Germline RECQL mutations are associated with breast cancer susceptibility

Cezary Cybulski; Jian Carrot-Zhang; Wojciech Kluźniak; Barbara Rivera; Aniruddh Kashyap; Dominika Wokołorczyk; Sylvie Giroux; Javad Nadaf; Nancy Hamel; Shiyu Zhang; Tomasz Huzarski; Jacek Gronwald; Tomasz Byrski; Marek Szwiec; Anna Jakubowska; Helena Rudnicka; Marcin Lener; Bartłomiej Masojć; Patrica N Tonin; Francois Rousseau; Bohdan Górski; Tadeusz Dębniak; Jacek Majewski; Jan Lubiński; William D Foulkes; Steven A Narod; Mohammad R Akbari

doi:10.1038/ng.3284

Germline RECQL mutations are associated with breast cancer susceptibility

Nat Genet. 2015 Jun;47(6):643-6. doi: 10.1038/ng.3284. Epub 2015 Apr 27.

Authors

Cezary Cybulski¹, Jian Carrot-Zhang², Wojciech Kluźniak¹, Barbara Rivera³, Aniruddh Kashyap¹, Dominika Wokołorczyk¹, Sylvie Giroux⁴, Javad Nadaf⁵, Nancy Hamel⁶, Shiyu Zhang⁷, Tomasz Huzarski¹, Jacek Gronwald¹, Tomasz Byrski¹, Marek Szwiec⁸, Anna Jakubowska¹, Helena Rudnicka¹, Marcin Lener¹, Bartłomiej Masojć¹, Patrica N Tonin⁶, Francois Rousseau⁹, Bohdan Górski¹, Tadeusz Dębniak¹, Jacek Majewski², Jan Lubiński¹, William D Foulkes¹⁰, Steven A Narod¹¹, Mohammad R Akbari¹¹

Affiliations

¹ Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.
² 1] Department of Human Genetics, McGill University, Montréal, Québec, Canada. [2] McGill University and Génome Québec Innovation Centre, Montréal, Québec, Canada.
³ 1] Department of Human Genetics, McGill University, Montréal, Québec, Canada. [2] Department of Medical Genetics, Lady Davis Institute, Jewish General Hospital, Montréal, Québec, Canada.
⁴ Unité de Recherche en Génétique Humaine et Moléculaire, Axe Santé des Populations et Pratiques Optimales en Santé, Centre de Recherche du Centre Hospitalier Universitaire de Québec, Québec, Québec, Canada.
⁵ Department of Human Genetics, McGill University, Montréal, Québec, Canada.
⁶ 1] Department of Human Genetics, McGill University, Montréal, Québec, Canada. [2] Department of Medical Genetics, McGill University, Montréal, Québec, Canada. [3] Research Institute of the McGill University Health Centre, Montréal, Québec, Canada.
⁷ Women's College Research Institute, Women's College Hospital, University of Toronto, Toronto, Ontario, Canada.
⁸ Tadeusz Koszarowski Regional Oncology Center, Opole, Poland.
⁹ 1] Unité de Recherche en Génétique Humaine et Moléculaire, Axe Santé des Populations et Pratiques Optimales en Santé, Centre de Recherche du Centre Hospitalier Universitaire de Québec, Québec, Québec, Canada. [2] Department of Molecular Biology, Medical Biochemistry and Pathology, Faculty of Medicine, Université Laval, Québec, Québec, Canada.
¹⁰ 1] Department of Human Genetics, McGill University, Montréal, Québec, Canada. [2] Department of Medical Genetics, Lady Davis Institute, Jewish General Hospital, Montréal, Québec, Canada. [3] Department of Medical Genetics, McGill University, Montréal, Québec, Canada. [4] Research Institute of the McGill University Health Centre, Montréal, Québec, Canada. [5] Program in Cancer Genetics, Departments of Oncology and Human Genetics, McGill University, Montréal, Québec, Canada.
¹¹ 1] Women's College Research Institute, Women's College Hospital, University of Toronto, Toronto, Ontario, Canada. [2] Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.

PMID: 25915596
DOI: 10.1038/ng.3284

Abstract

Several moderate- and high-risk breast cancer susceptibility genes have been discovered, but more are likely to exist. To discover new breast cancer susceptibility genes, we used 2 populations (from Poland and Quebec, Canada) and applied whole-exome sequencing in a discovery phase (n = 195), followed by validation. We identified rare recurrent RECQL mutations in each population. In Quebec, 7 of 1,013 higher-risk breast cancer cases and 1 of 7,136 newborns carried the c.634C>T (p.Arg215*) variant (P = 0.00004). In Poland, 30 of 13,136 unselected breast cancer cases and 2 of 4,702 controls carried the c.1667_1667+3delAGTA (p.K555delinsMYKLIHYSFR) variant (P = 0.008). RECQL is implicated in resolving stalled DNA replication forks to prevent double-stranded DNA (dsDNA) breaks. This function is related to that of other known breast cancer susceptibility genes, many of which are involved in repairing dsDNA breaks. We conclude that RECQL is a breast cancer susceptibility gene.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Base Sequence
Breast Neoplasms / genetics*
Case-Control Studies
DNA Mutational Analysis
Female
Gene Frequency
Genetic Association Studies
Genetic Predisposition to Disease
Germ-Line Mutation*
Humans
Molecular Sequence Data
Pedigree
RecQ Helicases / genetics*

Substances

RECQL protein, human
RecQ Helicases

Grants and funding

Canadian Institutes of Health Research/Canada