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Pathology of Tumors Associated With Pathogenic Germline Variants in 9 Breast Cancer Susceptibility Genes

Breast Cancer Association Consortium , Mavaddat N 1 , Dorling L 1 , Carvalho S 1 , Allen J 1 , González-Neira A 2 Show all authors , Keeman R 3 , Bolla MK 1 , Dennis J 1 , Wang Q 1 , Ahearn TU 4 , Andrulis IL 5 , Beckmann MW 6 , Behrens S 7 , Benitez J 2 , Bermisheva M 8 , Blomqvist C 9 , Bogdanova NV 10 , Bojesen SE 11 , Briceno I 12 , Brüning T 13 , Camp NJ 14 , Campbell A 15 , Castelao JE 16 , Chang-Claude J 7 , Chanock SJ 4 , Chenevix-Trench G 17 , Christiansen H 10 , Czene K 18 , Dörk T 19 , Eriksson M 18 , Evans DG 20 , Fasching PA 6 , Figueroa JD 21 , Flyger H 22 , Gabrielson M 18 , Gago-Dominguez M 23 , Geisler J 24 , Giles GG 25 , Guénel P 26 , Hadjisavvas A 27 , Hahnen E 28 , Hall P 18 , Hamann U 29 , Hartikainen JM 30 , Hartman M 31 , Hoppe R 32 , Howell A 33 , Jakubowska A 34 , Jung A 7 , Khusnutdinova EK 8 , Kristensen VN 35 , Li J 36 , Lim SH 37 , Lindblom A 38 , Loizidou MA 27 , Lophatananon A 39 , Lubinski J 34 , Madsen MJ 14 , Mannermaa A 30 , Manoochehri M 29 , Margolin S 40 , Mavroudis D 41 , Milne RL 25 , Mohd Taib NA 42 , Morra A 3 , Muir K 39 , Obi N 43 , Osorio A 2 , Park-Simon TW 19 , Peterlongo P 44 , Radice P 45 , Saloustros E 46 , Sawyer EJ 47 , Schmutzler RK 28 , Shah M 48 , Sim X 31 , Southey MC 25 , Thorne H 49 , Tomlinson I 50 , Torres D 29 , Truong T 26 , Yip CH 42 , Spurdle AB 17 , Vreeswijk MPG 51 , Dunning AM 48 , García-Closas M 4 , Pharoah PDP 1 , Kvist A 52 , Muranen TA 53 , Nevanlinna H 53 , Teo SH 42 , Devilee P 51 , Schmidt MK 3 , Easton DF 1

Affiliations 

  • 1 Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, England
  • 2 Human Cancer Genetics Programme, Spanish National Cancer Research Centre, Madrid, Spain
  • 3 Division of Molecular Pathology, the Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands
  • 4 Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland
  • 5 Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada
  • 6 Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
  • 7 Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany
  • 8 Institute of Biochemistry and Genetics, Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa, Russia
  • 9 Department of Oncology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
  • 10 Department of Radiation Oncology, Hannover Medical School, Hannover, Germany
  • 11 Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
  • 12 Medical Faculty, Universidad de La Sabana, Bogota, Colombia
  • 13 Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum, Bochum, Germany
  • 14 Department of Internal Medicine and Huntsman Cancer Institute, University of Utah, Salt Lake City
  • 15 Centre for Genomic and Experimental Medicine, Institute of Genetics & Cancer, University of Edinburgh, Edinburgh, Scotland
  • 16 Oncology and Genetics Unit, Instituto de Investigación Sanitaria Galicia Sur, Xerencia de Xestion Integrada de Vigo-SERGAS, Vigo, Spain
  • 17 Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
  • 18 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
  • 19 Gynaecology Research Unit, Hannover Medical School, Hannover, Germany
  • 20 Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, England
  • 21 Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, Scotland
  • 22 Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
  • 23 Fundación Pública Galega de Medicina Xenómica, Instituto de Investigación Sanitaria de Santiago de Compostela, Complejo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain
  • 24 Department of Oncology, Akershus University Hospital, Lørenskog, Norway
  • 25 Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia
  • 26 Paris-Saclay University, UVSQ, Gustave Roussy, Inserm, CESP, Villejuif, France
  • 27 Department of Cancer Genetics, Therapeutics and Ultrastructural Pathology, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus
  • 28 Center for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
  • 29 Molecular Genetics of Breast Cancer, German Cancer Research Center, Heidelberg, Germany
  • 30 Translational Cancer Research Area, University of Eastern Finland, Kuopio, Finland
  • 31 Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore
  • 32 Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany
  • 33 Division of Cancer Sciences, University of Manchester, Manchester, England
  • 34 Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
  • 35 Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway
  • 36 Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System, Singapore, Singapore
  • 37 Breast Department, KK Women's and Children's Hospital, Singapore, Singapore
  • 38 Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
  • 39 Division of Population Health, Health Services Research and Primary Care, School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, England
  • 40 Department of Oncology, Södersjukhuset, Stockholm, Sweden
  • 41 Department of Medical Oncology, University Hospital of Heraklion, Heraklion, Greece
  • 42 Department of Surgery, Faculty of Medicine University of Malaya, UM Cancer Research Institute, Kuala Lumpur, Malaysia
  • 43 Institute for Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • 44 Genome Diagnostics Program, IFOM-the FIRC Institute of Molecular Oncology, Milan, Italy
  • 45 Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
  • 46 Department of Oncology, University Hospital of Larissa, Larissa, Greece
  • 47 School of Cancer & Pharmaceutical Sciences, Comprehensive Cancer Centre, Guy's Campus, King's College London, London, England
  • 48 Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, England
  • 49 Research Department, Peter MacCallum Cancer Center, Melbourne, Victoria, Australia
  • 50 Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, England
  • 51 Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands
  • 52 Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
  • 53 Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
JAMA Oncol, 2022 Mar 01;8(3):e216744.
PMID: 35084436 DOI: 10.1001/jamaoncol.2021.6744

