Association of the rs1346044 Polymorphism of the Werner Syndrome Gene RECQL2 with Increased Risk and Premature Onset of Breast Cancer.

Karin Zins,Barbara Frech,Martin Schreiber,Dietmar Abraham,Eva Taubenschuss,Christian Schneeberger

doi:10.3390/ijms161226192

Abstract

Like other RECQ helicases, WRN/RECQL2 plays a crucial role in DNA replication and the maintenance of genome stability. Inactivating mutations in RECQL2 lead to Werner syndrome, a rare autosomal disease associated with premature aging and an increased susceptibility to multiple cancer types. We analyzed the association of two coding single-nucleotide polymorphisms in WRN, Cys1367Arg (rs1346044), and Arg834Cys (rs3087425), with the risk, age at onset, and clinical subclasses of breast cancer in a hospital-based case-control study of an Austrian population of 272 breast cancer patients and 254 controls. Here we report that the rare homozygous CC genotype of rs1346044 was associated with an approximately two-fold elevated breast cancer risk. Moreover, patients with the CC genotype exhibited a significantly increased risk of developing breast cancer under the age of 55 in both recessive and log-additive genetic models. CC patients developed breast cancer at a mean age of 55.2 ± 13.3 years and TT patients at 60.2 ± 14.7 years. Consistently, the risk of breast cancer was increased in pre-menopausal patients in the recessive model. These findings suggest that the CC genotype of WRN rs1346044 may contribute to an increased risk and a premature onset of breast cancer.

Highlights

Breast cancer is the most common cancer of women and the exploration of its causes and the biological complexity of this disease is an issue of public health importance [1,2]
Taking into account that the integrity of the genome is compromised in almost all cancers, it has been speculated that factors contributing to genetic stability such as the RECQL2 gene product might play a role in cancer, including breast cancer [3]
Two single nucleotide polymorphisms (SNPs) in RECQL2 were investigated in a hospital-based case-control study

Summary

Introduction

Breast cancer is the most common cancer of women and the exploration of its causes and the biological complexity of this disease is an issue of public health importance [1,2]. Taking into account that the integrity of the genome is compromised in almost all cancers, it has been speculated that factors contributing to genetic stability such as the RECQL2 gene product might play a role in cancer, including breast cancer [3]. The primary function of RECQL2 may be to repair DNA double-strand breaks by homologous recombination, which is essential to maintain genome integrity [8]. RECQL2 has been proposed to function as a “caretaker” of the genome, whose dysfunction is associated both with defective DNA repair and aging- and cancer-related phenotypes [9]. WS is characterized by genetic instability and the premature onset of disorders related to aging, such as graying and loss of hair, osteoporosis, atherosclerosis, diabetes mellitus, ocular cataracts, and cancer [8,11,12,13]. The rare single nucleotide polymorphism (SNP) Arg834Cys within the helicase domain of RECQL2, was shown to be associated with a reduced WRN helicase activity, while two common SNPs of RECQL2, Leu1074Phe, and Cys1367Arg, exhibited essentially wild-type-level helicase and exonuclease activities [17]

Results

Discussion

Conclusion