Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Molecular Cancer
Published in: Molecular Cancer 1/2008

Open Access 01-12-2008 | Research

Impact of BRAF, MLH1 on the incidence of microsatellite instability high colorectal cancer in populations based study

Authors: Hassan Brim, Pooneh Mokarram, Fakhraddin Naghibalhossaini, Mehdi Saberi-Firoozi, Mansour Al-Mandhari, Kamla Al-Mawaly, Rayhaneh Al-Mjeni, Abeer Al-Sayegh, Sandy Raeburn, Edward Lee, Francis Giardiello, Duane T Smoot, Alexander Vilkin, C Richard Boland, Ajay Goel, Mitra Hafezi, Mehdi Nouraie, Hassan Ashktorab

Published in: Molecular Cancer | Issue 1/2008

Login to get access

Abstract

We have identified an alternative pathway of tumorigenesis in sporadic colon cancer, involving microsatellite instability due to mismatched repair methylation, which may be driven by mutations in the BRAF gene (V600E). Colorectal cancer (CRC) is the most common cancer in the world, and African Americans show a higher incidence than other populations in the United States. We analyzed sporadic CRCs in Omani (of African origin, N = 61), Iranian (of Caucasian origin, N = 53) and African American (N = 95) patients for microsatellite instability, expression status of mismatched repair genes (hMLH1, hMSH2) and presence of the BRAF (V600E) mutation. In the Omani group, all tumors with BRAF mutations were located in the left side of the colon, and for African Americans, 88% [7] of tumors with BRAF mutations were found in the right side of the colon. In African Americans, 31% of tumors displayed microsatellite instability at two or more markers (MSI-H), while this rate was 26% and 13% for tumors in the Iranian and Omani groups, respectively. A majority of these MSI-H tumors were located in the proximal colon (right side) in African American and Iranian subjects, whereas most were located in the distal colon (left side) in Omani subjects. Defects in hMLH1 gene expression were found in 77% of MSI-H tumors in both African Americans and Iranians and in 38% of tumors in Omanis. BRAF mutations were observed in all subjects: 10% of tumors in African Americans (8/82), 2% of tumors in Iranians (1/53), and 19% of tumors in Omanis (11/59). Our findings suggest that CRC occurs at a younger age in Omani and Iranian patients, and these groups showed a lower occurrence of MSI-H than did African American patients. Our multivariate model suggests an important and significant role of hMLH1 expression and BRAF mutation in MSI-H CRC in these populations. The high occurrence of MSI-H tumors in African Americans may have significant implications for treatment, since patients with MSI-H lesions display a different response to chemotherapeutic agents such as 5-fluorouracil.
Literature
1.
Jemal A, Murray T, Ward E, Samuels A, Tiwari RC, Ghafoor A, Feuer EJ, Thun MJ: Cancer statistics, 2005. CA Cancer J Clin. 2005, 55 (1): 10-30.CrossRefPubMed
2.
Carethers JM: Racial and ethnic factors in the genetic pathogenesis of colorectal cancer. J Assoc Acad Minor Phys. 1999, 10 (3): 59-67.PubMed
3.
Ashktorab H, Smoot DT, Carethers JM, Rahmanian M, Kittles R, Vosganian G, Doura M, Nidhiry E, Naab T, Momen B, Shakhani S, Giardiello FM: High incidence of microsatellite instability in colorectal cancer from African Americans. Clin Cancer Res. 2003, 9 (3): 1112-1117.PubMed
