Large-scale cross-cancer fine-mapping of the 5p15.33 region reveals multiple independent signals

Hongjie Chen¹, Arunabha Majumdar^{2

3}, Lu Wang⁴, Siddhartha Kar⁵, Kevin M Brown⁶, Helian Feng⁷, Constance Turman⁸, Joe Dennis⁹, Douglas Easton⁹, Kyriaki Michailidou^{10

11}, Jacques Simard¹²; Breast Cancer Association Consortium (BCAC); Timothy Bishop¹³, Iona C Cheng¹⁴, Jeroen R Huyghe¹⁵, Stephanie L Schmit¹⁶; Colorectal Transdisciplinary Study (CORECT); Colon Cancer Family Registry Study (CCFR); Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO); Tracy A O'Mara¹⁷, Amanda B Spurdle¹⁷; Endometrial Cancer Association Consortium (ECAC); Puya Gharahkhani¹⁸, Johannes Schumacher¹⁹, Janusz Jankowski^{20

21}, Ines Gockel²²; Esophageal Cancer GWAS Consortium; Melissa L Bondy²³, Richard S Houlston²⁴, Robert B Jenkins²⁵, Beatrice Melin²⁶; Glioma International Case Control Consortium (GICC); Corina Lesseur^{27

28}, Andy R Ness^{29

30}, Brenda Diergaarde^{31

32}, Andrew F Olshan^{33

34}; Head-Neck Cancer GWAS Consortium; Christopher I Amos³⁵, David C Christiani^{8

36}, Maria T Landi⁶, James D McKay²⁸; International Lung Cancer Consortium (ILCCO); Myriam Brossard^{37

38}, Mark M Iles³⁹, Matthew H Law^{18

40}, Stuart MacGregor¹⁸; Melanoma GWAS Consortium; Jonathan Beesley¹⁷, Michelle R Jones⁴¹, Jonathan Tyrer⁴², Stacey J Winham⁴³; Ovarian Cancer Association Consortium (OCAC); Alison P Klein^{44

45}, Gloria Petersen⁴³, Donghui Li⁴⁶, Brian M Wolpin⁴⁷; Pancreatic Cancer Case-Control Consortium (PANC4); Pancreatic Cancer Cohort Consortium (PanScan); Rosalind A Eeles^{48

49}, Christopher A Haiman⁵⁰, Zsofia Kote-Jarai^{48

49}, Fredrick R Schumacher^{51

52}; PRACTICAL consortium; CRUK; BPC3; CAPS; PEGASUS; Paul Brennan²⁹, Stephen J Chanock⁶, Valerie Gaborieau²⁹, Mark P Purdue⁶; Renal Cancer GWAS Consortium; Paul Pharoah⁹, Rayjean J Hung³⁸, Laufey T Amundadottir⁶, Peter Kraft^{7

8}, Bogdan Pasaniuc^{2

53

54}, Sara Lindström^{1

15}

Affiliations

¹ Department of Epidemiology, University of Washington, Seattle, WA, USA.
² Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
³ Department of Mathematics, Indian Institute of Technology Hyderabad, Kandi, Telangana, India.
⁴ Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA.
⁵ Medical Research Council Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
⁶ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
⁷ Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁸ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁹ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
¹⁰ Biostatistics Unit, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
¹¹ Cyprus School of Molecular Medicine, Nicosia, Cyprus.
¹² Department of Molecular Medicine, Faculty of Medicine, Université Laval and Centre de recherche du CHU de Québec-Université Laval, Québec, QC, Canada.
¹³ Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.
¹⁴ Department of Epidemiology and Biostatistics, University of California at San Francisco, San Francisco, CA, USA.
¹⁵ Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
¹⁶ Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
¹⁷ Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
¹⁸ Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
¹⁹ Center for Human Genetics, University Hospital of Marburg, Marburg, Germany.
²⁰ College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi, UAE.
²¹ Comprehensive Clinical Trials Unit, University College London, London, UK.
²² Department of Visceral, Transplant, Thoracic, and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany.
²³ Department of Epidemiology and Population Health, Stanford University, Palo Alto, CA, USA.
²⁴ Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
²⁵ Department of Laboratory Medicine and Pathology, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Rochester, MN, USA.
²⁶ Department of Radiation Sciences, Umeå University, Umeå, Sweden.
²⁷ Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²⁸ International Agency for Research on Cancer, World Health Organization, Lyon, France.
²⁹ National Institute for Health Research (NIHR) Bristol Biomedical Research Centre, University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol, Bristol, UK.
³⁰ Bristol Dental School, University of Bristol, Bristol, UK.
³¹ Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
³² UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
³³ Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
³⁴ UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA.
³⁵ Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX, USA.
³⁶ Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
³⁷ Genetic Epidemiology and Functional Genomics of Multifactorial Diseases Team, Institut National de la Santé et de la Recherche Médicale (INSERM), UMRS-1124, Université Paris Descartes, Paris, France.
³⁸ Prosserman Centre for Population Health Research, Lunenfeld-Tanenbuaum Research Institute, Sinai Health System, Toronto, ON, Canada.
³⁹ Leeds Institute for Data Analytics, University of Leeds, Leeds, UK.
⁴⁰ School of Biomedical Sciences, Faculty of Health, and Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, QLD, Australia.
⁴¹ Center for Bioinformatics and Functional Genomics, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
⁴² Department of Oncology, University of Cambridge, Cambridge, UK.
⁴³ Department of Health Science Research, Mayo Clinic, Rochester, MN, USA.
⁴⁴ Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA.
⁴⁵ Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins School of Medicine, Baltimore, MD, USA.
⁴⁶ Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁴⁷ Department of Medical Oncology, Dana Farber Harvard Cancer Center, Boston, MA, USA.
⁴⁸ Oncogenetics Team, Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
⁴⁹ Cancer Genetics Unit, Royal Marsden NHS Foundation Trust, London, UK.
⁵⁰ Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA.
⁵¹ Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA.
⁵² Seidman Cancer Center, University Hospitals, Cleveland, OH, USA.
⁵³ Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁵⁴ Department of Computational Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.

