김재길 (Broad Institute of Harvard and MIT)

한빛사논문

조회1,838

Broad Institute of Harvard and MIT

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Nat. Genet., Published online 21 August 2017 | doi:10.1038/ng.3934 A mutational signature reveals alterations underlying deficient homologous recombination repair in breast cancer

Paz Polak^1-3,21 , Jaegil Kim^1,21, Lior Z Braunstein^1,4,21, Rosa Karlic⁵ , Nicholas J Haradhavala^1,2, Grace Tiao¹, Daniel Rosebrock¹, Dimitri Livitz¹ , Kirsten Kubler^1-3, Kent W Mouw^3,6, Atanas Kamburov^1-3, Yosef E Maruvka^1-3, Ignaty Leshchiner¹, Eric S Lander^1,7,8, Todd R Golub^1,3,9, Aviad Zick¹⁰, Alexandre Orthwein¹¹, Michael S Lawrence^1-3, Rajbir N Batra^12-14, Carlos Caldas^12-14, Daniel A Haber^2,3, Peter W Laird¹⁵ , Hui Shen¹⁵, Leif W Ellisen^2,3, Alan D D’Andrea^16,17, Stephen J Chanock¹⁸, William D Foulkes^11,19,21 & Gad Getz^1-3,20,21¹Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. ²Massachusetts General Hospital Center for Cancer Research, Charlestown, Massachusetts, USA. ³Harvard Medical School, Boston, Massachusetts, USA.⁴Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA. ⁵Bioinformatics Group, Division of Molecular Biology, Department of Biology, Faculty of Science, University of Zagreb, Zagreb, Croatia. ⁶Department of Radiation Oncology, Brigham & Women’s Hospital and Dana-Farber Cancer Institute, Boston, Massachusetts, USA. ⁷Department of Biology, MIT, Cambridge, Massachusetts, USA. ⁸Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA. ⁹Departments of Medical Oncology, Pathology, and Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. ¹⁰Department of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. ¹¹Department of Oncology, McGill University, Montreal, Quebec, Canada. ¹²Cancer Research UK Cambridge Institute, University of Cambridge Li Ka Shing Centre, Cambridge, UK. ¹³Cancer Research UK Cambridge Centre, Cambridge, UK. ¹⁴Department of Oncology, University of Cambridge Hutchison?MRC Research Centre, Cambridge Biomedical Campus, Cambridge, UK. ¹⁵Van Andel Research Institute, Grand Rapids, Michigan, USA. ¹⁶Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. ¹⁷Ludwig Center at Harvard, Harvard Medical School, Boston, Massachusetts, USA. ¹⁸Division of Cancer Epidemiology and Genetics, US National Cancer Institute, Bethesda, Maryland, USA. ¹⁹Department of Human Genetics, Lady Davis Institute for Medical Research and Research Institute McGill University Health Centre, McGill University, Montreal, Quebec, Canada. ²⁰Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA. ²¹These authors contributed equally to this work.

Correspondence to: Gad Getz

Abstract

Biallelic inactivation of BRCA1 or BRCA2 is associated with a pattern of genome-wide mutations known as signature 3. By analyzing ~1,000 breast cancer samples, we confirmed this association and established that germline nonsense and frameshift variants in PALB2, but not in ATM or CHEK2, can also give rise to the same signature. We were able to accurately classify missense BRCA1 or BRCA2 variants known to impair homologous recombination (HR) on the basis of this signature. Finally, we show that epigenetic silencing of RAD51C and BRCA1 by promoter methylation is strongly associated with signature 3 and, in our data set, was highly enriched in basal-like breast cancers in young individuals of African descent.

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형식Research article
게재일2017년 08월 (BRIC 등록일 2017-08-28)
연구진국외 연구진
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