. 2023 Jun 8;115(6):712-732.

doi: 10.1093/jnci/djad043.

Genome-wide analyses characterize shared heritability among cancers and identify novel cancer susceptibility regions

Sara Lindström^{1

2}, Lu Wang³, Helian Feng⁴, Arunabha Majumdar^{5

6}, Sijia Huo⁴, James Macdonald³, Tabitha Harrison¹, Constance Turman⁷, Hongjie Chen¹, Nicholas Mancuso⁸, Theo Bammler³; Breast Cancer Association Consortium (BCAC); Steve Gallinger⁹, Stephen B Gruber¹⁰, Marc J Gunter¹¹, Loic Le Marchand¹², Victor Moreno^{13

14

15

16}, Kenneth Offit^{17

18}; Colorectal Transdisciplinary Study (CORECT), Colon Cancer Family Registry Study (CCFR), Genetics And Epidemiology Of Colorectal Cancer Consortium (GECCO); Immaculata De Vivo^{7

19

20}, Tracy A O'Mara²¹, Amanda B Spurdle²¹, Ian Tomlinson²²; Endometrial Cancer Association Consortium (ECAC); Rebecca Fitzgerald²³, Puya Gharahkhani²⁴, Ines Gockel²⁵, Janusz Jankowski^{26

27}, Stuart Macgregor²⁴, Johannes Schumacher²⁸, Jill Barnholtz-Sloan^{29

30}, Melissa L Bondy³¹, Richard S Houlston³², Robert B Jenkins³³, Beatrice Melin³⁴, Margaret Wrensch³⁵, Paul Brennan¹¹, David C Christiani^{7

36}, Mattias Johansson¹¹, James Mckay¹¹, Melinda C Aldrich³⁷, Christopher I Amos³⁸, Maria Teresa Landi²⁹, Adonina Tardon³⁹; International Lung Cancer Consortium (ILCCO); D Timothy Bishop⁴⁰, Florence Demenais⁴¹, Alisa M Goldstein²⁹, Mark M Iles⁴⁰, Peter A Kanetsky⁴², Matthew H Law^{24

43}; Ovarian Cancer Association Consortium (OCAC); Laufey T Amundadottir²⁹, Rachael Stolzenberg-Solomon²⁹, Brian M Wolpin⁴⁴; Pancreatic Cancer Cohort Consortium (Panscan); Alison Klein^{45

46}, Gloria Petersen⁴⁷, Harvey Risch⁴⁸; Pancreatic Cancer Case-Control Consortium (Panc4), The PRACTICAL Consortium; Stephen J Chanock²⁹, Mark P Purdue²⁹, Ghislaine Scelo¹¹, Paul Pharoah⁴⁹, Siddhartha Kar⁵⁰, Rayjean J Hung⁵¹, Bogdan Pasaniuc^{5

52

53}, Peter Kraft^{4

7}

Affiliations

¹ Department of Epidemiology, University of Washington, Seattle, WA, USA.
² Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
³ Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA.
⁴ Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁵ Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁶ Department of Mathematics, Indian Institute of Technology Hyderabad, Kandi, Telangana, India.
⁷ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁸ Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁹ Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
¹⁰ Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, Duarte, CA, USA.
¹¹ International Agency for Research on Cancer, World Health Organization, Lyon, France.
¹² University of Hawaii Cancer Center, Honolulu, HI, USA.
¹³ Oncology Data Analytics Program, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
¹⁴ CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
¹⁵ Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain.
¹⁶ ONCOBEL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
¹⁷ Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
¹⁸ Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
¹⁹ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
²⁰ Harvard Radcliffe Institute, Cambridge, MA, USA.
²¹ Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
²² Cancer Research Centre, The University of Edinburgh, Edinburgh, UK.
²³ MRC Cancer Unit, Hutchison-MRC Research Centre, University of Cambridge, Cambridge, UK.
²⁴ Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
²⁵ Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany.
²⁶ Institute for Clinical Trials, University College London, Holborn, UK.
²⁷ University of the South Pacific, Suva, Fiji.
²⁸ Center for Human Genetics, University Hospital of Marburg, Marburg, Germany.
²⁹ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
³⁰ Trans-Divisional Research Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
³¹ Department of Epidemiology and Population Health, Stanford University, Palo Alto, CA, USA.
³² Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
³³ Department of Laboratory Medicine and Pathology, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Rochester, MN, USA.
³⁴ Department of Radiation Sciences, Umeå University, Umeå, Sweden.
³⁵ Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
³⁶ Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
³⁷ Department of Thoracic Surgery, Division of Epidemiology, Vanderbilt University Medical Center, Nashville, TN, USA.
³⁸ Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX, USA.
³⁹ University Institute of Oncology of the Principality of Asturias (IUOPA), University of Oviedo and Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Oviedo, Spain.
⁴⁰ Leeds Institute for Data Analytics, University of Leeds, Leeds, UK.
⁴¹ Université Paris Cité, Institut National de la Santé et de la Recherche Médicale (INSERM), UMR-1124, Paris, France.
⁴² Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
⁴³ School of Biomedical Sciences, Faculty of Health, and Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, Queensland, Australia.
⁴⁴ Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
⁴⁵ Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA.
⁴⁶ Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins School of Medicine, Baltimore, MD, USA.
⁴⁷ Department of Quantitative Health Science, Mayo Clinic, Rochester, MN, USA.
⁴⁸ Yale School of Public Health, Chronic Disease Epidemiology, New Haven, CT, USA.
⁴⁹ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁵⁰ Medical Research Council Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
⁵¹ Prosserman Centre for Population Health Research, Lunenfeld-Tanenbuaum Research Institute, Sinai Health System, Toronto, ON, Canada.
⁵² Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁵³ Department of Computational Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.