PMID: 34355204
PMCID: PMC8336922
DOI: 10.1016/j.xhgg.2021.100041

Large-scale cross-cancer fine-mapping of the 5p15.33 region reveals multiple independent signals

Hongjie Chen et al. HGG Adv. 2021.

. 2021 Jul 8;2(3):100041.

doi: 10.1016/j.xhgg.2021.100041. Epub 2021 Jun 12.

Authors

Affiliations

¹ Department of Epidemiology, University of Washington, Seattle, WA, USA.
² Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
³ Department of Mathematics, Indian Institute of Technology Hyderabad, Kandi, Telangana, India.
⁴ Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA.
⁵ Medical Research Council Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
⁶ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
⁷ Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁸ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁹ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
¹⁰ Biostatistics Unit, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
¹¹ Cyprus School of Molecular Medicine, Nicosia, Cyprus.
¹² Department of Molecular Medicine, Faculty of Medicine, Université Laval and Centre de recherche du CHU de Québec-Université Laval, Québec, QC, Canada.
¹³ Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.
¹⁴ Department of Epidemiology and Biostatistics, University of California at San Francisco, San Francisco, CA, USA.
¹⁵ Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
¹⁶ Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
¹⁷ Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
¹⁸ Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
¹⁹ Center for Human Genetics, University Hospital of Marburg, Marburg, Germany.
²⁰ College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi, UAE.
²¹ Comprehensive Clinical Trials Unit, University College London, London, UK.
²² Department of Visceral, Transplant, Thoracic, and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany.
²³ Department of Epidemiology and Population Health, Stanford University, Palo Alto, CA, USA.
²⁴ Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
²⁵ Department of Laboratory Medicine and Pathology, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Rochester, MN, USA.
²⁶ Department of Radiation Sciences, Umeå University, Umeå, Sweden.
²⁷ Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²⁸ International Agency for Research on Cancer, World Health Organization, Lyon, France.
²⁹ National Institute for Health Research (NIHR) Bristol Biomedical Research Centre, University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol, Bristol, UK.
³⁰ Bristol Dental School, University of Bristol, Bristol, UK.
³¹ Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
³² UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
³³ Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
³⁴ UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA.
³⁵ Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX, USA.
³⁶ Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
³⁷ Genetic Epidemiology and Functional Genomics of Multifactorial Diseases Team, Institut National de la Santé et de la Recherche Médicale (INSERM), UMRS-1124, Université Paris Descartes, Paris, France.
³⁸ Prosserman Centre for Population Health Research, Lunenfeld-Tanenbuaum Research Institute, Sinai Health System, Toronto, ON, Canada.
³⁹ Leeds Institute for Data Analytics, University of Leeds, Leeds, UK.
⁴⁰ School of Biomedical Sciences, Faculty of Health, and Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, QLD, Australia.
⁴¹ Center for Bioinformatics and Functional Genomics, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
⁴² Department of Oncology, University of Cambridge, Cambridge, UK.
⁴³ Department of Health Science Research, Mayo Clinic, Rochester, MN, USA.
⁴⁴ Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA.
⁴⁵ Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins School of Medicine, Baltimore, MD, USA.
⁴⁶ Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁴⁷ Department of Medical Oncology, Dana Farber Harvard Cancer Center, Boston, MA, USA.
⁴⁸ Oncogenetics Team, Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
⁴⁹ Cancer Genetics Unit, Royal Marsden NHS Foundation Trust, London, UK.
⁵⁰ Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA.
⁵¹ Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA.
⁵² Seidman Cancer Center, University Hospitals, Cleveland, OH, USA.
⁵³ Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁵⁴ Department of Computational Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.

