NBN Gene Polymorphisms and Cancer Susceptibility: A Systemic Review

Abstract

The relationship between DNA repair failure and cancer is well established as in the case of rare, high penetrant genes in high cancer risk families. Beside this, in the last two decades, several studies have investigated a possible association between low penetrant polymorphic variants in genes devoted to DNA repair pathways and risk for developing cancer. This relationship would be also supported by the observation that DNA repair processes may be modulated by sequence variants in DNA repair genes, leading to susceptibility to environmental carcinogens. In this framework, the aim of this review is to provide the reader with the state of the art on the association between common genetic variants and cancer risk, limiting the attention to single nucleotide polymorphisms (SNPs) of the NBN gene and providing the various odd ratios (ORs). In this respect, the NBN protein, together with MRE11 and RAD50, is part of the MRN complex which is a central player in the very early steps of sensing and processing of DNA double-strand breaks (DSBs), in telomere maintenance, in cell cycle control, and in genomic integrity in general. So far, many papers were devoted to ascertain possible association between common synonymous and non-synonymous NBN gene polymorphisms and increased cancer risk. However, the results still remain inconsistent and inconclusive also in meta-analysis studies for the most investigated E185Q NBN miscoding variant.

Genetics of Short Stature

“…Pericentrin ( PCNT) encodes a centrosomal protein in the microtubule network and the mutations cause MOPD II but also Seckel syndrome [66]. Moreover, clinical overlaps may occur between Seckel syndrome [56, 66], MOPD II [56, 66–68], Fanconi anemia ( FANC ) [56], LIG4 syndrome ( LIG4 ) [56, 69], and Nijimegen breakage syndrome ( NBS1 ) [56, 70–71]. Mutations in BLM cause Bloom syndrome which manifests as sun-sensitive skin and increased risk of malignancies, including leukemia, lymphoma, adeno-, and squamous cell carcinoma [72–73].…”

The germline variants in DNA repair genes in pediatric medulloblastoma: a challenge for current therapeutic strategies

“…This gene encodes the protein involved in DNA double-strand break repair, cell cycle checkpoint activation, telomere maintenance and meiotic recombination suggesting that molecular variants disrupting its function may lead to genome instability and carcinogenesis [28]. Furthermore, inactivation of proteins like RAD50 required for the homologous recombination machinery leads to defects in the nervous system development indicating that components of this system can play crucial role in development and progression of various neuro-oncological diseases [29].…”

Homologous Recombination Repair Polymorphisms, Cancer Susceptibility and Treatment Outcome

“…Rare NBN mutations were associated with chromosomal instability and increased susceptibility to cancer [15] and are presented in Table 2. The most common is a deletion of five nucleotides (675del5), common in Slavic populations [16], that leads to protein truncation [17].…”

“…Leads to protein truncation [17] Besides rare mutations, several common SNPs have been described in both the coding region and the regulatory regions of NBN gene (Table 1). By far the most frequently investigated polymorphism is NBN rs1805794 (p.Glu185Gln) that leads to amino acid change in BRCA1 Cterminal domain [6] and could therefore affect protein-protein interactions with other HRR proteins.…”