Association of Genetic Variants with Colorectal Cancer in the Extended MENA Region: A Systematic Review

Author(s): Mariem Sidenna, Reem Bux, Tasnim Fadl, Ugur Ozbek, Hatem Zayed*

Journal Name: Current Molecular Medicine

Volume 20 , Issue 4 , 2020

  Journal Home
Translate in Chinese
Become EABM
Become Reviewer
Call for Editor


Background: Colorectal cancer (CRC) is the third most common cancer worldwide and the third leading cause of cancer-related death. It is a heterogeneous disease that develops through different genetic and epigenetic mechanisms. To date, no comprehensive systematic review investigating genetic risk factors for familial and sporadic CRC has been performed on the extended MENA (eMENA) region.

Aims: This study aimed to systematically analyze genetic variations significantly associated with CRC in the eMENA region.

Methods: We searched four literature databases (PubMed, Scopus, Science Direct, and Web of Science) from the time of inception until May 2019 using broad search terms to obtain all reported genetic data related to eMENA patients with CRC. Variants with an OR>1 that are associated with CRC were identified.

Results: A total of 1,200 studies were obtained from our search method, 27 of which met the inclusion criteria for our systematic review, with a total of 8,230 CRC patients and 7,611 controls. Of these, 1,941 patients distributed throughout nine eMENA countries were found to carry 46 variants in 33 different genes. Interestingly, 19 variants were unique to CRC patients in the eMENA region.

Interpretation: This is the first systematic review to capture the spectrum of variants significantly associated with CRC in the eMENA region. There appears to be a distinctive clinical picture for eMENA patients with CRC, and the range and distribution of variants among patients from the eMENA region differ from those noted in other ethnic groups.

Keywords: Colorectal cancer, genetic variations, genotype-phenotype correlation, extended MENA region, heterogeneous disease, CRC.

