Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
NBN 657del5 heterozygous mutations and colorectal cancer risk in the Czech Republic
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.
Section snippets
Study population
The study population consisted of 771 patients with sporadic CRC, 614 hospital-based healthy controls with negative colonoscopy results for malignancy or idiopathic bowel diseases (Control Group I) and 818 healthy blood donors (Control Group II). Eligibility criteria for participation in the study included (i) age 29 years or more, (ii) Czech Caucasian origin, and (iii) consent to provide biological samples for genetic analysis. The investigated group of individuals was not collected
Results
The present study employed a simple PCR assays followed by direct sequencing of the positive results (Supplementary Fig. IB) to screen for and verify the presence of the NBN 657del5 in a population of CRC cases (750 affected individuals) and in two groups of controls (607 from Control Group I and 804 from Control Group II) (Table 1). In total, three heterozygous carriers of the NBN 657del5 were identified among the CRC cases screened, with a carrier frequency of 0.40% (95% CI: 0.14–1.17). Four
Discussion
In the present study, we investigated whether a specific mutation in NBN confers susceptibility to sporadic CRC, using a group of individuals affected by this cancer and two different control groups from the Czech Republic.
Three of the CRC patients were heterozygote carriers of the 657del5, while in the control groups five carriers had been found (four in the Control Group I and one in the Control Group II). The present results do not show any evidence for an increased risk of CRC in
Conflict of interest statement
All authors have no conflict of interests to declare.
Acknowledgments
Authors would like to thank Thomas O’Hearn II for his excellent technical support.
Funding: This study was supported by the grants: Czech Science Foundation, no.: GACR 310/07/1430 and GACR 305/09/P194, Internal Grant Agency of the Czech Ministry of Health, no.: IGA 8563-5/2005, and MSM0021620808.
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The c.657del5 variant in the NBN gene predisposes to pancreatic cancer
2016, GeneCitation Excerpt :The high frequencies of c.657del5 identified in PDAC patients in our and Lener et al. studies indicate that NBN is another DNA repair gene involved in PDAC-susceptibility. In comparison with our current study identifying 2.07% of c.657del5 carriers in unselected PDAC patients, earlier analyses found considerably lower frequencies of the mutation in Czech unselected BC (0.3%), colorectal cancer (0.3%), and lymphoma patients (0.8%) (Lhota et al., 2016; Pardini et al., 2009; Soucek et al., 2003). Our results and Lener et al. study (Lener et al., 2016) suggest that c.657del5 may be a novel PDAC-susceptibility allele significantly increasing the risk of PDAC development [combined OR calculated from this and Lener et al. studies comprising 624 pancreatic cancer patients (13 carriers of c.657del5) and 4915 controls (24 carriers) is 4.33; 95%CI 2.2–8.56; p < 0.001].
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