PMID: 36929942
PMCID: PMC10248849
DOI: 10.1093/jnci/djad043

Genome-wide analyses characterize shared heritability among cancers and identify novel cancer susceptibility regions

Sara Lindström et al. J Natl Cancer Inst. 2023.

. 2023 Jun 8;115(6):712-732.

doi: 10.1093/jnci/djad043.

Authors

Affiliations

¹ Department of Epidemiology, University of Washington, Seattle, WA, USA.
² Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
³ Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA.
⁴ Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁵ Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁶ Department of Mathematics, Indian Institute of Technology Hyderabad, Kandi, Telangana, India.
⁷ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁸ Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁹ Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
¹⁰ Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, Duarte, CA, USA.
¹¹ International Agency for Research on Cancer, World Health Organization, Lyon, France.
¹² University of Hawaii Cancer Center, Honolulu, HI, USA.
¹³ Oncology Data Analytics Program, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
¹⁴ CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
¹⁵ Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain.
¹⁶ ONCOBEL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
¹⁷ Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
¹⁸ Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
¹⁹ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
²⁰ Harvard Radcliffe Institute, Cambridge, MA, USA.
²¹ Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
²² Cancer Research Centre, The University of Edinburgh, Edinburgh, UK.
²³ MRC Cancer Unit, Hutchison-MRC Research Centre, University of Cambridge, Cambridge, UK.
²⁴ Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
²⁵ Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany.
²⁶ Institute for Clinical Trials, University College London, Holborn, UK.
²⁷ University of the South Pacific, Suva, Fiji.
²⁸ Center for Human Genetics, University Hospital of Marburg, Marburg, Germany.
²⁹ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
³⁰ Trans-Divisional Research Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
³¹ Department of Epidemiology and Population Health, Stanford University, Palo Alto, CA, USA.
³² Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
³³ Department of Laboratory Medicine and Pathology, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Rochester, MN, USA.
³⁴ Department of Radiation Sciences, Umeå University, Umeå, Sweden.
³⁵ Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
³⁶ Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
³⁷ Department of Thoracic Surgery, Division of Epidemiology, Vanderbilt University Medical Center, Nashville, TN, USA.
³⁸ Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX, USA.
³⁹ University Institute of Oncology of the Principality of Asturias (IUOPA), University of Oviedo and Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Oviedo, Spain.
⁴⁰ Leeds Institute for Data Analytics, University of Leeds, Leeds, UK.
⁴¹ Université Paris Cité, Institut National de la Santé et de la Recherche Médicale (INSERM), UMR-1124, Paris, France.
⁴² Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
⁴³ School of Biomedical Sciences, Faculty of Health, and Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, Queensland, Australia.
⁴⁴ Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
⁴⁵ Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA.
⁴⁶ Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins School of Medicine, Baltimore, MD, USA.
⁴⁷ Department of Quantitative Health Science, Mayo Clinic, Rochester, MN, USA.
⁴⁸ Yale School of Public Health, Chronic Disease Epidemiology, New Haven, CT, USA.
⁴⁹ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁵⁰ Medical Research Council Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
⁵¹ Prosserman Centre for Population Health Research, Lunenfeld-Tanenbuaum Research Institute, Sinai Health System, Toronto, ON, Canada.
⁵² Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁵³ Department of Computational Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.