Jeon J, Du M, Schoen RE, et al. Colorectal transdisciplinary study and genetics and epidemiology of colorectal cancer consortium. Determining risk of colorectal cancer and starting age of screening based on lifestyle, environmental, and genetic factors. Gastroenterology 2018; 154(8): 2152-64.
[] [PMID: 29458155]
Bogaert J, Prenen H. Molecular genetics of colorectal cancer. Ann Gastroenterol 2014; 27(1): 9-14.
[PMID: 24714764]
Youssef MR, Attia ZI, El-Baz RA, Roshdy S, Settin A. Genetic polymorphisms of NFκB1-94ins/delATTG and NFκBIA-881A/G genes in Egyptian patients with colorectal cancer. Fam Cancer 2017; 16(4): 517-24.
[] [PMID: 28389768]
Jasperson KW, Tuohy TM, Neklason DW, Burt RW. Hereditary and familial colon cancer. Gastroenterology 2010; 138(6): 2044-58.
[] [PMID: 20420945]
Chan AO, Soliman AS, Zhang Q, et al. Differing DNA methylation patterns and gene mutation frequencies in colorectal carcinomas from Middle Eastern countries. Clin Cancer Res 2005; 11(23): 8281-7.
[] [PMID: 16322286]
Scott RH, Homfray T, Huxter NL, et al. Familial T-cell non-Hodgkin lymphoma caused by biallelic MSH2 mutations. J Med Genet 2007; 44(7) e83
[] [PMID: 17601929]
Yuan ZQ, Wong N, Foulkes WD, et al. A missense mutation in both hMSH2 and APC in an Ashkenazi Jewish HNPCC kindred: implications for clinical screening. J Med Genet 1999; 36(10): 790-3.
[] [PMID: 10528862]
Abdel-Rahman SZ, Soliman AS, Bondy ML, et al. Inheritance of the 194Trp and the 399Gln variant alleles of the DNA repair gene XRCC1 are associated with increased risk of early-onset colorectal carcinoma in Egypt. Cancer Lett 2000; 159(1): 79-86.
[] [PMID: 10974409]
Skjelbred CF, Saebø M, Wallin H, et al. Polymorphisms of the XRCC1, XRCC3 and XPD genes and risk of colorectal adenoma and carcinoma, in a Norwegian cohort: a case control study. BMC Cancer 2006; 6: 67.
[] [PMID: 16542436]
Divine KK, Gilliland FD, Crowell RE, et al. The XRCC1 399 glutamine allele is a risk factor for adenocarcinoma of the lung. Mutat Res 2001; 461(4): 273-8.
[] [PMID: 11104903]
Ricci MT, Miccoli S, Turchetti D, et al. Type and frequency of MUTYH variants in Italian patients with suspected MAP: a retrospective multicenter study. J Hum Genet 2017; 62(2): 309-15.
[] [PMID: 27829682]
Nielsen M, Joerink-van de Beld MC, Jones N, et al. Analysis of MUTYH genotypes and colorectal phenotypes in patients With MUTYH-associated polyposis. Gastroenterology 2009; 136(2): 471-6.
[] [PMID: 19032956]
Aretz S, Tricarico R, Papi L, et al. MUTYH-associated polyposis (MAP): evidence for the origin of the common European mutations p.Tyr179Cys and p.Gly396Asp by founder events. Eur J Hum Genet 2014; 22(7): 923-9.
[] [PMID: 23361220]
Rantalainen V, Lahti J, Kajantie E, Tienari P, Eriksson JG, Raikkonen K. APOE ɛ4, rs405509, and rs440446 promoter and intron-1 polymorphisms and dementia risk in a cohort of elderly Finns-Helsinki Birth Cohort Study. Neurobiol Aging 2019; 73: 230.
[] [PMID: 30293724]
Gomes da Silva IIF, Angelo HD, Rushansky E, Mariano MH, Maia MMD, de Souza PRE. Interleukin (IL)-23 receptor, IL-17A and IL-17F gene polymorphisms in Brazilian patients with rheumatoid arthritis. Arch Immunol Ther Exp (Warsz) 2017; 65(6): 537-43.
[] [PMID: 28547498]
Yago T, Nanke Y, Kawamoto M, Kobashigawa T, Yamanaka H, Kotake S. IL-23 and Th17 Disease in Inflammatory Arthritis. J Clin Med 2017; 6(9): 81.
[] [PMID: 28850053]
Crous-Bou M, Rennert G, Salazar R, et al. Genetic polymorphisms in fatty acid metabolism genes and colorectal cancer. Mutagenesis 2012; 27(2): 169-76.
