Germline RECQL mutations are associated with breast cancer susceptibility.
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.
Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.
Cezary
C
Cybulski
1] Department of Human Genetics, McGill University, Montréal, Québec, Canada. [2] McGill University and Génome Québec Innovation Centre, Montréal, Québec, Canada.
Jian
J
Carrot-Zhang
Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.
Wojciech
W
Kluźniak
1] Department of Human Genetics, McGill University, Montréal, Québec, Canada. [2] Department of Medical Genetics, Lady Davis Institute, Jewish General Hospital, Montréal, Québec, Canada.
Barbara
B
Rivera
Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.
Aniruddh
A
Kashyap
Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.
Dominika
D
Wokołorczyk
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.
Sylvie
S
Giroux
Department of Human Genetics, McGill University, Montréal, Québec, Canada.
Javad
J
Nadaf
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.
Nancy
N
Hamel
Women's College Research Institute, Women's College Hospital, University of Toronto, Toronto, Ontario, Canada.
Shiyu
S
Zhang
Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.
Tomasz
T
Huzarski
Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.
Jacek
J
Gronwald
Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.
Tomasz
T
Byrski
Tadeusz Koszarowski Regional Oncology Center, Opole, Poland.
Marek
M
Szwiec
Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.
Anna
A
Jakubowska
Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.
Helena
H
Rudnicka
Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.
Marcin
M
Lener
Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.
Bartłomiej
B
Masojć
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.
Patrica N
PN
Tonin
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.
Francois
F
Rousseau
Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.
Bohdan
B
Górski
Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.
Tadeusz
T
Dębniak
1] Department of Human Genetics, McGill University, Montréal, Québec, Canada. [2] McGill University and Génome Québec Innovation Centre, Montréal, Québec, Canada.
Jacek
J
Majewski
Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.
Jan
J
Lubiński
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.
William D
0000000174274651
WD
Foulkes
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.
Steven A
SA
Narod
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.
Mohammad R
MR
Akbari
D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics*; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D008969:Molecular Sequence Data; D010375:Pedigree; D053484:RecQ Helicases / Q000235:genetics*
C506725:RECQL protein, human; D053484:RecQ Helicases