Common variability in oestrogen-related genes and pancreatic ductal adenocarcinoma risk in women

Giulia Peduzzi; Livia Archibugi; Verena Katzke; Manuel Gentiluomo; Gabriele Capurso; Anna Caterina Milanetto; Maria Gazouli; Mara Goetz; Hermann Brenner; Roel C.H. Vermeulen; Renata Talar-Wojnarowska; Giuseppe Vanella; Francesca Tavano; Maurizio Lucchesi; Beatrice Mohelnikova-Duchonova; Xuechen Chen; Vytautas Kiudelis; Péter Hegyi; Martin Oliverius; Hannah Stocker; Caterina Stornello; Ludmila Vodickova; Pavel Souček; John P. Neoptolemos; Sabrina Gloria Giulia Testoni; Luca Morelli; Rita T. Lawlor; Daniela Basso; Jakob R. Izbicki; Stefano Ermini; Juozas Kupcinskas; Raffaele Pezzilli; Ugo Boggi; Hanneke W.M. van Laarhoven; Andrea Szentesi; Bálint Erőss; Giovanni Capretti; Ben Schöttker; Jurgita Skieceviciene; Mateus Nóbrega Aoki; Casper H.J. van Eijck; Giulia Martina Cavestro; Federico Canzian; Daniele Campa

doi:10.1038/s41598-022-22973-9

Common variability in oestrogen-related genes and pancreatic ductal adenocarcinoma risk in women

Giulia Peduzzi, Livia Archibugi, Verena Katzke, Manuel Gentiluomo, Gabriele Capurso, Anna Caterina Milanetto, Maria Gazouli, Mara Goetz, Hermann Brenner, Roel C.H. Vermeulen, Renata Talar-Wojnarowska, Giuseppe Vanella, Francesca Tavano, Maurizio Lucchesi, Beatrice Mohelnikova-Duchonova, Xuechen Chen, Vytautas Kiudelis, Péter Hegyi, Martin Oliverius, Hannah StockerCaterina Stornello, Ludmila Vodickova, Pavel Souček, John P. Neoptolemos, Sabrina Gloria Giulia Testoni, Luca Morelli, Rita T. Lawlor, Daniela Basso, Jakob R. Izbicki, Stefano Ermini, Juozas Kupcinskas, Raffaele Pezzilli, Ugo Boggi, Hanneke W.M. van Laarhoven, Andrea Szentesi, Bálint Erőss, Giovanni Capretti, Ben Schöttker, Jurgita Skieceviciene, Mateus Nóbrega Aoki, Casper H.J. van Eijck, Giulia Martina Cavestro, Federico Canzian, Daniele Campa^*

^*Corresponding author for this work

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Abstract

The incidence of pancreatic ductal adenocarcinoma (PDAC) is different among males and females. This disparity cannot be fully explained by the difference in terms of exposure to known risk factors; therefore, the lower incidence in women could be attributed to sex-specific hormones. A two-phase association study was conducted in 12,387 female subjects (5436 PDAC cases and 6951 controls) to assess the effect on risk of developing PDAC of single nucleotide polymorphisms (SNPs) in 208 genes involved in oestrogen and pregnenolone biosynthesis and oestrogen-mediated signalling. In the discovery phase 14 polymorphisms showed a statistically significant association (P < 0.05). In the replication none of the findings were validated. In addition, a gene-based analysis was performed on the 208 selected genes. Four genes (NR5A2, MED1, NCOA2 and RUNX1) were associated with PDAC risk, but only NR5A2 showed an association (P = 4.08 × 10⁻⁵) below the Bonferroni-corrected threshold of statistical significance. In conclusion, despite differences in incidence between males and females, our study did not identify an effect of common polymorphisms in the oestrogen and pregnenolone pathways in relation to PDAC susceptibility. However, we validated the previously reported association between NR5A2 gene variants and PDAC risk.