[] [PMID: 22294764]
Yazdanpanahi N, Salehi R, Kamali S. RAD51 135G>C polymorphism and risk of sporadic colorectal cancer in Iranian population. J Cancer Res Ther 2018; 14(3): 614-8.
[] [PMID: 29893328]
Zayed H, Ouhtit A. Accredited genetic testing in the Arab Gulf region: reinventing the wheel. J Hum Genet 2016; 61(7): 673-4.
[] [PMID: 26984563]
Zayed H. The Arab genome: Health and wealth. Gene 2016; 592(2): 239-43.
[] [PMID: 27393651]
Zayed H. The Qatar genome project: translation of whole-genome sequencing into clinical practice. Int J Clin Pract 2016; 70(10): 832-4.
[] [PMID: 27586018]
Al-Ali M, Osman W, Tay GK, AlSafar HS. A 1000 Arab genome project to study the Emirati population. J Hum Genet 2018; 63(4): 533-6.
[] [PMID: 29410509]
Marafie MJ, Al-Awadi S, Al-Mosawi F, Elshafey A, Al-Ali W, Al-Mulla F. Impact of 226C>T MSH2 gene mutation on cancer phenotypes in two HNPCC-associated highly-consanguineous families from Kuwait: emphasis on premarital genetic testing. Fam Cancer 2009; 8(4): 289-98.
[] [PMID: 19669601]
Raskin L, Schwenter F, Freytsis M, et al. Characterization of two Ashkenazi Jewish founder mutations in MSH6 gene causing Lynch syndrome. Clin Genet 2011; 79(6): 512-22.
[] [PMID: 21155762]
Starinsky S, Figer A, Ben-Asher E, et al. Genotype phenotype correlations in Israeli colorectal cancer patients. Int J Cancer 2005; 114(1): 58-73.
[] [PMID: 15523694]
Guillem JG, Rapaport BS, Kirchhoff T, et al. A636P is associated with early-onset colon cancer in Ashkenazi Jews. J Am Coll Surg 2003; 196(2): 222-5.
[] [PMID: 12595050]
Schmit SL, Schumacher FR, Edlund CK, et al. A novel colorectal cancer risk locus at 4q32.2 identified from an international genome-wide association study. Carcinogenesis 2014; 35(11): 2512-9.
[] [PMID: 25023989]
Schmit SL, Gollub J, Shapero MH, et al. MicroRNA polymorphisms and risk of colorectal cancer. Cancer Epidemiol Biomarkers Prev 2015; 24(1): 65-72.
[] [PMID: 25342389]
Cetinkunar S, Gok I, Celep RB, et al. The effect of polymorphism in DNA repair genes RAD51 and XRCC2 in colorectal cancer in Turkish population. Int J Clin Exp Med 2015; 8(2): 2649-55.
[PMID: 25932214]
Parsafar S, Hematti S, Ghorbani F, Safari F, Tavassoli M. Polymorphic GT dinucleotide repeat in the PIK3CA gene and risk of colorectal cancer. Cancer Biomark 2015; 15(4): 397-403.
[] [PMID: 25835181]
Daraei A, Salehi R, Salehi M, et al. Effect of rs6983267 polymorphism in the 8q24 region and rs4444903 polymorphism in EGF gene on the risk of sporadic colorectal cancer in Iranian population. Med Oncol 2012; 29(2): 1044-9.
[] [PMID: 21567271]
Khatami F, Noorinayer B, Mohebi SR, et al. Effects of amino acid substitution polymorphisms of two DNA methyltransferases on susceptibility to sporadic colorectal cancer. Asian Pac J Cancer Prev 2009; 10(6): 1183-8.
[PMID: 20192566]
Abbasian MH, Abbasi B, Ansarinejad N, et al. Association of interleukin-1 gene polymorphism with risk of gastric and colorectal cancers in an Iranian population. Iran J Immunol 2018; 15(4): 321-8.
[PMID: 30593746]
Sadeghi H, Nazemalhosseini-Mojarad E, Yaghoob-Taleghani M, et al. miR-30a promoter variation contributes to the increased risk of colorectal cancer in an Iranian population. J Cell Biochem 2018; 120(5): 7734-40.
[PMID: 30387187]
Al Khaldi RM, Al Mulla F, Al Awadhi S, Kapila K, Mojiminiyi OA. Associations of single nucleotide polymorphisms in the adiponectin gene with adiponectin levels and cardio-metabolic risk factors in patients with cancer. Dis Markers 2011; 30(4): 197-212.
[] [PMID: 21694446]
