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

• Published in: American journal of human genetics 2023-04, Vol.110 (4), p.648-662
• Main Authors: Cybulski, Cezary, Zamani, Neda, Kluźniak, Wojciech, Milano, Larissa, Wokołorczyk, Dominika, Stempa, Klaudia, Rudnicka, Helena, Zhang, Shiyu, Zadeh, Maryam, Huzarski, Tomasz, Jakubowska, Anna, Dębniak, Tadeusz, Lener, Marcin, Szwiec, Marek, Domagała, Paweł, Samani, Amir Abbas, Narod, Steven, Gronwald, Jacek, Masson, Jean-Yves, Lubiński, Jan, Akbari, Mohammad R.
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - genetics; ATRIP; Biological Specimen Banks; Breast Neoplasms - genetics; Cell Cycle Proteins - genetics; DNA Damage; DNA-Binding Proteins - genetics; Female; hereditary breast cancer; homologous recombination deficiency; Humans; loss of heterozygosity; Poland - epidemiology; Polish population; Replication Protein A - genetics; Replication Protein A - metabolism; UK Biobank; United Kingdom - epidemiology
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2023.03.002

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