Different diabetes types and pancreatic ductal adenocarcinoma: a Mendelian randomization and pathway/gene-set analysis

Ting Zhang¹, Xing Hua^{1

2}, Chirayu Mohindroo³, Xiaoyu Wang^{1

2}, Diptavo Dutta¹, Jia Liu^{1

2}, Shilpa Katta^{1

2}, Shengchao A Li^{1

2}, Jiahui Wang^{1

2}, Samuel O Antwi⁴, Alan A Arslan^{5

6

7}, Laura E Beane Freeman¹, Paige M Bracci⁸, Federico Canzian⁹, Mengmeng Du¹⁰, Steven Gallinger¹¹, Phyllis J Goodman¹², Verena Katzke¹³, Charles Kooperberg¹⁴, Loic Le Marchand¹⁵, Rachel E Neale^{16

17}, Alpa V Patel¹⁸, Sandra Perdomo¹⁹, Xiao-Ou Shu²⁰, Kala Visvanathan^{21

22}, Stephen K Van Den Eeden²³, Emily White²⁴, Wei Zheng²⁰, Demetrius Albanes¹, Gabriella Andreotti¹, William R Bamlet²⁵, Paul Brennan²⁶, Julie E Buring^{27

28}, Stephen J Chanock¹, Yu Chen^{29

30

31}, Burcu Darst¹⁴, Pietro Ferrari³², Edward L Giovannucci^{27

33}, Michael Goggins³⁴, Christopher Haiman³⁵, Manal Hassan³⁶, Elizabeth A Holly⁸, Rayjean J Hung¹¹, Miranda R Jones²¹, Peter Kraft¹, Robert C Kurtz³⁷, Núria Malats^{38

39}, Steven C Moore¹, Kimmie Ng⁴⁰, Ann L Oberg²⁵, Irene Orlow¹⁰, Ulrike Peters⁴¹, Miquel Porta^{42

43}, Kari G Rabe²⁵, Nathaniel Rothman¹, Maria-José Sánchez^{44

45

46}, Howard D Sesso^{27

28}, Debra T Silverman¹, Melissa C Southey^{47

48

49}, Caroline Y Um¹⁸, James Yarmolinsky⁵⁰, Herbert Yu¹⁵, Chen Yuan⁴⁰, Jun Zhong¹, Brian M Wolpin⁴⁰, Harvey A Risch⁵¹, Laufey T Amundadottir¹, Alison P Klein^{21

22

34}, Kai Yu¹, Haoyu Zhang¹, Rachael Z Stolzenberg-Solomon¹

Affiliations

¹ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
² Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc, Rockville, MD, USA.
³ National Cancer Institute, Bethesda, MD, USA.
⁴ Department of Quantitative Health Sciences, Mayo Clinic College of Medicine and Science, Jacksonville, FL, USA.
⁵ Department of Obstetrics and Gynecology, New York University Grossman School of Medicine, New York, New York, USA.
⁶ Department of Population Health, New York University Grossman School of Medicine, New York, New York, USA.
⁷ Perlmutter Cancer Center, NYU Langone Health, New York, New York, USA.
⁸ Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA.
⁹ Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁰ Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹¹ Lunenfeld-Tanenbaum Research Institute, Sinai Health System and University of Toronto, Toronto, Ontario, Canada.
¹² SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
¹³ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁴ Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.
¹⁵ Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA.
¹⁶ Population Health Program, QIMR Berghofer, Brisbane, Queensland.
¹⁷ School of Public Health, University of Queensland, Brisbane, Queensland.
¹⁸ Department of Population Science, American Cancer Society, Atlanta, GA, USA.
¹⁹ Genomic Epidemiology Branch, International Agency for Research on Cancer, Lyon, France.
²⁰ Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
²¹ Department of Epidemiology, Johns Hopkins School of Public Health, Baltimore, MD, USA.
²² Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA.
²³ Division of Research, Kaiser Permanente Northern California, Pleasanton, CA, USA.
²⁴ Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
²⁵ Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA.
²⁶ Genomic Epidemiology Branch., International Agency for Research on Cancer, Lyon, France.
²⁷ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
²⁸ Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA.
²⁹ Department of Population Health, New York University School of Medicine, New York, NY, USA.
³⁰ Perlmutter Cancer Center, New York University School of Medicine, New York, NY, USA.
³¹ New York University Grossman School of Medicine, New York, NY, USA.
³² Nutrition and Metabolism Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France.
³³ Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
³⁴ Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins School of Medicine, Baltimore, MD, USA.
³⁵ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
³⁶ Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
³⁷ Gastroenterology, Hepatology, and Nutrition Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
³⁸ Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Centre, Madrid, Spain.
³⁹ CIBERONC, Madrid, Spain.
⁴⁰ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁴¹ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
⁴² CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain.
⁴³ Hospital del Mar Institute of Medical Research (IMIM), Universitat Autònoma de Barcelona, Barcelona, Spain.
⁴⁴ Escuela Andaluza de Salud Pública (EASP), Granada, Spain.
⁴⁵ Instituto de Investigación Biosanitaria ibs. GRANADA, Granada, Spain.
⁴⁶ Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
⁴⁷ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Victoria, Australia.
⁴⁸ Cancer Epidemiology and Intelligence Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
⁴⁹ Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.
⁵⁰ Imperial College London, UK.
⁵¹ Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA.