PMID: 34355204
PMCID: PMC8336922
DOI: 10.1016/j.xhgg.2021.100041

Abstract

Genome-wide association studies (GWASs) have identified thousands of cancer risk loci revealing many risk regions shared across multiple cancers. Characterizing the cross-cancer shared genetic basis can increase our understanding of global mechanisms of cancer development. In this study, we collected GWAS summary statistics based on up to 375,468 cancer cases and 530,521 controls for fourteen types of cancer, including breast (overall, estrogen receptor [ER]-positive, and ER-negative), colorectal, endometrial, esophageal, glioma, head/neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancer, to characterize the shared genetic basis of cancer risk. We identified thirteen pairs of cancers with statistically significant local genetic correlations across eight distinct genomic regions. Specifically, the 5p15.33 region, harboring the TERT and CLPTM1L genes, showed statistically significant local genetic correlations for multiple cancer pairs. We conducted a cross-cancer fine-mapping of the 5p15.33 region based on eight cancers that showed genome-wide significant associations in this region (ER-negative breast, colorectal, glioma, lung, melanoma, ovarian, pancreatic, and prostate cancer). We used an iterative analysis pipeline implementing a subset-based meta-analysis approach based on cancer-specific conditional analyses and identified ten independent cross-cancer associations within this region. For each signal, we conducted cross-cancer fine-mapping to prioritize the most plausible causal variants. Our findings provide a more in-depth understanding of the shared inherited basis across human cancers and expand our knowledge of the 5p15.33 region in carcinogenesis.

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Conflict of interest statement

B.M.W. has received research grants from Celgene and Eli Lilly and has consulting relationship with BioLineRx, Celgene, and Grail. R.A.E. has received speaker honoraria from the GU-ASCO meeting (January 2016), RMH FR meeting (November 2017, supported by Janssen), University of Chicago invited talk (May 2018), and ESMO (September 2019, supported by Bayer & Ipsen) and served as member of external expert committee at the Prostate Dx Advisory Panel (June 2020). All other authors declare no competing interests.

Figures

**Figure 1**
Analytical pipeline for the study Regions with significant pairwise local genetic correlation were first identified by ρHESS. For regions harboring disproportionally high shared heritability across cancers, joint test of ASSET two-sided meta-analysis and COJO conditional analysis was then repeatedly conducted to identify independent signals, until no variant reached genome-wide significance (p < 5 × 10⁻⁸) in two-sided ASSET meta-analysis. For each signal, GWAS summary statistics conditional on other signals of selected cancer were used in multi-trait fine-mapping to estimate the posterior probability of being causal.

**Figure 2**
Pairwise local genetic correlation between selected cancer types at chromosome 5p15.33 (982,252–2,132,442 bp) Cancer pairs with statistically significant (p value < 0.05/1,703 = 2.94 × 10⁻⁵) local genetic correlation are annotated with an asterisk.

**Figure 3**
Categorizing 14 cancer types into three tiers based on their p value distribution at 5p15.33 Pattern A cancers (A) have one single peak by the *TERT* gene; pattern B cancers (B) have a broader signal at the *CLPTM1L* gene as well as a signal by the *TERT* gene; pattern C cancers (C) have no genome-wide significant association in this region. Genome-wide significant levels at p value = 5 × 10⁻⁸ are marked with red dashed line in (A)–(C). Distribution of Z scores at the 5p15.33 region from the GWAS results of ER-negative breast, glioma, and prostate cancer (D). Only variants with p < 0.05 for both cancers are included. While the associations for ER-negative breast cancer and glioma overlap, the SNP associations with ER-negative breast cancer and prostate, as well as glioma and prostate, are in opposite directions.

**Figure 4**
Distribution of two-sided subset-based meta-analysis p values across eight cancer types at the 5p15.33 region Index variants of ten independent candidate signals, identified by the iterative COJO-ASSET analysis, are annotated and marked in red.

**Figure 5**
Correlation matrix showing the pairwise linkage disequilibrium (LD) between 10 candidate signals, identified using an iterative COJO-ASSET analysis LD was calculated based on the European ancestry populations in 1000 Genomes (1000G) Project.

**Figure 6**
Open chromatin in different cancer types Genomic location of tissue-specific open chromatin narrow peaks, which were used as functional prior in the fine-mapping analysis.

See this image and copyright information in PMC

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Large-scale cross-cancer fine-mapping of the 5p15.33 region reveals multiple independent signals

Affiliations

Large-scale cross-cancer fine-mapping of the 5p15.33 region reveals multiple independent signals

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Grants and funding

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