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Diagnostic Pathology
Published in: Diagnostic Pathology 1/2015

Open Access 01-12-2015 | Research

Epigenetics could explain some Moroccan population colorectal cancers peculiarities: microsatellite instability pathway exploration

Authors: Mohammed Sekal, Hassania Ameurtesse, Laila Chbani, Karim Ouldim, Sanae Bennis, Mohammed Abkari, Amal Boulouz, Dafr Allah Benajah, Basher Benjelloun, Abdelmalek Ousadden, Khalid Ait Taleb, Said Ait Laalim, Imane Toghrai, Khalid Mazaz, Samia Arifi, Nawfel Mellas, Karima El Rhazi, Taoufiq Harmouch, Sidi Adil Ibrahimi, Afaf Amarti Riffi

Published in: Diagnostic Pathology | Issue 1/2015

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Abstract

Background

Colorectal Cancers (CRC) are one of the most common malignancies in the world. Their incidence in Morocco, between 2005 and 2007, was 5.6 for 100000 inhabitants, which is very low compared to what found in developed countries. In addition, CRCs show a high frequency of rectal localizations, and occurs in a younger population in Morocco compared to what found in developed countries.
The purpose of this study is to confirm these CRC peculiarities in Morocco and try to explain them by exploring the microsatellite instability molecular pathway.

Methods

This is a prospective observational study conducted since January 2010, including 385 patients admitted in Hassan II University Hospital of Fez. We collected clinical, radiological and pathological data. We investigated the expression of mismatch repair (MMR) proteins in 214 patients and BRAF gene mutations in 159 patients.

Results

Mean age was 55.08 +/− 15.16 years. 36.5 % of patients were less than 50 years old and 49.3 % of tumors were localized in the rectum. Loss of MMR protein expression was observed in 11.2 % of cases. It was independently associated with individual or family history of cancer belonging to Hereditary Non-Polyposis Colorectal Cancer (HNPCC) spectrum (p = 0.01) and proximal localization (p = 0.02). No BRAF mutation was detected in all cases.

Conclusions

These results confirm the high occurrence of CRCs to young patients and the high frequency of rectal localizations in Moroccan population. They mostly show an absence of BRAF mutation, supposing a rarity of MLH1 promoter hypermethylation pathway, which may even partially explain the CRC peculiarities in our context.

