MLH1 -93G>A and I219V polymorphisms are susceptible to increased risk of sporadic colorectal cancer in a Turkish population

Year 2017, Volume: 47 Issue: 2, 63 - 67, 18.10.2017

Ezgi Öztaş Umay Çilingir Ahmet Akyüz Hakan T. Yanar Gül Özhan

https://doi.org/10.5152/IstanbulJPharm.2017.0010

Abstract

Colorectal cancer (CRC) comprises
approximately 10% of all cancers and is a major cause of cancer-related
morbidity and mortality despite current diagnostic and treatment improvements.
DNA damage and altered DNA replication through the deregulation of related
genes cause genomic instability in sporadic CRC. DNA repair is very complex;
many factors play a role to ensure that the restoration of errors occurs during
the transfer of genetic material. MutL homolog 1 (MLH1) is one of the vital DNA
repair genes responsible for genomic stability. Together with environmental
factors, the genetic background may be associated with CRC development; thus,
genetic polymorphisms are considered as risk factors. The present prospective
case–control study aimed to determine the association between 93G>A and
I219V polymorphisms of MLH1 and CRC susceptibility in a Turkish population. The
genotyping of 158 patients and 164 age- and sex-matched controls was performed
by polymerase chain reaction-restriction fragment length polymorphism. Two
variants, 93G>A and I219V, were associated with an increased risk of CRC.
Individuals with A allele of 93G>A had an approximately 2-fold risk (OR:
1.92, 95% CI: 1.22–3.04; p<0.01) and those with G allele of I219V had an
approximately 3-fold risk (OR: 2.82, 95% CI: 1.76–4.52; p<0.01) of
developing CRC. Our results provide novel information for understanding the
influence of MLH1 on CRC risk in the Turkish population; however, further
studies with a larger number of participants are required.

