Exome sequencing identifies a recurrent variant in SERPINA3 associating with hereditary susceptibility to breast cancer.

Susanna Koivuluoma,Robert Winqvist,Timo Kumpula,Jukka Moilanen,Anna Tervasmäki,Outi Kuismin,Saila Kauppila,Katri Pylkäs

doi:10.1016/j.ejca.2020.10.033

Abstract

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. 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. 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). 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.

Highlights

Since the identification of the major breast cancer susceptibility genes, BRCA1 and BRCA2, extensive efforts have been taken to find additional inherited risk factors [1]
Koivuluoma et al / European Journal of Cancer 143 (2021) 46e51. 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. a 2020 The Author(s)
Even in the era of massive parallel sequencing, the analysis has often been limited to DNA damage response (DDR) pathway and has resulted in the identification of rare breast cancer predisposing alleles e.g. in RECQL, FANCM and ERCC3 genes [3e6]

Summary

Introduction

Since the identification of the major breast cancer susceptibility genes, BRCA1 and BRCA2, extensive efforts have been taken to find additional inherited risk factors [1]. The moderate-to-high-risk susceptibility genes are all characterized by rare, mostly loss-offunction pathogenic variants conferring breast cancer predisposition Despite these findings, so far identified genetic susceptibility factors explain only about half of the familial component of breast cancer [7], making the identification of additional inherited risk factors and understanding their contribution to disease onset imperative. Identified genetic susceptibility factors explain only about half of the familial component of breast cancer [7], making the identification of additional inherited risk factors and understanding their contribution to disease onset imperative For this purpose, here we have performed exome sequencing for 98 Northern Finnish breast cancer patients with indication of hereditary disease susceptibility. SERPINA3 c.918-1G>C carriers were significantly more likely to have a rare tumor subtype, medullary breast cancer, than the non-carriers (4/26, 15.4%, p Z 0.000014, OR 42.9, 95% CI 11.7e157.1)

Methods

Results

Conclusion