Virtual Slides

The virtual slide(s) for this article can be found here: http://​www.​diagnosticpathol​ogy.​diagnomx.​eu/​vs/​5868184711716884​
Literature
1.
2.
3.
4.
Laila C, Imane H, Mohamed B, Chakib N, Afaf A. Digestive cancers in Morocco: Fez-Boulemane region. Pan Afr Med J. 2012;13:46.
5.
Roock WD, Vriendt VD, Normanno N, Ciardiello F, Tejpar SKRAS, BRAF. PIK3CA, and PTEN mutations: implications for targeted therapies in metastatic colorectal cancer. Lancet Oncol. 2011;12:594–603.PubMedCrossRef
6.
7.
8.
Poynter JN, Siegmund KD, Weisenberger DJ, Long TI, Thibodeau SN, Lindor N, et al. Molecular characterization of MSI-H colorectal cancer by MLHI promoter methylation, immunohistochemistry, and mismatch repair germline mutation screening. Cancer Epidemiol Biomarkers Prev. 2008;17:3208–15.PubMedCentralPubMedCrossRef
9.
Tannergard P, Liu T, Weger A, Nordenskjold M, Lindblom A. Tumorigenesis in colorectal tumors from patients with hereditary non-polyposis colorectal cancer. Hum Genet. 1997;101:51–5.PubMedCrossRef
10.
Kloor M, Staffa L, Ahadova A, von Knebel Doeberitz M. Clinical significance of microsatellite instability in colorectal cancer. Langenbecks Arch Surg. 2014;399(1):23–31.PubMedCrossRef
11.
Peltomäki P. Deficient DNA, mismatch repair: a common etiologic factor for colon cancer. Hum Mol Genet. 2001;10:735–40.PubMedCrossRef
12.
Hampel H, Frankel WL, Martin E, et al. Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). N Engl J Med. 2005;352(18):1851–60.PubMedCrossRef
13.
Morimoto LM, Newcomb PA, Ulrich CM, et al. Risk factors for hyperplastic and adenomatous polyps: evidence for malignant potential? Cancer Epidemiol Biomarkers Prev. 2002;11(10Pt1):1012–8.PubMed
14.
Weisenberger DJ, Siegmund KD, Campan M, et al. CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat Genet. 2006;38:787–93.PubMedCrossRef
15.
Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949–54.PubMedCrossRef
16.
Rajagopalan H, Bardelli A, Lengauer C, Kinzler KW, Vogelstein B, et al. Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status. Nature. 2002;418(6901):934.PubMedCrossRef
17.
Bettstetter M, Dechant S, Ruemmele P, Grabowski M, Keller G, et al. Distinction of hereditary non polyposis colorectal cancer and sporadic microsatellite-unstable colorectal cancer through quantification of MLH1 methylation by real-time PCR. Clin Cancer Res. 2007;13:3221–8.PubMedCrossRef
18.
Domingo E, Niessen RC, Oliveira C, Alhopuro P, Moutinho C, Espin E, et al. BRAF-V600E is not involved in the colorectal tumorigenesis of HNPCC in patients with functional MLH1 and MSH2 genes. Oncogene. 2005;24:3995–8.PubMedCrossRef
19.
Truninger K, Menigatti M, Luz J, et al. Immunohistochemical analysis reveals high frequency of PMS2 defects in colorectal cancer. Gastroenterology. 2005;128(5):1160–71.PubMedCrossRef
20.
Belshaw NJ, Elliott GO, Williams EA, Bradburn DM, Mills SJ, et al. Use of DNA from human stools to detect aberrant CpG island methylation of genes implicated in colorectal cancer. Cancer Epidemiol Biomarkers Prev. 2004;13(9):1495–501.PubMed
21.
Kumar K, Brim H, Giardiello F, Smoot DT, Nouraie M, et al. Distinct BRAF (V600E) and KRAS mutations in high microsatellite instability sporadic colorectal cancer in African Americans. Clin Cancer Res. 2009;15(4):1155–61.PubMedCentralPubMedCrossRef
22.
23.
Koo JH, Leong RW. Sex differences in epidemiological, clinical and pathological characteristics of colorectal cancer. J Gastroenterol Hepatol. 2010;25:33–42.PubMedCrossRef
24.
Bennani B, Gilles S, Fina F, Nanni I, Ibrahimi A, Amarti Riffi A, et al. Mutation analysis of BRAF exon 15 and KRAS codons 12 and 13 in Moroccan patients with colorectal cancer. Int J Biol Markers. 2010;25(4):179–84.PubMed
25.
Aissi S, Buisine MP, Al PN. Somatic molecular changes and histo-pathological features of colorectal cancer in Tunisia. World J Gastroenterol. 2013;19(32):5286–94.PubMedCentralPubMedCrossRef
26.
27.
Remontet L, Estève J, Bouvier AM, Grosclaude P, Launoy G, Menegoz F, et al. Cancer incidence and mortality in France over the period 1978–2000. Public Rev Epidemiol Sante. 2003;51(1Pt1):3–30.
28.
Gaedcke J, Grade M, Al JK. KRAS and BRAF mutations in patients with rectal cancer treated with preoperative chemoradiotherapy. Radiother Oncol. 2010;94:76–81.PubMedCrossRef
