Variants in ATRIP are associated with breast cancer susceptibility in the Polish population and UK Biobank

Cezary Cybulski; Neda Zamani; Wojciech Kluźniak; Larissa Milano; Dominika Wokołorczyk; Klaudia Stempa; Helena Rudnicka; Shiyu Zhang; Maryam Zadeh; Tomasz Huzarski; Anna Jakubowska; Tadeusz Dębniak; Marcin Lener; Marek Szwiec; Paweł Domagała; Amir Abbas Samani; Steven Narod; Jacek Gronwald; Jean-Yves Masson; Jan Lubiński; Mohammad R Akbari

doi:10.1016/j.ajhg.2023.03.002

Variants in ATRIP are associated with breast cancer susceptibility in the Polish population and UK Biobank

Am J Hum Genet. 2023 Apr 6;110(4):648-662. doi: 10.1016/j.ajhg.2023.03.002. Epub 2023 Mar 27.

Authors

Cezary Cybulski¹, Neda Zamani², Wojciech Kluźniak¹, Larissa Milano³, Dominika Wokołorczyk¹, Klaudia Stempa¹, Helena Rudnicka¹, Shiyu Zhang⁴, Maryam Zadeh², Tomasz Huzarski⁵, Anna Jakubowska⁶, Tadeusz Dębniak¹, Marcin Lener¹, Marek Szwiec⁷, Paweł Domagała⁸, Amir Abbas Samani⁹, Steven Narod¹⁰, Jacek Gronwald¹, Jean-Yves Masson³, Jan Lubiński¹, Mohammad R Akbari¹¹

Affiliations

¹ International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University in Szczecin, Szczecin, Poland.
² Women's College Research Institute, Women's College Hospital, University of Toronto, Toronto, ON, Canada; Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
³ Genome Stability Laboratory, CHU de Québec Research Center, Oncology Axis; Department of Molecular Biology, Medical Biochemistry and Pathology; Laval University Cancer Research Center, Québec City, QC, Canada.
⁴ Women's College Research Institute, Women's College Hospital, University of Toronto, Toronto, ON, Canada.
⁵ Department of Clinical Genetics and Pathology, University of Zielona Góra, Zielona Góra, Poland.
⁶ International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University in Szczecin, Szczecin, Poland; Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University in Szczecin, Szczecin, Poland.
⁷ Department of Surgery and Oncology, University of Zielona Góra, Zielona Góra, Poland.
⁸ Department of Pathology, Pomeranian Medical University in Szczecin, Szczecin, Poland.
⁹ Department of Laboratory Medicine and Pathology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada; Humber River Hospital, University of Toronto, Toronto, ON, Canada.
¹⁰ Women's College Research Institute, Women's College Hospital, University of Toronto, Toronto, ON, Canada; Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, ON, Canada; Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada.
¹¹ Women's College Research Institute, Women's College Hospital, University of Toronto, Toronto, ON, Canada; Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, ON, Canada; Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada. Electronic address: mohammad.akbari@utoronto.ca.

Abstract

Several breast cancer susceptibility genes have been discovered, but more are likely to exist. To identify additional breast cancer susceptibility genes, we used the founder population of Poland and performed whole-exome sequencing on 510 women with familial breast cancer and 308 control subjects. We identified a rare mutation in ATRIP (GenBank: NM_130384.3: c.1152_1155del [p.Gly385Ter]) in two women with breast cancer. At the validation phase, we found this variant in 42/16,085 unselected Polish breast cancer-affected individuals and in 11/9,285 control subjects (OR = 2.14, 95% CI = 1.13-4.28, p = 0.02). By analyzing the sequence data of the UK Biobank study participants (450,000 individuals), we identified ATRIP loss-of-function variants among 13/15,643 breast cancer-affected individuals versus 40/157,943 control subjects (OR = 3.28, 95% CI = 1.76-6.14, p < 0.001). Immunohistochemistry and functional studies showed the ATRIP c.1152_1155del variant allele is weakly expressed compared to the wild-type allele, and truncated ATRIP fails to perform its normal function to prevent replicative stress. We showed that tumors of women with breast cancer who have a germline ATRIP mutation have loss of heterozygosity at the site of ATRIP mutation and genomic homologous recombination deficiency. ATRIP is a critical partner of ATR that binds to RPA coating single-stranded DNA at sites of stalled DNA replication forks. Proper activation of ATR-ATRIP elicits a DNA damage checkpoint crucial in regulating cellular responses to DNA replication stress. Based on our observations, we conclude ATRIP is a breast cancer susceptibility gene candidate linking DNA replication stress to breast cancer.

Keywords: ATRIP; Polish population; UK Biobank; hereditary breast cancer; homologous recombination deficiency; loss of heterozygosity.

Publication types

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

MeSH terms

Adaptor Proteins, Signal Transducing* / genetics
Biological Specimen Banks
Breast Neoplasms* / genetics
Cell Cycle Proteins / genetics
DNA Damage
DNA-Binding Proteins* / genetics
Female
Humans
Poland / epidemiology
Replication Protein A / genetics
Replication Protein A / metabolism
United Kingdom / epidemiology

Substances

Adaptor Proteins, Signal Transducing
ATRIP protein, human
Cell Cycle Proteins
DNA-Binding Proteins
Replication Protein A

Abstract

Publication types

MeSH terms

Substances

Grants and funding