4.
Ashktorab H, Smoot DT, Farzanmehr H, Fidelia-Lambert M, Momen B, Hylind L, Iacosozio-Dononue C, Carethers MJ, Goel A, Boland CR, Giardiello FM: Clinicopathological features and msi in colorectal cancers from African Americans. Int J Cancer. 2005.
5.
Gray KD, Ballard BR, Washington MK, Belue R, Grady WM, Chapman WC, Stain SC: Do adverse histopathologic findings in colorectal cancer patients explain disparate outcomes?. J Natl Med Assoc. 2006, 98 (3): 348-351.PubMedCentralPubMed
6.
Moore WE, Moore LH: Intestinal floras of populations that have a high risk of colon cancer. Appl Environ Microbiol. 1995, 61 (9): 3202-3207.PubMedCentralPubMed
7.
Suzuki K, Mitsuoka T: Increase in faecal nitrosamines in Japanese individuals given a Western diet. Nature. 1981, 294 (5840): 453-456. 10.1038/294453a0CrossRefPubMed
8.
9.
Hassan MO, Albarwani S, Al Yahyaee S, Al Haddabi S, Rizwi S, Jaffer A, Al-Lawati J, Cai G, Comuzzie AG, Bayoumi RA: A family study in Oman: large, consanguineous, polygamous Omani Arab pedigrees. Community Genet. 2005, 8 (1): 56-60. 10.1159/000083341CrossRefPubMed
10.
Tanira MO, Al-Mukhaini MK, Al-Hinai AT, Al Balushi KA, Ahmed IS: Frequency of CYP2C9 genotypes among Omani patients receiving warfarin and its correlation with warfarin dose. Community Genet. 2007, 10 (1): 32-37. 10.1159/000096279CrossRefPubMed
11.
Ansari R, Mahdavinia M, Sadjadi A, Nouraie M, Kamangar F, Bishehsari F, Fakheri H, Semnani S, Arshi S, Zahedi MJ, Darvish-Moghadam S, Mansour-Ghanaei F, Mosavi A, Malekzadeh R: Incidence and age distribution of colorectal cancer in Iran: results of a population-based cancer registry. Cancer Lett. 2006, 240 (1): 143-147. 10.1016/j.canlet.2005.09.004CrossRefPubMed
12.
Bishehsari F, Mahdavinia M, Malekzadeh R, Verginelli F, Catalano T, Sotoudeh M, Bazan V, Agnese V, Esposito DL, De Lellis L, Semeraro D, Colucci G, Hormazdi M, Rakhshani N, Cama A, Piantelli M, Iacobelli S, Russo A, Mariani-Costantini R: Patterns of K-ras mutation in colorectal carcinomas from Iran and Italy (a Gruppo Oncologico dell'Italia Meridionale study): influence of microsatellite instability status and country of origin. Ann Oncol. 2006, 17 Suppl 7: vii91-vii96. 10.1093/annonc/mdl959PubMed
13.
Fazeli MS, Adel MG, Lebaschi AH: Colorectal carcinoma: a retrospective, descriptive study of age, gender, subsite, stage, and differentiation in Iran from 1995 to 2001 as observed in Tehran University. Dis Colon Rectum. 2007, 50 (7): 990-995. 10.1007/s10350-007-0248-zCrossRefPubMed
14.
Nasidze I, Quinque D, Ozturk M, Bendukidze N, Stoneking M: MtDNA and Y-chromosome variation in Kurdish groups. Ann Hum Genet. 2005, 69 (Pt 4): 401-412. 10.1046/j.1529-8817.2005.00174.xCrossRefPubMed
15.
Ebert MP, Model F, Mooney S, Hale K, Lograsso J, Tonnes-Priddy L, Hoffmann J, Csepregi A, Rocken C, Molnar B, Schulz HU, Malfertheiner P, Lofton-Day C: Aristaless-like homeobox-4 gene methylation is a potential marker for colorectal adenocarcinomas. Gastroenterology. 2006, 131 (5): 1418-1430. 10.1053/j.gastro.2006.08.034CrossRefPubMed
16.
Benson AB, Ajani JA, Catalano RB, Engelking C, Kornblau SM, Martenson JA, McCallum R, Mitchell EP, O'Dorisio TM, Vokes EE, Wadler S: Recommended guidelines for the treatment of cancer treatment-induced diarrhea. J Clin Oncol. 2004, 22 (14): 2918-2926. 10.1200/JCO.2004.04.132CrossRefPubMed