Original language	English
Article number	18100
Journal	Scientific Reports
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41598-022-22973-9
Publication status	Published - 27 Oct 2022

Bibliographical note

Acknowledgements
The research used the genotyping data provided by the EPIC, we would like to thank the contributors from the UK. The EPIC-Norfolk study (https://doi-org.eur.idm.oclc.org/10.22025/2019.10.105.00004) has received funding from the Medical Research Council [MR/N003284/1 and MC-UU_12015/1] and Cancer Research UK [C864/A14136]. We are grateful to all the participants who have been part of the project and to the many members of the study teams at the University of Cambridge who have enabled this research. This work was supported by intramural funding of DKFZ (Federico Canzian), by Fondazione Tizzi (www.fondazionetizzi.it) and by Fondazione Arpa (www.fondazionearpa.it) (Daniele Campa), by the Czech Health Research Council, project no.: NV19-03-00097 (Beatrice Mohelnikova-Duchonova), by AZV, NU21-07-00247 and Operational Programme Integrated Infrastructure for the project: Integrative strategy in development of personalized medicine of selected malignant tumours and its impact on quality of life, IMTS: 313011V446, co-financed by the European Regional Development Fund (Ludmila Vodickova), by National operation Programm: National Institute for cancer research LX22NPO05102 (Ludmila Vodickova). The research leading to these results has received funding from AIRC under IG 2021-ID. 26201 project-P.I. Gabriele Capurso. This work was supported by Italian Ministry of Health grants (Ricerca Corrente 2022–2024) to Fondazione “Casa Sollievo della Sofferenza” IRCCS Hospital, San Giovanni Rotondo (FG), Italy and by the “5x1000” voluntary contribution.

Publisher Copyright: © 2022, The Author(s).

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Peduzzi, G., Archibugi, L., Katzke, V., Gentiluomo, M., Capurso, G., Milanetto, A. C., Gazouli, M., Goetz, M., Brenner, H., Vermeulen, R. C. H., Talar-Wojnarowska, R., Vanella, G., Tavano, F., Lucchesi, M., Mohelnikova-Duchonova, B., Chen, X., Kiudelis, V., Hegyi, P., Oliverius, M., ... Campa, D. (2022). Common variability in oestrogen-related genes and pancreatic ductal adenocarcinoma risk in women. Scientific Reports, 12(1), Article 18100. https://doi.org/10.1038/s41598-022-22973-9

@article{d9572e82ae2245c79cde77967e930cfb,

title = "Common variability in oestrogen-related genes and pancreatic ductal adenocarcinoma risk in women",

abstract = "The incidence of pancreatic ductal adenocarcinoma (PDAC) is different among males and females. This disparity cannot be fully explained by the difference in terms of exposure to known risk factors; therefore, the lower incidence in women could be attributed to sex-specific hormones. A two-phase association study was conducted in 12,387 female subjects (5436 PDAC cases and 6951 controls) to assess the effect on risk of developing PDAC of single nucleotide polymorphisms (SNPs) in 208 genes involved in oestrogen and pregnenolone biosynthesis and oestrogen-mediated signalling. In the discovery phase 14 polymorphisms showed a statistically significant association (P < 0.05). In the replication none of the findings were validated. In addition, a gene-based analysis was performed on the 208 selected genes. Four genes (NR5A2, MED1, NCOA2 and RUNX1) were associated with PDAC risk, but only NR5A2 showed an association (P = 4.08 × 10−5) below the Bonferroni-corrected threshold of statistical significance. In conclusion, despite differences in incidence between males and females, our study did not identify an effect of common polymorphisms in the oestrogen and pregnenolone pathways in relation to PDAC susceptibility. However, we validated the previously reported association between NR5A2 gene variants and PDAC risk.",

author = "Giulia Peduzzi and Livia Archibugi and Verena Katzke and Manuel Gentiluomo and Gabriele Capurso and Milanetto, {Anna Caterina} and Maria Gazouli and Mara Goetz and Hermann Brenner and Vermeulen, {Roel C.H.} and Renata Talar-Wojnarowska and Giuseppe Vanella and Francesca Tavano and Maurizio Lucchesi and Beatrice Mohelnikova-Duchonova and Xuechen Chen and Vytautas Kiudelis and P{\'e}ter Hegyi and Martin Oliverius and Hannah Stocker and Caterina Stornello and Ludmila Vodickova and Pavel Sou{\v c}ek and Neoptolemos, {John P.} and Testoni, {Sabrina Gloria Giulia} and Luca Morelli and Lawlor, {Rita T.} and Daniela Basso and Izbicki, {Jakob R.} and Stefano Ermini and Juozas Kupcinskas and Raffaele Pezzilli and Ugo Boggi and {van Laarhoven}, {Hanneke W.M.} and Andrea Szentesi and B{\'a}lint Er{\H o}ss and Giovanni Capretti and Ben Sch{\"o}ttker and Jurgita Skieceviciene and Aoki, {Mateus N{\'o}brega} and {van Eijck}, {Casper H.J.} and Cavestro, {Giulia Martina} and Federico Canzian and Daniele Campa",

