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Aggregation tests identify new gene associations with breast cancer in populations with diverse ancestry.
Mueller, Stefanie H; Lai, Alvina G; Valkovskaya, Maria; Michailidou, Kyriaki; Bolla, Manjeet K; Wang, Qin; Dennis, Joe; Lush, Michael; Abu-Ful, Zomoruda; Ahearn, Thomas U; Andrulis, Irene L; Anton-Culver, Hoda; Antonenkova, Natalia N; Arndt, Volker; Aronson, Kristan J; Augustinsson, Annelie; Baert, Thais; Freeman, Laura E Beane; Beckmann, Matthias W; Behrens, Sabine; Benitez, Javier; Bermisheva, Marina; Blomqvist, Carl; Bogdanova, Natalia V; Bojesen, Stig E; Bonanni, Bernardo; Brenner, Hermann; Brucker, Sara Y; Buys, Saundra S; Castelao, Jose E; Chan, Tsun L; Chang-Claude, Jenny; Chanock, Stephen J; Choi, Ji-Yeob; Chung, Wendy K; Colonna, Sarah V; Cornelissen, Sten; Couch, Fergus J; Czene, Kamila; Daly, Mary B; Devilee, Peter; Dörk, Thilo; Dossus, Laure; Dwek, Miriam; Eccles, Diana M; Ekici, Arif B; Eliassen, A Heather; Engel, Christoph; Evans, D Gareth; Fasching, Peter A.
Affiliation
  • Mueller SH; Institute of Health Informatics, University College London, London, UK.
  • Lai AG; Institute of Health Informatics, University College London, London, UK.
  • Valkovskaya M; Division of Psychiatry, University College London, London, UK.
  • Michailidou K; Biostatistics Unit, The Cyprus Institute of Neurology and Genetics, 2371, Nicosia, Cyprus.
  • Bolla MK; Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, 2371, Nicosia, Cyprus.
  • Wang Q; Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK.
  • Dennis J; Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK.
  • Lush M; Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK.
  • Abu-Ful Z; Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK.
  • Ahearn TU; Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK.
  • Andrulis IL; Clalit National Cancer Control Center, Carmel Medical Center and Technion Faculty of Medicine, 35254, Haifa, Israel.
  • Anton-Culver H; Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20850, USA.
  • Antonenkova NN; Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, M5G 1X5, Canada.
  • Arndt V; Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada.
  • Aronson KJ; Department of Medicine, Genetic Epidemiology Research Institute, University of California Irvine, Irvine, CA, 92617, USA.
  • Augustinsson A; N.N. Alexandrov Research Institute of Oncology and Medical Radiology, 223040, Minsk, Belarus.
  • Baert T; Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
  • Freeman LEB; Department of Public Health Sciences, and Cancer Research Institute, Queen's University, Kingston, ON, K7L 3N6, Canada.
  • Beckmann MW; Department of Cancer Epidemiology, Clinical Sciences, Lund University, 222 42, Lund, Sweden.
  • Behrens S; Leuven Multidisciplinary Breast Center, Department of Oncology, Leuven Cancer Institute, University Hospitals Leuven, 3000, Louvain, Belgium.
  • Benitez J; Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20850, USA.
  • Bermisheva M; Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg (FAU), 91054, Erlangen, Germany.
  • Blomqvist C; Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
  • Bogdanova NV; Biomedical Network On Rare Diseases (CIBERER), 28029, Madrid, Spain.
  • Bojesen SE; Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), 28029, Madrid, Spain.
  • Bonanni B; Institute of Biochemistry and Genetics, Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa, 450054, Russia.
  • Brenner H; Department of Oncology, Helsinki University Hospital, University of Helsinki, 00290, Helsinki, Finland.
  • Brucker SY; Department of Oncology, Örebro University Hospital, 70185, Örebro, Sweden.
  • Buys SS; N.N. Alexandrov Research Institute of Oncology and Medical Radiology, 223040, Minsk, Belarus.
  • Castelao JE; Department of Radiation Oncology, Hannover Medical School, 30625, Hannover, Germany.
  • Chan TL; Gynaecology Research Unit, Hannover Medical School, 30625, Hannover, Germany.
  • Chang-Claude J; Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, 2730, Herlev, Denmark.
  • Chanock SJ; Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, 2730, Herlev, Denmark.
  • Choi JY; Faculty of Health and Medical Sciences, University of Copenhagen, 2200, Copenhagen, Denmark.
  • Chung WK; Division of Cancer Prevention and Genetics, IEO, European Institute of Oncology IRCCS, 20141, Milan, Italy.
  • Colonna SV; Division of Preventive Oncology, German Cancer Research Center (DKFZ), National Center for Tumor Diseases (NCT), 69120, Heidelberg, Germany.
  • Cornelissen S; Department of Gynecology and Obstetrics, University of Tübingen, 72076, Tübingen, Germany.
  • Couch FJ; Department of Medicine, Huntsman Cancer Institute, Salt Lake City, UT, 84112, USA.
  • Czene K; Oncology and Genetics Unit, Instituto de Investigación Sanitaria Galicia Sur (IISGS), Xerencia de Xestion Integrada de Vigo-SERGAS, 36312, Vigo, Spain.
  • Daly MB; Hong Kong Hereditary Breast Cancer Family Registry, Hong Kong, China.
  • Devilee P; Department of Molecular Pathology, Hong Kong Sanatorium and Hospital, Hong Kong, China.
  • Dörk T; Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
  • Dossus L; Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
  • Dwek M; Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20850, USA.
  • Eccles DM; Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, 03080, Korea.
  • Ekici AB; Cancer Research Institute, Seoul National University, Seoul, 03080, Korea.
  • Eliassen AH; Institute of Health Policy and Management, Seoul National University Medical Research Center, Seoul, 03080, Korea.
  • Engel C; Departments of Pediatrics and Medicine, Columbia University, New York, NY, 10032, USA.
  • Fasching PA; Department of Medicine, Huntsman Cancer Institute, Salt Lake City, UT, 84112, USA.
Genome Med ; 15(1): 7, 2023 01 26.
Article de En | MEDLINE | ID: mdl-36703164
ABSTRACT