Stormorken AT, Bowitz-Lothe IM, Norèn T, et al. Immunohistochemistry identifies carriers of mismatch repair gene defects causing hereditary nonpolyposis colorectal cancer. J Clin Oncol 2005; 23(21): 4705-12.
[] [PMID: 16034045]
Ye L, Wang G, Tang Y, Bai J. A population-specific correlation between ADIPOQ rs2241766 and rs 1501299 and colorectal cancer risk: a meta-analysis for debate. Int J Clin Oncol 2017; 22(2): 307-15.
[] [PMID: 27704292]
Elsaid A, Elshazli R, El-Tarapely F, Darwish H, Abdel-Malak C. Association of monoallelic MUTYH mutation among Egyptian patients with colorectal cancer. Fam Cancer 2017; 16(1): 83-90.
[] [PMID: 27631816]
Fu W, Zhuo ZJ, Chen YC, et al. NFKB1 -94insertion/deletion ATTG polymorphism and cancer risk: Evidence from 50 case-control studies. Oncotarget 2017; 8(6): 9806-22.
[] [PMID: 28039461]
Yu J, Huang Y, Liu L, et al. Genetic polymorphisms of Wnt/β-catenin pathway genes are associated with the efficacy and toxicities of radiotherapy in patients with nasopharyngeal carcinoma. Oncotarget 2016; 7(50): 82528-37.
[] [PMID: 27769064]
Angelini S, Ravegnini G, Nannini M, et al. Folate-related polymorphisms in gastrointestinal stromal tumours: susceptibility and correlation with tumour characteristics and clinical outcome. Eur J Hum Genet 2015; 23(6): 817-23.
[] [PMID: 25227144]
Murali A, Varghese BT, Kumar RR, Kannan S. Combination of genetic variants in cyclin D1 and retinoblastoma genes predict clinical outcome in oral cancer patients. Tumour Biol 2016; 37(3): 3609-17.
[] [PMID: 26459309]
Liang J, Lin C, Hu F, et al. APC polymorphisms and the risk of colorectal neoplasia: a HuGE review and meta-analysis. Am J Epidemiol 2013; 177(11): 1169-79.
[] [PMID: 23576677]
Feldman M, Hershkovitz I, Sklan EH, et al. Detection of a tumor suppressor gene variant predisposing to colorectal cancer in an 18th century Hungarian mummy. PLoS One 2016; 11(2) e0147217
[] [PMID: 26863316]
Yurgelun MB, Kulke MH, Fuchs CS, et al. Cancer susceptibility gene mutations in individuals with colorectal cancer. J Clin Oncol 2017; 35(10): 1086-95.
[] [PMID: 28135145]
Omrane I, Baroudi O, Bougatef K, et al. Significant association between IL23R and IL17F polymorphisms and clinical features of colorectal cancer. Immunol Lett 2014; 158(1-2): 189-94.
[] [PMID: 24440568]
Ma M, Jin GJ, Yun K, et al. Correlation of IL-1F genetic polymorphisms with the risk of colorectal cancer among Chinese populations. Tumour Biol 2015; 36(2): 807-14.
[] [PMID: 25296730]
Brim H, Mokarram P, Naghibalhossaini F, et al. Impact of BRAF, MLH1 on the incidence of microsatellite instability high colorectal cancer in populations based study. Mol Cancer 2008; 7: 68.
[] [PMID: 18718023]
Prahallad A, Sun C, Huang S, et al. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature 2012; 483(7387): 100-3.
[] [PMID: 22281684]
Karam RA, Al Jiffry BO, Al Saeed M, Abd El Rahman TM, Hatem M, Amer MG. DNA repair genes polymorphisms and risk of colorectal cancer in Saudi patients. Arab J Gastroenterol 2016; 17(3): 117-20.
[] [PMID: 27686263]
Al Obeed OA, Vaali-Mohamed MA, Alkhayal KA, et al. IL-17 and colorectal cancer risk in the Middle East: gene polymorphisms and expression. Cancer Manag Res 2018; 10: 2653-61.
[] [PMID: 30233234]
Gao JF, Zhang H, Lv J, Wang L, Fan YY. Associations of the IL-17A rs2275913 and IL-17F rs763780 polymorphisms with the risk of digestive system neoplasms: A meta-analysis. Int Immunopharmacol 2019; 67: 248-59.
[] [PMID: 30562686]
