochondrial metabolism using Multi-marker Analysis of GenoMic Annotation (MAGMA) software. Results: In the discovery phase, we identified 49 n-mtSNPs and no mtSNPs associated with PDAC risk (P < 0.05). In the second phase, none of the findings were replicated. In the gene-level analysis, we observed that three genes (TERT, SUGCT, and SURF1) involved in the mitochondrial metabolism showed an association below the Bonferroni-corrected threshold of statistical significance (P = 0.05/1588 = 3.1 × 10–5). Conclusions: Even though the mitochondrial metabolism might be involved in PDAC etiology, our results, obtained in a study with one of the largest sample sizes to date, show that neither n-mtSNPs nor mtSNPs are associated with PDAC risk. Impact: This large case–control study does not support a role of the genetic variability of the mitochondrial function in PDAC risk.

U2 - 10.1158/1055-9965.EPI-21-0353

DO - 10.1158/1055-9965.EPI-21-0353

M3 - Article

C2 - 34526302

SN - 1055-9965

VL - 30

SP - 2342

EP - 2345

JO - Cancer Epidemiology Biomarkers and Prevention

JF - Cancer Epidemiology Biomarkers and Prevention

IS - 12

ER -

Genetic Polymorphisms Involved in Mitochondrial Metabolism and Pancreatic Cancer Risk

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