NBN 657del5 heterozygous mutations and colorectal cancer risk in the Czech Republic

Abstract

The most frequent Nijmegen breakage syndrome (NBS)-causing mutation is a 5-base pair deletion in gene coding for nibrin (NBN 657del5), which results in a non-fully functional protein product and is particularly frequent in Central and Eastern Europe. Recent studies have investigated whether NBN 657del5 carriage may predispose to an increased risk of different types of cancer. The Czech Republic has one of the highest incidences of colorectal cancer in the world as well as high incidence of NBS. To assess whether NBN 657del5 associates with an increased risk of sporadic colorectal cancer, we have screened 771 colorectal cancer patients, 614 controls with negative colonoscopy and 818 healthy blood donors from the Czech Republic. There were no significant differences between the frequencies of heterozygous carriers among the three groups. The present results do not provide any evidence that the exceeding risk of CRC in this population is attributable to the high frequency of heterozygous carriage of the NBN 657del5.

Introduction

Nijmegen breakage syndrome (NBS; MIM 251260) is an autosomal recessive chromosomal instability disorder characterized by microcephaly, growth retardation, immunodeficiency, hypersensitivity to X-irradiation and a marked susceptibility to cancer [1]. The gene mutated in NBS was identified in 1998 as NBS1 (MIM: 602667) [2], but currently NBN is the most common name for it. Nibrin, the product of this gene, is part of the MRE11/RAD50 complex, which is involved in the repair of DNA double strand breaks (DSBs) and in cell cycle checkpoints [3], [4]. Disease-causing NBN mutations impair the cellular DNA damage response and result in chromosomal instability and cell cycle checkpoint defects [5], [6]. This dual gatekeeper/caretaker character of nibrin may explain the complex NBS phenotype, including the very high incidence of lymphomas and other malignant tumors in NBS patients [5], [7].

The most common NBS-causing mutation is a 5-base pair deletion of NBN, 657del5, which results in a truncated and non-fully functional protein. Mutation 657del5 is particularly frequent in Central and Eastern Europe (population frequency 0.6%) [8], but rarely found in other regions [9]. NBS patients are particularly prone to develop malignancies at a young age (especially lymphoma and leukemia) and it has also been observed that relatives of NBS patients show an increased cancer risk [10], [11]. NBS shows many common clinical and molecular features with ataxia–telangiectasia (A–T:MIM: 208900), as well as a pathogenic relationship [12]. Su and Swift [13] demonstrated that heterozygous relatives of A–T probands have a twofold excess of different malignant tumors as compared to non-carriers. Moreover, it has been observed that lymphocytes from carriers of mutated forms of NBN have intermediate sensitivity to ionizing radiations as compared to non-carriers and mutant homozygotes [14].

On the basis of these observations, several studies have been conducted to evaluate if heterozygous carriage of NBN 657del5 predisposes to an increased risk of cancer of any type. Although these studies need further confirmation [9], increased risks of lymphoma/leukemia [15], breast cancer [16] and gastrointestinal lymphoma [17] have been reported.

Colorectal cancer (CRC, MIM: 114500) shows a remarkably high incidence in the Czech Republic, being the third highest in the world and the highest for rectal cancer worldwide [18]. Because a high frequency of NBN 657del5 is observed in the Slavic population, we have hypothesized that at least part of the cases could be attributed to the status of carrier of the mutation. Thus, we have carried out a case–control association study to evaluate whether this deletion can modulate CRC susceptibility in the Czech Republic.