note = "Acknowledgements The research used the genotyping data provided by the EPIC, we would like to thank the contributors from the UK. The EPIC-Norfolk study (https://doi-org.eur.idm.oclc.org/10.22025/2019.10.105.00004) has received funding from the Medical Research Council [MR/N003284/1 and MC-UU_12015/1] and Cancer Research UK [C864/A14136]. We are grateful to all the participants who have been part of the project and to the many members of the study teams at the University of Cambridge who have enabled this research. This work was supported by intramural funding of DKFZ (Federico Canzian), by Fondazione Tizzi (www.fondazionetizzi.it) and by Fondazione Arpa (www.fondazionearpa.it) (Daniele Campa), by the Czech Health Research Council, project no.: NV19-03-00097 (Beatrice Mohelnikova-Duchonova), by AZV, NU21-07-00247 and Operational Programme Integrated Infrastructure for the project: Integrative strategy in development of personalized medicine of selected malignant tumours and its impact on quality of life, IMTS: 313011V446, co-financed by the European Regional Development Fund (Ludmila Vodickova), by National operation Programm: National Institute for cancer research LX22NPO05102 (Ludmila Vodickova). The research leading to these results has received funding from AIRC under IG 2021-ID. 26201 project-P.I. Gabriele Capurso. This work was supported by Italian Ministry of Health grants (Ricerca Corrente 2022–2024) to Fondazione “Casa Sollievo della Sofferenza” IRCCS Hospital, San Giovanni Rotondo (FG), Italy and by the “5x1000” voluntary contribution. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

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doi = "10.1038/s41598-022-22973-9",

language = "English",

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Peduzzi, G, Archibugi, L, Katzke, V, Gentiluomo, M, Capurso, G, Milanetto, AC, Gazouli, M, Goetz, M, Brenner, H, Vermeulen, RCH, Talar-Wojnarowska, R, Vanella, G, Tavano, F, Lucchesi, M, Mohelnikova-Duchonova, B, Chen, X, Kiudelis, V, Hegyi, P, Oliverius, M, Stocker, H, Stornello, C, Vodickova, L, Souček, P, Neoptolemos, JP, Testoni, SGG, Morelli, L, Lawlor, RT, Basso, D, Izbicki, JR, Ermini, S, Kupcinskas, J, Pezzilli, R, Boggi, U, van Laarhoven, HWM, Szentesi, A, Erőss, B, Capretti, G, Schöttker, B, Skieceviciene, J, Aoki, MN, van Eijck, CHJ, Cavestro, GM, Canzian, F & Campa, D 2022, 'Common variability in oestrogen-related genes and pancreatic ductal adenocarcinoma risk in women', Scientific Reports, vol. 12, no. 1, 18100. https://doi.org/10.1038/s41598-022-22973-9

TY - JOUR

T1 - Common variability in oestrogen-related genes and pancreatic ductal adenocarcinoma risk in women

AU - Peduzzi, Giulia

AU - Archibugi, Livia

AU - Katzke, Verena

AU - Gentiluomo, Manuel

AU - Capurso, Gabriele

AU - Milanetto, Anna Caterina

AU - Gazouli, Maria

AU - Goetz, Mara

AU - Brenner, Hermann

AU - Vermeulen, Roel C.H.

AU - Talar-Wojnarowska, Renata

AU - Vanella, Giuseppe

AU - Tavano, Francesca

AU - Lucchesi, Maurizio

AU - Mohelnikova-Duchonova, Beatrice

AU - Chen, Xuechen

AU - Kiudelis, Vytautas

AU - Hegyi, Péter

AU - Oliverius, Martin

AU - Stocker, Hannah

AU - Stornello, Caterina

AU - Vodickova, Ludmila

AU - Souček, Pavel

AU - Neoptolemos, John P.

AU - Testoni, Sabrina Gloria Giulia

AU - Morelli, Luca

AU - Lawlor, Rita T.

AU - Basso, Daniela

AU - Izbicki, Jakob R.

AU - Ermini, Stefano

AU - Kupcinskas, Juozas

AU - Pezzilli, Raffaele

AU - Boggi, Ugo

AU - van Laarhoven, Hanneke W.M.

AU - Szentesi, Andrea

AU - Erőss, Bálint

AU - Capretti, Giovanni

AU - Schöttker, Ben

AU - Skieceviciene, Jurgita

AU - Aoki, Mateus Nóbrega

AU - van Eijck, Casper H.J.

