Advertisement

Structural, functional analysis and association of MSH6 rs1800932, rs1042821 polymorphisms with clinical outcome in North Indian lung cancer patients treated with platinum-based doublet chemotherapy

      Abstract

      Background

      In this study, we have done structural and functional analysis of rs1800932 rs1042821 polymorphisms and tried to estimate any association of these polymorphisms with clinical outcomes in north Indian lung cancer patients.

      Methods

      Genotyping of 500 lung cancer patients was completed utilizing PCR-RFLP (Polymerase chain reaction- Restriction fragment length polymorphism). MedCalc statistical software was used to calculate adjusted and unadjusted odds ratios. Various computational tools like SIFT PROVEAN are used for functional analysis. Structural analysis was completed via MODELLER and CHIMERA.

      Results

      In our study, patients suffering from small cell lung cancer (SCLC) and harboring heterozygous genotype (AG) for MSH6 (rs1800932) polymorphism have reported a significant increase in median survival time (MST) (20.6 vs. 7.6 months, p = 0.03). Furthermore, for MSH6 rs1042821 polymorphism, patients undergoing docetaxel and carbo/cisplatin combination chemotherapeutic regimen and carrying heterogeneous genotype (CT) reported a significant increase in MST (16.6 vs.8.36 months, p = 0.03) and a corresponding decrease in hazard ratio 0.42 (95% CI= 0.18–1.03). Structural and Functional analysis of rs1042821 polymorphism revealed that it is present in the non-coding region of MSH6 protein and is significantly associated with increased overall survival.

      Conclusions

      These results suggest that MSH6 rs1800932 rs1042821 polymorphisms are involved in increasing the overall survival of lung cancer patients, further confirmed by computational analysis.

      Key Indexing Terms

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to The American Journal of the Medical Sciences
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Zhou G.
        Tobacco, air pollution, environmental carcinogenesis, and thoughts on conquering strategies of lung cancer.
        Cancer Biol Med. 2019; 16: 700
        • Jemal A.
        • Siegel R.
        • Xu J.
        • et al.
        Cancer statistics, 2010.
        CA Cancer J Clin. 2010; 60: 277-300
        • Shields P.G.
        • CC Harris
        Cancer risk and low-penetrance susceptibility genes in gene–environment interactions.
        J Clin Oncol. 2000; 18: 2309-2315
        • Lawania S.
        • Singh N.
        • Behera D.
        • et al.
        XPG polymorphisms and their association with lung cancer susceptibility, overall survival and response in North Indian patients treated with platinum-based doublet chemotherapy.
        Future Oncol. 2019; 15: 151-165
        • Landi S.
        • Gemignani F.
        • Canzian F.
        • et al.
        DNA repair and cell cycle control genes and the risk of young-onset lung cancer.
        Cancer Res. 2006; 66: 11062-11069
        • Li L.Y.
        • Guan Y.D.
        • Chen X.S.
        • Yang J.M.
        • et al.
        DNA Repair Pathways in Cancer Therapy and Resistance.
        Front Pharmacol. 2021; 11: 2520
        • Goellner Eva M.
        Chromatin remodeling and mismatch repair: access and excision.
        DNA Repair (Amst). 2020; 85102733
        • Liu W.
        • Dong X.
        • Mai M.
        • Taniguchi K.
        • et al.
        Mutations in AXIN2 cause colorectal cancer with defective mismatch repair by activating β-catenin/TCF signalling.
        Nature Genet. 2000; 26: 146-147
        • Wang L.
        • Cunningham J.M.
        • Winters J.L.
        • et al.
        BRAF mutations in colon cancer are not likely attributable to defective DNA mismatch repair.
        Cancer Res. 2003; 63: 5209-5212
        • Edelmann W.
        • Yang K.
        • Umar A.
        • et al.
        Mutation in the mismatch repair gene Msh6 causes cancer susceptibility.
        Cell. 1997; 91: 467-477
        • Santos L.S.
        • Silva S.N.
        • Gil O.M.
        • et al.
        Mismatch repair single nucleotide polymorphisms and thyroid cancer susceptibility.
        Oncol Lett. 2018; 15: 6715-6726
        • Liu J.
        • Zheng B.
        • Li Y.
        • et al.
        Genetic polymorphisms of DNA repair pathways in sporadic colorectal carcinogenesis.
        J Cancer. 2019; 10: 1417
        • Curtin K.
        • Samowitz W.S.
        • Wolff R.K.
        • et al.
        MSH6 G39E polymorphism and CpG island methylator phenotype in colon cancer.
        Mol Carcinog. 2009; 48 (Published in cooperation with the University of Texas MD Anderson Cancer Center): 989-994
        • Smith T.R.
        • Levine E.A.
        • Freimanis R.I.
        • et al.
        Polygenic model of DNA repair genetic polymorphisms in human breast cancer risk.
        Carcinogenesis. 2008; 29: 2132-2138
        • Singh A.
        • Singh N.
        • Behera D.
        • et al.
        Role of polymorphic XRCC6 (Ku70)/XRCC7 (DNA-PKcs) genes towards susceptibility and prognosis of lung cancer patients undergoing platinum based doublet chemotherapy.
        Mol Biol Rep. 2018; 45: 253-261
        • Walia H.K.
        • Singh N.
        • Sharma S.
        Association of NQO1Pro187Ser polymorphism with clinical outcomes and survival of lung cancer patients treated with platinum chemotherapy.
        Pers Med. 2021; 18: 333-346
        • Hasnain M.J.U.
        • Shoaib M.
        • Qadri S.
        • et al.
        Computational analysis of functional single nucleotide polymorphisms associated with SLC26A4 gene.
        PLoS One. 2020; 15e0225368
        • Ibrahim A.M.
        • Albakry A.M.
        • Alla N.W.
        • et al.
        Computational Analysis of Single Nucleotide Polymorphism (SNPs) in Human MYOC Gene.
        Int J Genet Eng. 2020; 8: 1-6
        • Pray L.
        DNA replication and causes of mutation.
        Nature Educ. 2008; 1: 214
        • Aleskandarany M.
        • Caracappa D.
        • Nolan C.C.
        • et al.
        DNA damage response markers are differentially expressed in BRCA-mutated breast cancers.
        Breast Cancer Res Treat. 2015; 150: 81-90
        • Vymetalkova V.
        • Pardini B.
        • Rosa F.
        • et al.
        Variations in mismatch repair genes and colorectal cancer risk and clinical outcome.
        Mutagenesis. 2014; 29: 259-265
        • Dong X.
        • Jiao L.
        • Li Y.
        • et al.
        Significant associations of mismatch repair gene polymorphisms with clinical outcome of pancreatic cancer.
        J Clin Oncol. 2009; 27: 1592
        • Mazaheri M.
        • Karimian M.
        • Behjati M.
        • et al.
        Association analysis of rs1049255 and rs4673 transitions in p22phox gene with coronary artery disease: a case-control study and a computational analysis.
        Ir J Med Sci. 2017; 186: 921-928
        • Stec I.
        • Nagl S.B.
        • van Ommen G.J.B.
        • den Dunnen J.T.
        The PWWP domain: a potential protein–protein interaction domain in nuclear proteins influencing differentiation?.
        FEBS Lett. 2000; 473: 1-5