Inherited Variants in BLM and the Risk and Clinical Characteristics of Breast Cancer.

Wojciech Kluźniak,Karina Mordak,Sylwia Morawska,Aniruddh Kashyap,Marcin Lener,Tomasz Huzarski,Paweł Domagała,Steven A Narod,Cezary Cybulski,Małgorzata Stawicka,Bogna Rusak,Katarzyna Gliniewicz,Jan Lubiński,Anna Jakubowska,Marek Szwiec,Magdalena Cechowska,Dominika Wokołorczyk,Jacek Gronwald,Helena Rudnicka,Klaudia Stempa,Mohammad Reza Akbari ,Joanna Jarkiewicz‐Tretyn ,Tadeusz Dȩbniak

doi:10.3390/cancers11101548

Abstract

Bloom Syndrome is a rare recessive disease which includes a susceptibility to various cancers. It is caused by homozygous mutations of the BLM gene. To investigate whether heterozygous carriers of a BLM mutation are predisposed to breast cancer, we sequenced BLM in 617 patients from Polish families with a strong family history of breast cancer. We detected a founder mutation (c.1642C>T, p.Gln548Ter) in 3 of the 617 breast cancer patients (0.49%) who were sequenced. Then, we genotyped 14,804 unselected breast cancer cases and 4698 cancer-free women for the founder mutation. It was identified in 82 of 14,804 (0.55%) unselected cases and in 26 of 4698 (0.55%) controls (OR = 1.0; 95%CI 0.6–1.6). Clinical characteristics of breast cancers in the BLM mutation carriers and non-carriers were similar. Loss of the wild-type BLM allele was not detected in cancers from the BLM mutation carriers. No cancer type was more common in the relatives of mutation carriers compared to relatives of non-carriers. The BLM founder mutation p.Gln548Ter, which in a homozygous state is a cause of Bloom syndrome, does not appear to predispose to breast cancer in a heterozygous state. The finding casts doubt on the designation of BLM as an autosomal dominant breast cancer susceptibility gene.

Highlights

Homozygous mutations of the BLM gene are the cause of a rare recessive genetic disorder, Bloom syndrome, which is characterized by chromosomal instability, immunodeficiency, and a predisposition to different malignancies, including breast cancer [1]
We identified a truncating mutation of the BLM gene in three of 617 women with hereditary breast cancer who underwent full gene sequencing
We reviewed the pedigrees of women who carry the BLM mutation to see if there might be an excess of cancers at any site in first- or second-degree relatives

Summary

Introduction

Homozygous mutations of the BLM gene are the cause of a rare recessive genetic disorder, Bloom syndrome, which is characterized by chromosomal instability, immunodeficiency, and a predisposition to different malignancies, including breast cancer [1]. BLM plays many different functions in maintenance of genomic integrity [4]. It is required for fork stability during unperturbed. BLM plays an important role in homologous recombination DNA repair [6]. It senses DNA damage and recruits other repair proteins to the site of DNA breaks after irradiation in an ATM-dependent manner [7]. BLM is part of the BRCA1 multi-subunit protein complex, referred to as the BRCA1-genome surveillance complex, which includes other DNA damage repair proteins such as MSH2-MSH6 and MLH1, as well as ATM, NBS1, and MRE11 [8]

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Discussion

Conclusion