BACKGROUND:

Low-frequency variants play an important role in breast cancer (BC) susceptibility. Gene-based methods can increase power by combining multiple variants in the same gene and help identify target genes.

METHODS:

We evaluated the potential of gene-based aggregation in the Breast Cancer Association Consortium cohorts including 83,471 cases and 59,199 controls. Low-frequency variants were aggregated for individual genes' coding and regulatory regions. Association results in European ancestry samples were compared to single-marker association results in the same cohort. Gene-based associations were also combined in meta-analysis across individuals with European, Asian, African, and Latin American and Hispanic ancestry.

RESULTS:

In European ancestry samples, 14 genes were significantly associated (q < 0.05) with BC. Of those, two genes, FMNL3 (P = 6.11 × 10-6) and AC058822.1 (P = 1.47 × 10-4), represent new associations. High FMNL3 expression has previously been linked to poor prognosis in several other cancers. Meta-analysis of samples with diverse ancestry discovered further associations including established candidate genes ESR1 and CBLB. Furthermore, literature review and database query found further support for a biologically plausible link with cancer for genes CBLB, FMNL3, FGFR2, LSP1, MAP3K1, and SRGAP2C.

CONCLUSIONS:

Using extended gene-based aggregation tests including coding and regulatory variation, we report identification of plausible target genes for previously identified single-marker associations with BC as well as the discovery of novel genes implicated in BC development. Including multi ancestral cohorts in this study enabled the identification of otherwise missed disease associations as ESR1 (P = 1.31 × 10-5), demonstrating the importance of diversifying study cohorts.
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Texte intégral: 1 Collection: 01-internacional Base de données: MEDLINE Sujet principal: Tumeurs du sein Type d'étude: Risk_factors_studies / Systematic_reviews Limites: Female / Humans Langue: En Journal: Genome Med Année: 2023 Type de document: Article Pays d'affiliation: Royaume-Uni
Texte intégral
Ajouter à My VHL
Imprimer
XML
PubMed Links
Recherche sur Google

Texte intégral: 1 Collection: 01-internacional Base de données: MEDLINE Sujet principal: Tumeurs du sein Type d'étude: Risk_factors_studies / Systematic_reviews Limites: Female / Humans Langue: En Journal: Genome Med Année: 2023 Type de document: Article Pays d'affiliation: Royaume-Uni