Kutikhin AG, Yuzhalin AE, Volkov AN, Zhivotovskiy AS, Brusina EB. Correlation between genetic polymorphisms within IL-1B and TLR4 genes and cancer risk in a Russian population: a case-control study. Tumour Biol 2014; 35(5): 4821-30.
[] [PMID: 24446182]
Arbour NC, Lorenz E, Schutte BC, et al. TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat Genet 2000; 25(2): 187-91.
[] [PMID: 10835634]
Zhang B, Jia WH, Matsuo K, et al. Genome-wide association study identifies a new SMAD7 risk variant associated with colorectal cancer risk in East Asians. Int J Cancer 2014; 135(4): 948-55.
[] [PMID: 24448986]
Pérez-Ramírez C, Alnatsha A, Cañadas-Garre M, et al. Cytokine single-nucleotide polymorphisms and risk of non-small-cell lung cancer. Pharmacogenet Genomics 2017; 27(12): 438-44.
[] [PMID: 28930110]
Canbay E, Kahraman OT, Bugra D, et al. Association between PTEN IVS4 polymorphism and development of colorectal cancer in a Turkish population. Expert Opin Ther Targets 2013; 17(1): 1-6.
[] [PMID: 23062208]
Wang Y, Yang H, Luo JI, Ge J. Impact of PTEN IVS4 Polymorphism (rs3830675) on cancer susceptibility: An updated meta-analysis. Cancer Genomics Proteomics 2015; 12(5): 263-9.
[PMID: 26417029]
Özhan G, Kara M, Sari FM, Yanar HT, Ercan G, Alpertunga B. Associations between the functional polymorphisms in the ABCB1 transporter gene and colorectal cancer risk: a case-control study in Turkish population. Toxicol Mech Methods 2013; 23(4): 235-9.
[] [PMID: 23193993]
Martinelli M, Scapoli L, Cura F, et al. Colorectal cancer susceptibility: apparent gender-related modulation by ABCB1 gene polymorphisms. J Biomed Sci 2014; 21: 89.
[] [PMID: 25355168]
Krupa R, Sliwinski T, Wisniewska-Jarosinska M, et al. Polymorphisms in RAD51, XRCC2 and XRCC3 genes of the homologous recombination repair in colorectal cancer--a case control study. Mol Biol Rep 2011; 38(4): 2849-54.
[] [PMID: 21104022]
Haerian MS, Haerian BS, Molanaei S, et al. MIR196A2 rs11614913 contributes to susceptibility to colorectal cancer in Iranian population: A multi-center case-control study and meta-analysis. Gene 2018; 669: 82-90.
[] [PMID: 29802998]
Dikaiakos P, Gazouli M, Rizos S, Zografos G, Theodoropoulos GE. Evaluation of genetic variants in miRNAs in patients with colorectal cancer. Cancer Biomark 2015; 15(2): 157-62.
[] [PMID: 25519012]
Sibin MK, Harshitha SM, Narasingarao KV, Dhananjaya IB, Dhaval PS, Chetan GK. Effect of rs11614913 polymorphism on mature miR196a2 expression and its target gene HOXC8 expression in human glioma. J Mol Neurosci 2017; 61(2): 144-51.
[] [PMID: 27796868]
Damavand B, Derakhshani S, Saeedi N, et al. Intronic polymorphisms of the SMAD7 gene in association with colorectal cancer. Asian Pac J Cancer Prev 2015; 16(1): 41-4.
[] [PMID: 25640388]
Serrano-Fernandez P, Dymerska D, Kurzawski G, et al. Cumulative small effect genetic markers and the risk of colorectal cancer in Poland, Estonia, Lithuania, and Latvia. Gastroenterol Res Pract 2015; 2015 204089
[] [PMID: 26101521]
Azimzadeh P, Romani S, Mohebbi SR, et al. Association of polymorphisms in microRNA-binding sites and colorectal cancer in an Iranian population. Cancer Genet 2012; 205(10): 501-7.
[] [PMID: 22939228]
Tong Z, Li Q, Zhang J, Wei Y, Miao G, Yang X. Association between interleukin 6 and interleukin 16 gene polymorphisms and coronary heart disease risk in a Chinese population. J Int Med Res 2013; 41(4): 1049-56.
[] [PMID: 23881440]

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2020
Page: [286 - 298]
Pages: 13
DOI: 10.2174/1566524019666191014170136
Price: $65

Article Metrics

PDF: 17
PRC: 1