Pleiotropy-guided transcriptome imputation from normal and tumor tissues identifies candidate susceptibility genes for breast and ovarian cancer

Siddhartha P Kar^#^{1

2}, Daniel P C Considine^#³, Jonathan P Tyrer⁴, Jasmine T Plummer^{5

6}, Stephanie Chen^{5

6}, Felipe S Dezem^{5

6}, Alvaro N Barbeira⁷, Padma S Rajagopal⁸, Will T Rosenow⁹, Fernando Moreno¹⁰, Clara Bodelon¹¹, Jenny Chang-Claude^{12

13}, Georgia Chenevix-Trench¹⁴, Anna deFazio^{15

16}, Thilo Dörk¹⁷, Arif B Ekici^{18

19}, Ailith Ewing^{20

21}, George Fountzilas²², Ellen L Goode²³, Mikael Hartman^{24

25}, Florian Heitz^{26

27}, Peter Hillemanns²⁸, Estrid Høgdall^{29

30}, Claus K Høgdall³¹, Tomasz Huzarski^{32

33}, Allan Jensen³⁴, Beth Y Karlan³⁵, Elza Khusnutdinova^{36

37}, Lambertus A Kiemeney³⁸, Susanne K Kjaer^{29

39}, Rüdiger Klapdor²⁸, Martin Köbel⁴⁰, Jingmei Li^{24

41}, Clemens Liebrich⁴², Taymaa May⁴³, Håkan Olsson⁴⁴, Jennifer B Permuth⁴⁵, Paolo Peterlongo⁴⁶, Paolo Radice⁴⁷, Susan J Ramus^{48

49}, Marjorie J Riggan⁵⁰, Harvey A Risch⁵¹, Emmanouil Saloustros⁵², Jacques Simard⁵³, Lukasz M Szafron⁵⁴, Linda Titus⁵⁵, Cheryl L Thompson⁵⁶, Robert A Vierkant⁵⁷, Stacey J Winham⁵⁸, Wei Zheng⁵⁹, Jennifer A Doherty⁶⁰, Andrew Berchuck⁶¹, Kate Lawrenson^{5

62}, Hae Kyung Im⁷, Ani W Manichaikul^{9

63}, Paul D P Pharoah^{3

4}, Simon A Gayther⁵, Joellen M Schildkraut⁶⁴

Affiliations

¹ Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
² Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
³ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁴ Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
⁵ Center for Bioinformatics and Functional Genomics, Department of Biomedical Science, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
⁶ Department of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, CA, USA.
⁷ Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, IL, USA.
⁸ Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL, USA.
⁹ Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
¹⁰ Department of Oncology, Hospital Clínico San Carlos, Madrid, Spain.
¹¹ Divison of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
¹² Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹³ Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹⁴ Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
¹⁵ Centre for Cancer Research, The Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW, Australia.
¹⁶ Department of Gynaecological Oncology, Westmead Hospital, Sydney, NSW, Australia.
¹⁷ Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
¹⁸ Institute of Human Genetics, University Hospital Erlangen, Erlangen, Germany.
¹⁹ Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen, Erlangen, Germany.
²⁰ MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
²¹ Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
²² Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.
²³ Department of Quantitative Health Sciences, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA.
²⁴ Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System, Singapore, Singapore.
²⁵ Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore.
²⁶ Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte/Evang., Essen, Germany.
²⁷ Department of Gynecology, Center for Oncologic Surgery, Charité Campus Virchow-Klinikum, Berlin, Germany.
²⁸ Department of Gynecology and Obstetrics, Hannover Medical School, Hannover, Germany.
²⁹ Department of Virus, Lifestyle, and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark.
³⁰ Molecular Unit, Department of Pathology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark.
³¹ The Juliane Marie Centre, Department of Gynecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
³² Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.
³³ Department of Genetics and Pathology, University of Zielona Góra, Zielona Góra, Poland.
³⁴ Department of Lifestyle, Reproduction, and Cancer, Danish Cancer Society Research Center, Copenhagen, Denmark.
³⁵ David Geffen School of Medicine, Department of Obstetrics and Gynecology, University of California at Los Angeles, Los Angeles, CA, USA.
³⁶ Institute of Biochemistry and Genetics, Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa, Russia.
³⁷ Department of Genetics and Fundamental Medicine, Bashkir State University, Ufa, Russia.
³⁸ Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
³⁹ Department of Gynaecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
⁴⁰ Department of Pathology and Laboratory Medicine, University of Calgary, Foothills Medical Center, Calgary, AB, Canada.
⁴¹ Genome Institute of Singapore, Human Genetics, Singapore, Singapore.
⁴² Department of Obstetrics and Gynecology, Klinikum Wolfsburg, Wolfsburg, Germany.
⁴³ Division of Gynecologic Oncology, University Health Network, Princess Margaret Hospital, Toronto, ON, Canada.
⁴⁴ Division of Oncology, Department of Clinical Sciences, Lund University, Lund, Sweden.
⁴⁵ Departments of Cancer Epidemiology and Gastrointestinal Oncology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
⁴⁶ Genome Diagnostics Program, IFOM-The FIRC Institute of Molecular Oncology, Milan, Italy.
⁴⁷ Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy.
⁴⁸ School of Women's and Children's Health, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.
⁴⁹ Adult Cancer Program, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.
⁵⁰ Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC, USA.
⁵¹ Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA.
⁵² Department of Oncology, University Hospital of Larissa, Larissa, Greece.
⁵³ Genomics Center, Centre Hospitalier Universitaire de Québec - Université Laval Research Center, Québec City, QC, Canada.
⁵⁴ Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland.
⁵⁵ Muskie School of Public Service, University of Southern Maine, Portland, ME, USA.
⁵⁶ Department of Nutrition, Case Western Reserve University, Cleveland, OH, USA.
⁵⁷ Department of Quantitative Health Sciences, Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, MN, USA.
⁵⁸ Department of Quantitative Health Sciences, Division of Computational Biology, Mayo Clinic, Rochester, MN, USA.
⁵⁹ Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
⁶⁰ Huntsman Cancer Institute, Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA.
⁶¹ Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC, USA.
⁶² Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
⁶³ Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA.
⁶⁴ Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA.

