Analysis of the Polymorphism [gIVS12-6T≫C] in the hMSH2 Gene in Lymphoma and Leukemia

Abstract

Given the importance of mismatch repairing genes in keeping the genetic stability in cells, any alterations in their structure or function could generate instability in the genome and predispose the development of oncogenic processes. hMSH2 is the principal gene involved in the post-replicating DNA mismatch repair system. In this study, exon 13 of the hMSH2 gene was analyzed in different neoplasias, leukemias and lymphomas. The aim of our work was to determine the association between the presence of polymorphisms in this region with the development of alterations in the hematological system. The 227 samples including lymphoma, leukemia and myelodysplasic syndromes, where analyzed by PCR-SSCP followed by automated sequencing. A single nucleotide polymorphism was found in 30 individuals. This polymorphism is a T to C substitution at the -6 intronic splice acceptor site of exon 13 of hMSH2 gene [gIVS12-6T > C]. In the lymphoma group the polymorphism frequency found was 0.09, with statistical significant differences (p < 0.01) when compared to the control group. On the other hand, the frequency of the leukemia group was the same of that of the control group (0.05). These findings agree with previous research results of other investigation groups. The results suggest a probable association of the polymorphism with the development of lymphomas but not with leukemia.

Clinical and biological relevance of single-nucleotide polymorphisms and acquired somatic mutations of the BCL6 first intron in follicular lymphoma

“…In NHL, SNPs of several genes have been previously related to lymphoma susceptibility, such as genes coding for xenobiotic proteins (GSTT1, PON1, Methionine synthase), 26,27 inflammation regulator cytokines (IL1, IL10, TNFa), [28][29][30] mismatch repairing elements (hMSH2), 31 or oncoproteins (H-ras 1). 32 Since BCL6 plays a crucial role during both normal B-cell maturation and lymphomagenesis, it has been hypothesized that constitutional or acquired mutations of putative functional elements may impact on lymphoma predisposition or lymphoma outcome.…”

Analysis of the hMSH2 Gene Variants in Head and Neck Cancer

“…An association between the CC genotype and reduced cancer risk needs to be interpreted cautiously and analyzed in larger patient cohorts because the frequency of the variant homozygotes is low in the population and there are also data in the literature in the reverse direction. The homozygous variant allele has been found to confer a higher risk in two earlier reports on colorectal cancer (Goessl et al, 1997) and ulcerative colitis (Brentnall et al, 1995) and in a recent study on non-Hodgkin lymphoma (Paz-y-Mino et al, 2003). In patients with supraglottic laryngeal cancer, a reduced risk associated with the variant CC genotype was also observed, which, however, did not reach statistical significance.…”

“…We did not observe any significant difference between the allele frequencies in the patients and healthy individuals. In the literature there are two case-control studies on patients with leukemia and colon cancer (Paz-y-Mino et al, 2003;Kim et al, 2004) and one on patients with non-Hodgkin lymphoma (Paz-y-Mino et al, 2002), all of which have failed to find any difference between the allele and genotype frequencies in the patients and the control group. Our data on head and neck cancer are in agreement with these reports.…”

“…MSH2-defective mice display much higher susceptibility to lymphoid tumors (Reitmair et al, 1995), and alterations in this gene have been reported in different cancer types (Goessl et al, 1997;Paz-y-Mino et al, 2003). Inactivation of the hMSH2 gene has also been associated with increased risk of developing head and neck cancer (Cheng et al, 1998).…”

Multiplex SNaPshot Genotyping for Detecting Loss of Heterozygosity in the Mismatch-Repair Genes MLH1 and MSH2 in Microsatellite-Unstable Tumors

“…The role played by these SNPs is not fully clear, although there is evidence to suggest that they contribute to the development of various types of cancer (3)(4)(5)(6)(7), including those of the colorectum (8,9 ) and endometrium (10 ).…”