PMID: 41206949
DOI: 10.1093/jnci/djaf308

Different diabetes types and pancreatic ductal adenocarcinoma: a Mendelian randomization and pathway/gene-set analysis

Ting Zhang et al. J Natl Cancer Inst. 2025.

. 2025 Nov 9:djaf308.

doi: 10.1093/jnci/djaf308. Online ahead of print.

Authors

Affiliations

¹ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
² Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc, Rockville, MD, USA.
³ National Cancer Institute, Bethesda, MD, USA.
⁴ Department of Quantitative Health Sciences, Mayo Clinic College of Medicine and Science, Jacksonville, FL, USA.
⁵ Department of Obstetrics and Gynecology, New York University Grossman School of Medicine, New York, New York, USA.
⁶ Department of Population Health, New York University Grossman School of Medicine, New York, New York, USA.
⁷ Perlmutter Cancer Center, NYU Langone Health, New York, New York, USA.
⁸ Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA.
⁹ Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁰ Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹¹ Lunenfeld-Tanenbaum Research Institute, Sinai Health System and University of Toronto, Toronto, Ontario, Canada.
¹² SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
¹³ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁴ Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.
¹⁵ Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA.
¹⁶ Population Health Program, QIMR Berghofer, Brisbane, Queensland.
¹⁷ School of Public Health, University of Queensland, Brisbane, Queensland.
¹⁸ Department of Population Science, American Cancer Society, Atlanta, GA, USA.
¹⁹ Genomic Epidemiology Branch, International Agency for Research on Cancer, Lyon, France.
²⁰ Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
²¹ Department of Epidemiology, Johns Hopkins School of Public Health, Baltimore, MD, USA.
²² Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA.
²³ Division of Research, Kaiser Permanente Northern California, Pleasanton, CA, USA.
²⁴ Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
²⁵ Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA.
²⁶ Genomic Epidemiology Branch., International Agency for Research on Cancer, Lyon, France.
²⁷ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
²⁸ Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA.
²⁹ Department of Population Health, New York University School of Medicine, New York, NY, USA.
³⁰ Perlmutter Cancer Center, New York University School of Medicine, New York, NY, USA.
³¹ New York University Grossman School of Medicine, New York, NY, USA.
³² Nutrition and Metabolism Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France.
³³ Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
³⁴ Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins School of Medicine, Baltimore, MD, USA.
³⁵ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
³⁶ Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
³⁷ Gastroenterology, Hepatology, and Nutrition Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
³⁸ Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Centre, Madrid, Spain.
³⁹ CIBERONC, Madrid, Spain.
⁴⁰ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁴¹ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
⁴² CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain.
⁴³ Hospital del Mar Institute of Medical Research (IMIM), Universitat Autònoma de Barcelona, Barcelona, Spain.
⁴⁴ Escuela Andaluza de Salud Pública (EASP), Granada, Spain.
⁴⁵ Instituto de Investigación Biosanitaria ibs. GRANADA, Granada, Spain.
⁴⁶ Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
⁴⁷ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Victoria, Australia.
⁴⁸ Cancer Epidemiology and Intelligence Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
⁴⁹ Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.
⁵⁰ Imperial College London, UK.
⁵¹ Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA.

PMID: 41206949
DOI: 10.1093/jnci/djaf308

Abstract

Background: The associations between different types of diabetes, characterized by distinct pathophysiology and genetic architecture, and pancreatic ductal adenocarcinoma (PDAC) risk are not understood.

Methods: We investigated associations of genetic susceptibility to type 2 diabetes (T2D), eight T2D mechanistic clusters, type 1 diabetes (T1D), and maturity-onset diabetes of the young (MODY) with PDAC risk. We used genome-wide association study (GWAS) summary-level statistics for T2D (242,283 cases, 1,569,734 controls), T1D (18,942 cases, 501,638 controls), and PDAC (10,244 cases and 360,535 controls) in individuals of European ancestry.

Results: Two-sample Mendelian randomization (MR) using the Robust Adjusted Profile Score (MR-RAPS) method indicated that genetically predicted T2D was associated with PDAC risk (OR = 1.10; 95% CI 1.05-1.15), particularly the T2D obesity (OR = 1.28; 95% CI 1.15-1.42) and lipodystrophy (OR = 1.25; 95% CI 1.03-1.51) clusters. No association was observed for T1D with PDAC risk (OR = 1.01; 95% CI 0.99-1.02). Pathway/gene-set analysis using the summary-based Adaptive Rank Truncated Product (sARTP) method revealed a significant association between the MODY gene-sets and PDAC risk (P = 1.5 × 10-8), which remained after excluding 20 known PDAC GWAS loci (P = 7.6 × 10-4). HNF1A, FOXA3, and HNF4A were the top contributing genes after excluding the previously identified GWAS loci regions.

Conclusions: Our results from this genetic association study support that T2D, particularly the obesity and lipodystrophy mechanistic clusters, and MODY genomic susceptibility regions play a role in the etiology of PDAC.

Keywords: Maturity-onset diabetes of the young; Mendelian Randomization; Pancreatic ductal adenocarcinoma; Type 1 Diabetes; Type 2 Diabetes.

Published by Oxford University Press 2025.

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Different diabetes types and pancreatic ductal adenocarcinoma: a Mendelian randomization and pathway/gene-set analysis

Affiliations

Different diabetes types and pancreatic ductal adenocarcinoma: a Mendelian randomization and pathway/gene-set analysis

Authors

Affiliations

Abstract

LinkOut - more resources

Full Text Sources