Keywords

MLH1 polymorphism, colorectal cancer, PCR-RFLP

References

• • Abbas T, Keaton MA, Dutta A (2013). Genomic instability in cancer. Cold Spring Harb Perspect Biol 5: a012914. [CrossRef] • Allan JM, Shorto J, Adlard J, Bury J, Coggins R, George R, Katory M, Quirke P, Richman S, Scott D, Scott K, Seymour M, Travis LB, Worrillow LJ, Bishop DT, Cox A (2008). MLH1− 93G> A promoter polymorphism and risk of mismatch repair deficient colorectal cancer. Int J Cancer 123: 2456-2459. [CrossRef] • Anderson GR (2001). Genomic instability in cancer. Curr Sci 81: 501-507. [CrossRef] • Aykan F (2000). Kolorektal Kanserler. In: Topuz E, Aydiner A and Karadeniz AN (eds.). Klinik Onkoloji, İstanbul Üniversitesi, Onkoloji Enstitüsü Yayınları, İstanbul, pp 90-95. • Berndt SI, Platz EA, Fallin MD, Thuita LW, Hoffman SC, Helzlsouer KJ (2007). Mismatch repair polymorphisms and the risk of colorectal cancer. Int J Cancer 120: 1548-1554. [CrossRef] • Burmester JK, Suarez BK, Lin JH, Jin CH, Miller RD, Zhang KQ, Salzman SA, Reding DJ, Catalona WJ (2004). Analysis of candidate genes for prostate cancer. Hum Hered 57: 172-178. [CrossRef] • Campbell PT, Curtin K, Ulrich CM, Samowitz WS, Bigler J, Velicer CM, Slattery ML (2009). Mismatch repair polymorphisms and risk of colon cancer, tumour microsatellite instability and interactions with lifestyle factors. Gut 58: 661-667. [CrossRef] • Curtin NJ (2012). DNA repair dysregulation from cancer driver to therapeutic target. Nat Rev Cancer 12: 801-817. [CrossRef] • Fan Y, Wang W, Zhu M, Zhou J, Peng J, Xu L, Hua Z, Gao X, Wang Y (2007). Analysis of hMLH1 missense mutations in East Asian patients with suspected hereditary nonpolyposis colorectal cancer. Clin Cancer Res 13: 7515-7521. [CrossRef] • Fredriksson H, Ikonen T, Autio V, Matikainen MP, Helin HJ, Tammela TLJ, Koivisto PA, Schleutker J (2006). Identification of germline MLH1 alterations in familial prostate cancer. Eur J Cancer 42: 2802-2806. [CrossRef] • Haggar FA and Boushey RP (2009). Colorectal cancer epidemiology: incidence, mortality, survival, and risk factors. Clin Colon Rectal Surg 22: 191-197. [CrossRef] • Huxley RR, Ansary-Moghaddam A, Clifton P, Czernichow S, Parr CL, Woodward M (2009). The impact of dietary and lifestyle risk factors on risk of colorectal cancer: a quantitative overview of the epidemiological evidence. Int J Cancer 125: 71-180. [CrossRef] • Kim JC, Roh SA, Koo KH, In HK, Kim HC, Chang SY, Lee KH, Kim JS, Lee HI, Bodmer WF (2004). Genotyping possible polymorphic variants of human mismatch repair genes in healthy Korean individuals and sporadic colorectal cancer patients. Fam Cancer 3: 129-137. [CrossRef] • Liu B, Nicolaides NC, Markowitz S, Willson JK, Parsons RE, Jen J, Papadopolous N, Peltomaki P, de la Chapelle A, Hamilton SR, Kinzler KW, Vogelstein B (1995). Mismatch repair gene defects in sporadic colorectal cancers with microsatellite instability. Nat Genet 9: 48-55. [CrossRef] • Milanizadeh S, Khanyaghma M, Haghighi MM, Mohebbi S, Damavand B, Almasi S, Azimzadeh P, Zali M (2013). Molecular analysis of imperative polymorphisms of MLH1 gene in sporadic colorectal cancer. Cancer Biomark 13: 427-432. [CrossRef] • Milanowska K, Krwawicz J, Papaj G, Kosinski J, Poleszak K, Lesiak J, Osinska E, Rother K, Bujnicki JM (2010). REPAIRtoire-a database of DNA repairs pathways. Nucleic Acids Res 39: 788-792. [CrossRef] • Mrkonjic M, Roslin NM, Greenwood CM, Raptis S, Pollett A, Laird PW, Thibodeau SN (2010). Specific variants in the MLH1 gene region may drive DNA methylation, loss of protein expression, and MSI-H colorectal cancer. PLoS One 5: e13314. [CrossRef] • Negrini S, Gorgoulis VG, Halazonetis TD (2010). Genomic instability- an evolving hallmark of cancer. Nat Rev Mol Cell Biol 11: 220-228. [CrossRef] • Ohsawa T, Sahara T, Muramatsu S, Nishimura Y, Yathuoka T, Tanaka Y, Yamaguchi K, Ishida H, Akagi K (2009). Colorectal cancer susceptibility associated with the hMLH1 V384D variant. Mol Med Rep 2: 887-891. • Peng HX, Xu X, Yang R, Chu YM, Yang DM, Xu Y, Zhou FL, Ma WZ, Zhang XJ, Guan M, Yang ZH, Jin ZD (2015). Molecular analysis of MLH1 variants in Chinese sporadic colorectal cancer patients. Genet Mol Res doi: 10.4238/gmr.15027689. [CrossRef] • Picelli S, Zajac P, Zhou XL, Edler D, Lenander C, Dalen J, Hjern F, Lundgvist N, Lindforss U, Pahlman L, Smedh K, Törngvist A, Holm J, Janson M, Andersson M, Ekelund S, Olsson L, Lundeberg J, Lindblom A (2010). Common variants in human CRC genes as low-risk alleles. Eur J Cancer 46: 1041-1048. [CrossRef] • Rajender S, Pooja S, Kranthi Kumar MV, Karwasra R, Singh L, Thangaraj K (2010). R659X mutation in the MLH1 gene in hereditary nonpolyposis colorectal cancer (HNPCC) in an Indian extended family. Indian J Med Res 131: 64-70. • Richter JM, Pino MS, Austin TR, Campbell E, Szymonifka J, Russo AL, Hong TS, Borger D, Iafrate AJ, Chung DC (2014). Genetic mechanisms in interval colon cancers. Dig Dis Sci 59: 2255- 2263. [CrossRef] • Santibanez Koref M, Wilson V, Cartwright N, Cunnington MS, Mathers JC, Bishop DT, Curtis A, Dunlop MG, Burn J (2010). MLH1 Differential allelic expression in mutation carriers and controls. Ann Hum Genet 74: 479-488. [CrossRef] • Savio AJ, Mrkonjic M, Lemire M, Gallinger S, Knight JA, Bapat B (2017). The dynamic DNA methylation landscape of the mutL homolog 1 shore is altered by MLH1 -93G> A polymorphism in normal tissues and colorectal cancer. Clin Epigenetics 9: 26-39. [CrossRef] • Siegel RL, Miller KD, Jemal A (2015). Cancer statistics, 2015. CA Cancer J Clin 65: 5-29. [CrossRef] • Tantoğlu U (2012). Herediter non polipozis kolorektal kanser, ailesel kolorektal kanser ve sporadik kolorektal kanser hastalarının soyağacı, mismatch repair gen mutasyonuna bağlı mikrosatellit instabilite oranlarının karşılaştırılması. Ankara Üniversitesi, Tıp Fakültesi, Tıpta Uzmanlık Tezi, Ankara. • Valentin MD, Da Silva FC, Santos EMM, Da Silva AD, Ferreira FO, Junior SA, Gomy I, Vaccaro C, Redal MA, Valle AD,Sarroca C, Rasmussen LJ, Carraro DM, Rossi BM (2012). Evaluation of MLH1 I219V polymorphism in unrelated South American individuals suspected of having Lynch syndrome. Anticancer Res 32: 4347- 4351. • Wang T, Liu Y, Sima L, Shi L, Wang Z, Ni C, Zhang Z, Wang M (2012). Association between MLH1 -93G> a polymorphism and risk of colorectal cancer. PLoS one 7: e50449. [CrossRef] • Whiffin N, Broderick P, Lubbe SJ, Pittman AM, Peneger S, Chandler I, Houlston RS (2011). MLH1 -93G> A is a risk factor for MSI colorectal cancer. Carcinogenesis 32: 1157-1161. [CrossRef] • Yu JH, Bigler J, Whitton J, Potter JD, Ulrich CM (2006). Mismatch repair polymorphisms and colorectal polyps: hMLH1− 93G> A variant modifies risk associated with smoking. Am J Gastroenterol 101: 1313-1319. [CrossRef] • Zhang LL, Tang XJ, Wang XY, Zhu YW, Peng XB, Gong L (2016). A promoter polymorphism in the hMLH1 gene (-93G/A) associated with sporadic colorectal cancer. Oncol Lett 12: 4035-4040. [CrossRef]