Susanna Koivuluoma1, Anna Tervasmäki1, Saila Kauppila2, Robert Winqvist1, Timo Kumpula1, Outi Kuismin3, Jukka Moilanen3, Katri Pylkäs4. 1. Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit and Biocenter Oulu, NordLab Oulu, University of Oulu, Oulu, Finland. 2. Department of Pathology, Oulu University Hospital, University of Oulu, Oulu, Finland. 3. Department of Clinical Genetics, Oulu University Hospital, Medical Research Center Oulu and PEDEGO Research Unit, University of Oulu, Oulu, Finland. 4. Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit and Biocenter Oulu, NordLab Oulu, University of Oulu, Oulu, Finland. Electronic address: katri.pylkas@oulu.fi.
Abstract
BACKGROUND: Breast cancer is strongly influenced by hereditary risk factors. Yet, the known susceptibility genes and genomic loci explain only about half of the familial component of the disease. To identify novel breast cancer predisposing gene defects, here we have performed massive parallel sequencing for Northern Finnish breast cancer cases. METHODS: Ninety-eight breast cancer cases with indication of hereditary disease susceptibility were exome sequenced. Data filtering strategy focused on predictably deleterious rare variants that were still enriched in the sequenced cohort. Findings were confirmed with additional, geographically matched breast cancer cohorts. RESULTS: A recurrent heterozygous splice acceptor variant, c.918-1G>C, in SERPINA3, was identified, and it was significantly enriched both in the hereditary (6/201, 3.0%, p = 0.006, OR 5.1, 95% CI 1.7-14.8) and unselected breast cancer cohort (26/1569, 1.7%, p = 0.009, OR 2.8, 95% CI 1.3-6.2). SERPINA3 c.918-1G>C carriers were also significantly more likely to have a rare tumor subtype, medullary breast cancer, than the non-carriers (4/26, 15.4%, p = 0.000014, OR 42.9, 95% CI 11.7-157.1). CONCLUSION: These findings demonstrate that c.918-1G>C germline variant in SERPINA3 gene, encoding a member of the serine protease inhibitor class, is a novel breast cancer predisposing allele.
BACKGROUND:Breast cancer is strongly influenced by hereditary risk factors. Yet, the known susceptibility genes and genomic loci explain only about half of the familial component of the disease. To identify novel breast cancer predisposing gene defects, here we have performed massive parallel sequencing for Northern Finnish breast cancer cases. METHODS: Ninety-eight breast cancer cases with indication of hereditary disease susceptibility were exome sequenced. Data filtering strategy focused on predictably deleterious rare variants that were still enriched in the sequenced cohort. Findings were confirmed with additional, geographically matched breast cancer cohorts. RESULTS: A recurrent heterozygous splice acceptor variant, c.918-1G>C, in SERPINA3, was identified, and it was significantly enriched both in the hereditary (6/201, 3.0%, p = 0.006, OR 5.1, 95% CI 1.7-14.8) and unselected breast cancer cohort (26/1569, 1.7%, p = 0.009, OR 2.8, 95% CI 1.3-6.2). SERPINA3 c.918-1G>C carriers were also significantly more likely to have a rare tumor subtype, medullary breast cancer, than the non-carriers (4/26, 15.4%, p = 0.000014, OR 42.9, 95% CI 11.7-157.1). CONCLUSION: These findings demonstrate that c.918-1G>C germline variant in SERPINA3 gene, encoding a member of the serine protease inhibitor class, is a novel breast cancer predisposing allele.
Authors: Susanna Koivuluoma; Sandra Vorimo; Tiina M Mattila; Anna Tervasmäki; Timo Kumpula; Outi Kuismin; Robert Winqvist; Jukka Moilanen; Tuomo Mantere; Katri Pylkäs Journal: Fam Cancer Date: 2022-05-20 Impact factor: 2.375