^# Contributed equally.

PMID: 34317694
PMCID: PMC8312632
DOI: 10.1016/j.xhgg.2021.100042

Pleiotropy-guided transcriptome imputation from normal and tumor tissues identifies candidate susceptibility genes for breast and ovarian cancer

Siddhartha P Kar et al. HGG Adv. 2021.

. 2021 Jul 8;2(3):100042.

doi: 10.1016/j.xhgg.2021.100042. Epub 2021 Jun 16.

Authors

Affiliations

¹ Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
² Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
³ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁴ Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
⁵ Center for Bioinformatics and Functional Genomics, Department of Biomedical Science, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
⁶ Department of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, CA, USA.
⁷ Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, IL, USA.
⁸ Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL, USA.
⁹ Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
¹⁰ Department of Oncology, Hospital Clínico San Carlos, Madrid, Spain.
¹¹ Divison of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
¹² Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹³ Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹⁴ Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
¹⁵ Centre for Cancer Research, The Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW, Australia.
¹⁶ Department of Gynaecological Oncology, Westmead Hospital, Sydney, NSW, Australia.
¹⁷ Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
¹⁸ Institute of Human Genetics, University Hospital Erlangen, Erlangen, Germany.
¹⁹ Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen, Erlangen, Germany.
²⁰ MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
²¹ Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
²² Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.
²³ Department of Quantitative Health Sciences, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA.
²⁴ Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System, Singapore, Singapore.
²⁵ Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore.
²⁶ Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte/Evang., Essen, Germany.
²⁷ Department of Gynecology, Center for Oncologic Surgery, Charité Campus Virchow-Klinikum, Berlin, Germany.
²⁸ Department of Gynecology and Obstetrics, Hannover Medical School, Hannover, Germany.
²⁹ Department of Virus, Lifestyle, and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark.
³⁰ Molecular Unit, Department of Pathology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark.
³¹ The Juliane Marie Centre, Department of Gynecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
³² Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.
³³ Department of Genetics and Pathology, University of Zielona Góra, Zielona Góra, Poland.
³⁴ Department of Lifestyle, Reproduction, and Cancer, Danish Cancer Society Research Center, Copenhagen, Denmark.
³⁵ David Geffen School of Medicine, Department of Obstetrics and Gynecology, University of California at Los Angeles, Los Angeles, CA, USA.
³⁶ Institute of Biochemistry and Genetics, Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa, Russia.
³⁷ Department of Genetics and Fundamental Medicine, Bashkir State University, Ufa, Russia.
³⁸ Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
³⁹ Department of Gynaecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
⁴⁰ Department of Pathology and Laboratory Medicine, University of Calgary, Foothills Medical Center, Calgary, AB, Canada.
⁴¹ Genome Institute of Singapore, Human Genetics, Singapore, Singapore.
⁴² Department of Obstetrics and Gynecology, Klinikum Wolfsburg, Wolfsburg, Germany.
⁴³ Division of Gynecologic Oncology, University Health Network, Princess Margaret Hospital, Toronto, ON, Canada.
⁴⁴ Division of Oncology, Department of Clinical Sciences, Lund University, Lund, Sweden.
⁴⁵ Departments of Cancer Epidemiology and Gastrointestinal Oncology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
⁴⁶ Genome Diagnostics Program, IFOM-The FIRC Institute of Molecular Oncology, Milan, Italy.
⁴⁷ Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy.
⁴⁸ School of Women's and Children's Health, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.
⁴⁹ Adult Cancer Program, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.
⁵⁰ Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC, USA.
⁵¹ Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA.
⁵² Department of Oncology, University Hospital of Larissa, Larissa, Greece.
⁵³ Genomics Center, Centre Hospitalier Universitaire de Québec - Université Laval Research Center, Québec City, QC, Canada.
⁵⁴ Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland.
⁵⁵ Muskie School of Public Service, University of Southern Maine, Portland, ME, USA.
⁵⁶ Department of Nutrition, Case Western Reserve University, Cleveland, OH, USA.
⁵⁷ Department of Quantitative Health Sciences, Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, MN, USA.
⁵⁸ Department of Quantitative Health Sciences, Division of Computational Biology, Mayo Clinic, Rochester, MN, USA.
⁵⁹ Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
⁶⁰ Huntsman Cancer Institute, Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA.
⁶¹ Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC, USA.
⁶² Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
⁶³ Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA.
⁶⁴ Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA.