29.
Goel A, Arnold CN, Niedzwiecki D, Carethers JM, Dowell JM, Al WL. Frequent inactivation of PTEN by promoter hypermethylation in microsatellite instability-high sporadic colorectal cancers. Cancer Res. 2004;64:3014–21.PubMedCrossRef
30.
Hitchins MP, Wong JJ, Suthers G, et al. Inheritance of a cancer-associated MLH1 germ-line epimutation. N Engl J Med. 2007;356:697–705.PubMedCrossRef
31.
Kaminsky ZA, Tang T, Wang SC, Ptak C, Oh GH, Wong AH A. DNA methylation profiles in monozygotic and dizygotic twins. Nat Genet. 2009;41:240–5.PubMedCrossRef
32.
Levine AJ, Win AK, Buchanan DD, Jenkins MA, Baron JA, Young JP, et al. Cancer risks for the relatives of colorectal cancer cases with a methylated MLH1 promoter region: data from the Colorectal Cancer Family Registry. Cancer Prev Res (Phila). 2012;5(2):328–35.CrossRef
33.
Ahuja N, Issa JP. Aging, methylation and cancer. Histol Histopathol. 2000;15:835–42.PubMed
34.
Casillas Jr MA, Lopatina N, Andrews LG, Tollefsbol TO. Transcriptional control of the DNA methyltransferases is altered in aging and neoplastically-transformed human fibroblasts. Mol Cell Biochem. 2003;252:33–43.PubMedCrossRef
35.
Wilson VL, Jones PA. DNA methylation decreases in aging but not in immortal cells. Science. 1983;220:1055–7.PubMedCrossRef
36.
Moroccans’ High Commission for Planning. Social Indicators Morocco 2010. p:14.
37.
38.
39.
40.
Fraga MF, Ballestar E, Paz MF, Ropero S, Setien F, Ballestar ML A. Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci U S A. 2005;102:10604–9.PubMedCentralPubMedCrossRef
41.
Breitling LP, Yang R, Korn B, Burwinkel B, Brenner H. Tobacco-smoking-related differential DNA methylation: 27 K discovery and replication. Am J Hum Genet. 2011;88:450–7.PubMedCentralPubMedCrossRef
42.
Limsui D, Vierkant RA, Tillmans LS, et al. Cigarette smoking and colorectal cancer risk by molecularly defined subtypes. J Natl Cancer Inst. 2010;102:1012–22.PubMedCentralPubMedCrossRef
43.
Mortusewicz O, Schermelleh L, Walter J, Cardoso MC, Leonhardt H. Recruitment of DNA methyltransferase I to DNA repair sites. Proc Natl Acad Sci U S A. 2005;102:8905–9.PubMedCentralPubMedCrossRef
44.
45.
Kim YI. Nutritional epigenetics: Impact of folate deficiency on DNA methylation and colon cancer susceptibility. J Nutr. 2005;135(11):2703–9.PubMed
46.
Cravo ML, Glória LM, Selhub J, et al. Hyperhomocysteinemia in chronic alcoholism: Correlation with folate, vitamin B-12, and vitamin B-6 status. Am J Clin Nutr. 1996;63(2):220–4.PubMed
47.
Van Engeland M, Weijenberg MP, Roemen GM, et al. Effects of dietary folate and alcohol intake on promoter methylation in sporadic colorectal cancer: The Netherlands cohort study on diet and cancer. Cancer Res. 2003;63(12):3133–7.PubMed
48.
Fedirko V, Tramacere I, Bagnardi V, Rota M, Scotti L, Islami F, et al. Alcohol drinking and colorectal cancer risk: an overall and dose–response meta-analysis of published studies. Ann Oncol. 2011;22:1958–72.PubMedCrossRef
49.
Bamia C, Lagiou P, Buckland G, Al TA. Mediterranean diet and colorectal cancer risk: results from a European cohort. Eur J Epidemiol. 2013;28(4):317–28.PubMedCrossRef
50.
Schwingshackl L, Hoffmann G. Adherence to Mediterranean diet and risk of cancer: A systematic review and meta-analysis of observational studies. Int J Cancer. 2014;135(8):1884–97.PubMedCrossRef
51.
52.
Itzkowitz SH et al. Improved fecal DNA test for colorectal cancer screening. Clin Gastroenterol Hepatol. 2007;5:111–7.PubMedCrossRef
Metadata
Title
Epigenetics could explain some Moroccan population colorectal cancers peculiarities: microsatellite instability pathway exploration
Authors
Mohammed Sekal
Hassania Ameurtesse
Laila Chbani
Karim Ouldim
Sanae Bennis
Mohammed Abkari
Amal Boulouz
Dafr Allah Benajah
Basher Benjelloun
Abdelmalek Ousadden
Khalid Ait Taleb
Said Ait Laalim
Imane Toghrai
Khalid Mazaz
Samia Arifi
Nawfel Mellas
Karima El Rhazi
Taoufiq Harmouch
Sidi Adil Ibrahimi
Afaf Amarti Riffi
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Diagnostic Pathology / Issue 1/2015
Electronic ISSN: 1746-1596
DOI
https://doi.org/10.1186/s13000-015-0326-9

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