PMID: 36929942
PMCID: PMC10248849
DOI: 10.1093/jnci/djad043

Abstract

Background: The shared inherited genetic contribution to risk of different cancers is not fully known. In this study, we leverage results from 12 cancer genome-wide association studies (GWAS) to quantify pairwise genome-wide genetic correlations across cancers and identify novel cancer susceptibility loci.

Methods: We collected GWAS summary statistics for 12 solid cancers based on 376 759 participants with cancer and 532 864 participants without cancer of European ancestry. The included cancer types were breast, colorectal, endometrial, esophageal, glioma, head and neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancers. We conducted cross-cancer GWAS and transcriptome-wide association studies to discover novel cancer susceptibility loci. Finally, we assessed the extent of variant-specific pleiotropy among cancers at known and newly identified cancer susceptibility loci.

Results: We observed widespread but modest genome-wide genetic correlations across cancers. In cross-cancer GWAS and transcriptome-wide association studies, we identified 15 novel cancer susceptibility loci. Additionally, we identified multiple variants at 77 distinct loci with strong evidence of being associated with at least 2 cancer types by testing for pleiotropy at known cancer susceptibility loci.

Conclusions: Overall, these results suggest that some genetic risk variants are shared among cancers, though much of cancer heritability is cancer-specific and thus tissue-specific. The increase in statistical power associated with larger sample sizes in cross-disease analysis allows for the identification of novel susceptibility regions. Future studies incorporating data on multiple cancer types are likely to identify additional regions associated with the risk of multiple cancer types.

PubMed Disclaimer

Conflict of interest statement

BMW reports Grants from Celgene, Eli Lilly; Consulting for BioLineRx, Celgene, Grail; outside of the presented work. No other conflicts of interest exist.

Stephen J. Chanock and Harvey Risch, JNCI Associate Editors and coauthors on this manuscript, were not involved in the editorial review or decision to publish the article.

Figures

**Figure 1.**
Pairwise genetic correlations between cancers. **(A)** Matrix of pairwise genetic correlations. **(B)** Genetic correlation network. Distance between nodes, edge shade, and edge thickness corresponds to genetic correlation magnitudes. **Dashed lines** indicate negative correlations. BRCA = breast cancer; CMM = cutaneous melanoma; CRC =colorectal cancer; ENDO = endometrial cancer; ESC = esophageal cancer; HNC = head and neck cancer; OVCA = ovarian cancer; PANC = pancreatic cancer; PRCA = prostate cancer; RCC = renal cancer (see Supplementary Table 1, available online for numerical values and corresponding P values). (Fruchterman and Reingold, 1991).

**Figure 2.**
Cancer-specific association results for the lead single-nucleotide polymorphisms of 7 newly identified cancer susceptibility loci. The **circles** correspond to cancer-specific log(odds ratios), with color corresponding to direction of effect and size and shade corresponding to magnitude of effect. *Cancer-specific P < .05. **Cancer-specific P < .001. See Supplementary Table 5 (available online) for cancer-specific odds ratios and P values. NA denotes instances where the variant was not present in the corresponding cancer.

**Figure 3.**
Regions in the genome with evidence of variant-specific pleiotropy. Colors correspond to regions with 4 sets of 3-cancer pleiotropy (**blue**), 1 combination of 3-cancer pleiotropy (**light green**), 9 combinations of pairwise cancer pleiotropy (**red**), 8 combinations of pairwise cancer pleiotropy (**black**), 3 combinations of pairwise cancer pleiotropy (**pink**), 2 combinations of pairwise cancer pleiotropy (**dark green**), and 1 combination of pairwise cancer pleiotropy (**yellow**). Full results from the pleiotropic analyses can be found in Supplementary Tables 10-12 (available online).

See this image and copyright information in PMC

References

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Genome-wide analyses characterize shared heritability among cancers and identify novel cancer susceptibility regions

Affiliations

Genome-wide analyses characterize shared heritability among cancers and identify novel cancer susceptibility regions

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources