Analysis of the Oxidative Damage Repair GenesNUDT1,OGG1, andMUTYHin Patients from Mismatch Repair Proficient HNPCC Families (MSS-HNPCC)

Abstract

Purpose: Several studies have described molecular differences between microsatellite stable hereditary nonpolyposis colorectal cancer (MSS-HNPCC) and microsatellite unstable Lynch syndrome tumors (MSI-HNPCC). These differences highlight the possibility that other instability forms could explain cancer susceptibility in this group of families.The base excision repair (BER) pathway is the major DNA repair pathway for oxidative DNA damage. A defect in this pathway can result in DNA transversion mutations and a subsequent increased cancer risk. Mutations in MUTYH have been associated with increased colorectal cancer (CRC) risk while no association has been described for OGG1 or NUDT1.Experimental Design: We performed mutational screening of the three genes involved in defense against oxidative DNA damage in a set of 42 MSS-HNPCC families.Results: Eight rare variants and 5 frequent variants were found in MSS-HNPCC patients. All variants were previously described by other authors except variant c.285C>T in OGG1. Segregation studies were done and in silico programs were used to estimate the level of amino acid conservation, protein damage prediction, and possible splicing alterations. Variants OGG1 c.137G>A; MUTYH c.1187G>A were detected in Amsterdam I families and cosegregate with cancer. Analysis of OGG1 c.137G>A transcripts showed an inactivation of the splicing donor of exon 1. Conclusions: Two rare variants (OGG1 c.137G>A; MUTYH c.1187G>A) and one common polymorphism (NUDT1 c.426C>T) were associated with CRC risk. We show that the BER pathway can play a significant role in a number of MSS-HNPCC colorectal cancers. More studies could be of interest in order to gain further understanding of yet unexplained CRC susceptibility cases.

BRCA2 gene: a candidate for clinical testing in familial colorectal cancer type X

“…All variants are named according to the Human Genome Variation Society (HGVS) and to the reference transcript NM_000059 3. Variants were classified according to their pathogenicity risk.…”

Germline variation in the oxidative DNA repair genesNUDT1andOGG1is not associated with hereditary colorectal cancer or polyposis

“…The only variant identified in the OGG1 gene (NM_016821.2) with a population MAF < 1% was c.137G>A (p.R46Q) (rs104893751; MAF GnomAD = 0.22% (600/275,590)). It had been previously shown that this variant might affect splicing causing the insertion of intron 1 (Garre et al., ; Kohno et al., ), having been associated with CRC predisposition when occurring in the germline (Garre et al., ).…”

Inhibition of β2-Microglobulin/Hemochromatosis Enhances Radiation Sensitivity by Induction of Iron Overload in Prostate Cancer Cells

“…Next, we sought to determine changes in stress response proteins in β2-M knockdown prostate cancer cells. Using C4-2B control and β2-M knockdown prostate cancer cells (KD β2-M ) we tested the levels of stress response proteins such as heat shock protein 27 (HSP27) 17 and heat shock protein 70 (HSP70) 18 and DNA repair enzymes such as N-methylpurine-DNA glycosylase (MPG) 19 and nudix (nucleoside diphosphate linked moiety X)-type motif 1 (NUDT1) 20. Interestingly, the stress response and heat shock proteins were downregulated in β2-M knockdown clones KD β2-M (Figure 2D).…”