AU - Cavestro, Giulia Martina

AU - Canzian, Federico

AU - Campa, Daniele

N1 - Acknowledgements The research used the genotyping data provided by the EPIC, we would like to thank the contributors from the UK. The EPIC-Norfolk study (https://doi-org.eur.idm.oclc.org/10.22025/2019.10.105.00004) has received funding from the Medical Research Council [MR/N003284/1 and MC-UU_12015/1] and Cancer Research UK [C864/A14136]. We are grateful to all the participants who have been part of the project and to the many members of the study teams at the University of Cambridge who have enabled this research. This work was supported by intramural funding of DKFZ (Federico Canzian), by Fondazione Tizzi (www.fondazionetizzi.it) and by Fondazione Arpa (www.fondazionearpa.it) (Daniele Campa), by the Czech Health Research Council, project no.: NV19-03-00097 (Beatrice Mohelnikova-Duchonova), by AZV, NU21-07-00247 and Operational Programme Integrated Infrastructure for the project: Integrative strategy in development of personalized medicine of selected malignant tumours and its impact on quality of life, IMTS: 313011V446, co-financed by the European Regional Development Fund (Ludmila Vodickova), by National operation Programm: National Institute for cancer research LX22NPO05102 (Ludmila Vodickova). The research leading to these results has received funding from AIRC under IG 2021-ID. 26201 project-P.I. Gabriele Capurso. This work was supported by Italian Ministry of Health grants (Ricerca Corrente 2022–2024) to Fondazione “Casa Sollievo della Sofferenza” IRCCS Hospital, San Giovanni Rotondo (FG), Italy and by the “5x1000” voluntary contribution. Publisher Copyright: © 2022, The Author(s).

PY - 2022/10/27

Y1 - 2022/10/27

N2 - The incidence of pancreatic ductal adenocarcinoma (PDAC) is different among males and females. This disparity cannot be fully explained by the difference in terms of exposure to known risk factors; therefore, the lower incidence in women could be attributed to sex-specific hormones. A two-phase association study was conducted in 12,387 female subjects (5436 PDAC cases and 6951 controls) to assess the effect on risk of developing PDAC of single nucleotide polymorphisms (SNPs) in 208 genes involved in oestrogen and pregnenolone biosynthesis and oestrogen-mediated signalling. In the discovery phase 14 polymorphisms showed a statistically significant association (P < 0.05). In the replication none of the findings were validated. In addition, a gene-based analysis was performed on the 208 selected genes. Four genes (NR5A2, MED1, NCOA2 and RUNX1) were associated with PDAC risk, but only NR5A2 showed an association (P = 4.08 × 10−5) below the Bonferroni-corrected threshold of statistical significance. In conclusion, despite differences in incidence between males and females, our study did not identify an effect of common polymorphisms in the oestrogen and pregnenolone pathways in relation to PDAC susceptibility. However, we validated the previously reported association between NR5A2 gene variants and PDAC risk.

AB - The incidence of pancreatic ductal adenocarcinoma (PDAC) is different among males and females. This disparity cannot be fully explained by the difference in terms of exposure to known risk factors; therefore, the lower incidence in women could be attributed to sex-specific hormones. A two-phase association study was conducted in 12,387 female subjects (5436 PDAC cases and 6951 controls) to assess the effect on risk of developing PDAC of single nucleotide polymorphisms (SNPs) in 208 genes involved in oestrogen and pregnenolone biosynthesis and oestrogen-mediated signalling. In the discovery phase 14 polymorphisms showed a statistically significant association (P < 0.05). In the replication none of the findings were validated. In addition, a gene-based analysis was performed on the 208 selected genes. Four genes (NR5A2, MED1, NCOA2 and RUNX1) were associated with PDAC risk, but only NR5A2 showed an association (P = 4.08 × 10−5) below the Bonferroni-corrected threshold of statistical significance. In conclusion, despite differences in incidence between males and females, our study did not identify an effect of common polymorphisms in the oestrogen and pregnenolone pathways in relation to PDAC susceptibility. However, we validated the previously reported association between NR5A2 gene variants and PDAC risk.

UR - http://www.scopus.com/inward/record.url?scp=85140891990&partnerID=8YFLogxK

U2 - 10.1038/s41598-022-22973-9

DO - 10.1038/s41598-022-22973-9

M3 - Article

C2 - 36302831

AN - SCOPUS:85140891990

SN - 2045-2322

VL - 12

JO - Scientific Reports

JF - Scientific Reports

IS - 1

M1 - 18100

ER -

Common variability in oestrogen-related genes and pancreatic ductal adenocarcinoma risk in women

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