Abstract

IMPORTANCE: Rare germline genetic variants in several genes are associated with increased breast cancer (BC) risk, but their precise contributions to different disease subtypes are unclear. This information is relevant to guidelines for gene panel testing and risk prediction.

OBJECTIVE: To characterize tumors associated with BC susceptibility genes in large-scale population- or hospital-based studies.

DESIGN, SETTING, AND PARTICIPANTS: The multicenter, international case-control analysis of the BRIDGES study included 42 680 patients and 46 387 control participants, comprising women aged 18 to 79 years who were sampled independently of family history from 38 studies. Studies were conducted between 1991 and 2016. Sequencing and analysis took place between 2016 and 2021.

EXPOSURES: Protein-truncating variants and likely pathogenic missense variants in ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, RAD51D, and TP53.

MAIN OUTCOMES AND MEASURES: The intrinsic-like BC subtypes as defined by estrogen receptor, progesterone receptor, and ERBB2 (formerly known as HER2) status, and tumor grade; morphology; size; stage; lymph node involvement; subtype-specific odds ratios (ORs) for carrying protein-truncating variants and pathogenic missense variants in the 9 BC susceptibility genes.

RESULTS: The mean (SD) ages at interview (control participants) and diagnosis (cases) were 55.1 (11.9) and 55.8 (10.6) years, respectively; all participants were of European or East Asian ethnicity. There was substantial heterogeneity in the distribution of intrinsic subtypes by gene. RAD51C, RAD51D, and BARD1 variants were associated mainly with triple-negative disease (OR, 6.19 [95% CI, 3.17-12.12]; OR, 6.19 [95% CI, 2.99-12.79]; and OR, 10.05 [95% CI, 5.27-19.19], respectively). CHEK2 variants were associated with all subtypes (with ORs ranging from 2.21-3.17) except for triple-negative disease. For ATM variants, the association was strongest for the hormone receptor (HR)+ERBB2- high-grade subtype (OR, 4.99; 95% CI, 3.68-6.76). BRCA1 was associated with increased risk of all subtypes, but the ORs varied widely, being highest for triple-negative disease (OR, 55.32; 95% CI, 40.51-75.55). BRCA2 and PALB2 variants were also associated with triple-negative disease. TP53 variants were most strongly associated with HR+ERBB2+ and HR-ERBB2+ subtypes. Tumors occurring in pathogenic variant carriers were of higher grade. For most genes and subtypes, a decline in ORs was observed with increasing age. Together, the 9 genes were associated with 27.3% of all triple-negative tumors in women 40 years or younger.

CONCLUSIONS AND RELEVANCE: The results of this case-control study suggest that variants in the 9 BC risk genes differ substantially in their associated pathology but are generally associated with triple-negative and/or high-grade disease. Knowing the age and tumor subtype distributions associated with individual BC genes can potentially aid guidelines for gene panel testing, risk prediction, and variant classification and guide targeted screening strategies.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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