^# Contributed equally.

PMID: 34317694
PMCID: PMC8312632
DOI: 10.1016/j.xhgg.2021.100042

Abstract

Familial, sequencing, and genome-wide association studies (GWASs) and genetic correlation analyses have progressively unraveled the shared or pleiotropic germline genetics of breast and ovarian cancer. In this study, we aimed to leverage this shared germline genetics to improve the power of transcriptome-wide association studies (TWASs) to identify candidate breast cancer and ovarian cancer susceptibility genes. We built gene expression prediction models using the PrediXcan method in 681 breast and 295 ovarian tumors from The Cancer Genome Atlas and 211 breast and 99 ovarian normal tissue samples from the Genotype-Tissue Expression project and integrated these with GWAS meta-analysis data from the Breast Cancer Association Consortium (122,977 cases/105,974 controls) and the Ovarian Cancer Association Consortium (22,406 cases/40,941 controls). The integration was achieved through application of a pleiotropy-guided conditional/conjunction false discovery rate (FDR) approach in the setting of a TWASs. This identified 14 candidate breast cancer susceptibility genes spanning 11 genomic regions and 8 candidate ovarian cancer susceptibility genes spanning 5 genomic regions at conjunction FDR < 0.05 that were >1 Mb away from known breast and/or ovarian cancer susceptibility loci. We also identified 38 candidate breast cancer susceptibility genes and 17 candidate ovarian cancer susceptibility genes at conjunction FDR < 0.05 at known breast and/or ovarian susceptibility loci. The 22 genes identified by our cross-cancer analysis represent promising candidates that further elucidate the role of the transcriptome in mediating germline breast and ovarian cancer risk.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

Figures

**Figure 1**
Overview of datasets and analyses in this study Flowchart providing an overview of the datasets used and the various steps in the analysis. GTEx, Genotype-Tissue Expression project; TCGA, The Cancer Genome Atlas; GWAS, genome-wide association study; FDR, false discovery rate.

**Figure 2**
True discovery rate of S-PrediXcan associations for each cancer stratified by associations with the other cancer True discovery rate against the negative logarithm (base 10) of the p value for each cancer for subsets of genes based on strength of association with the other cancer. The y axis of each plot is the true discovery rate, which is defined as 1 − conditional FDR (cFDR). For a given ordered analytic combination of datasets (e.g., GTEx normal breast tissue as transcriptome reference panel-breast cancer GWAS-ovarian cancer GWAS, plotted in the upper left corner) we observed that, in general, for progressively smaller S-PrediXcan p values of the second cancer type (indicated by the key “Threshold p” next to each plot), the true discovery rate (y axis) for association with the primary cancer type approached 100% at progressively larger S-PrediXcan p values for the primary cancer type (x axis; negative logarithm [base 10] of the p values). Only p values > 10⁻⁶ are plotted on the x axis. BC, overall breast cancer risk; OC, all invasive ovarian cancer risk.

See this image and copyright information in PMC

References

1. Miki Y., Swensen J., Shattuck-Eidens D., Futreal P.A., Harshman K., Tavtigian S., Liu Q., Cochran C., Bennett L.M., Ding W., et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science. 1994;266:66–71. - PubMed
1. Wooster R., Bignell G., Lancaster J., Swift S., Seal S., Mangion J., Collins N., Gregory S., Gumbs C., Micklem G. Identification of the breast cancer susceptibility gene BRCA2. Nature. 1995;378:789–792. - PubMed
1. Lord C.J., Ashworth A. PARP inhibitors: Synthetic lethality in the clinic. Science. 2017;355:1152–1158. - PMC - PubMed
1. Jiang X., Finucane H.K., Schumacher F.R., Schmit S.L., Tyrer J.P., Han Y., Michailidou K., Lesseur C., Kuchenbaecker K.B., Dennis J., et al. Shared heritability and functional enrichment across six solid cancers. Nat. Commun. 2019;10:431. - PMC - PubMed
1. Lawrenson K., Kar S., McCue K., Kuchenbaeker K., Michailidou K., Tyrer J., Beesley J., Ramus S.J., Li Q., Delgado M.K., et al. GEMO Study Collaborators. EMBRACE. Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON) KConFab Investigators. Australian Ovarian Cancer Study Group Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus. Nat. Commun. 2016;7:12675. - PMC - PubMed

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Pleiotropy-guided transcriptome imputation from normal and tumor tissues identifies candidate susceptibility genes for breast and ovarian cancer

Affiliations

Pleiotropy-guided transcriptome imputation from normal and tumor tissues identifies candidate susceptibility genes for breast and ovarian cancer

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Grants and funding

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Full Text Sources

Miscellaneous