17.
Tanaka H, Deng G, Matsuzaki K, Kakar S, Kim GE, Miura S, Sleisenger MH, Kim YS: BRAF mutation, CpG island methylator phenotype and microsatellite instability occur more frequently and concordantly in mucinous than non-mucinous colorectal cancer. Int J Cancer. 2006, 118 (11): 2765-2771. 10.1002/ijc.21701CrossRefPubMed
18.
Rajagopalan H, Bardelli A, Lengauer C, Kinzler KW, Vogelstein B, Velculescu VE: Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status. Nature. 2002, 418 (6901): 934- 10.1038/418934aCrossRefPubMed
19.
Grady WM: Genomic instability and colon cancer. Cancer Metastasis Rev. 2004, 23 (1-2): 11-27. 10.1023/A:1025861527711CrossRefPubMed
20.
21.
Boland CR, Thibodeau SN, Hamilton SR, Sidransky D, Eshleman JR, Burt RW, Meltzer SJ, Rodriguez-Bigas MA, Fodde R, Ranzani GN, Srivastava S: A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res. 1998, 58 (22): 5248-5257.PubMed
22.
Wiggers T, Arends JW, Schutte B, Volovics L, Bosman FT: A multivariate analysis of pathologic prognostic indicators in large bowel cancer. Cancer. 1988, 61 (2): 386-395. 10.1002/1097-0142(19880115)61:2<386::AID-CNCR2820610231>3.0.CO;2-JCrossRefPubMed
23.
Cravo ML, Fidalgo PO, Lage PA, Albuquerque CM, Chaves PP, Claro I, Gomes T, Gaspar C, Soares JO, Nobre-Leitao C: Validation and simplification of Bethesda guidelines for identifying apparently sporadic forms of colorectal carcinoma with microsatellite instability. Cancer. 1999, 85 (4): 779-785. 10.1002/(SICI)1097-0142(19990215)85:4<779::AID-CNCR4>3.0.CO;2-CCrossRefPubMed
24.
Domingo E, Niessen RC, Oliveira C, Alhopuro P, Moutinho C, Espin E, Armengol M, Sijmons RH, Kleibeuker JH, Seruca R, Aaltonen LA, Imai K, Yamamoto H, Schwartz S, Hofstra RM: BRAF-V600E is not involved in the colorectal tumorigenesis of HNPCC in patients with functional MLH1 and MSH2 genes. Oncogene. 2005, 24 (24): 3995-3998. 10.1038/sj.onc.1208569CrossRefPubMed
25.
Samowitz WS, Albertsen H, Sweeney C, Herrick J, Caan BJ, Anderson KE, Wolff RK, Slattery ML: Association of smoking, CpG island methylator phenotype, and V600E BRAF mutations in colon cancer. J Natl Cancer Inst. 2006, 98 (23): 1731-1738.CrossRefPubMed
26.
Spring KJ, Zhao ZZ, Karamatic R, Walsh MD, Whitehall VL, Pike T, Simms LA, Young J, James M, Montgomery GW, Appleyard M, Hewett D, Togashi K, Jass JR, Leggett BA: High prevalence of sessile serrated adenomas with BRAF mutations: a prospective study of patients undergoing colonoscopy. Gastroenterology. 2006, 131 (5): 1400-1407. 10.1053/j.gastro.2006.08.038CrossRefPubMed
27.
Brose MS, Volpe P, Feldman M, Kumar M, Rishi I, Gerrero R, Einhorn E, Herlyn M, Minna J, Nicholson A, Roth JA, Albelda SM, Davies H, Cox C, Brignell G, Stephens P, Futreal PA, Wooster R, Stratton MR, Weber BL: BRAF and RAS mutations in human lung cancer and melanoma. Cancer Res. 2002, 62 (23): 6997-7000.PubMed
28.
Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA: Mutations of the BRAF gene in human cancer. Nature. 2002, 417 (6892): 949-954. 10.1038/nature00766CrossRefPubMed
29.
Konishi K, Takimoto M, Kaneko K, Makino R, Hirayama Y, Nozawa H, Kurahashi T, Kumekawa Y, Yamamoto T, Ito H, Yoshikawa N, Kusano M, Nakayama K, Rembacken BJ, Ota H, Imawari M: BRAF mutations and phosphorylation status of mitogen-activated protein kinases in the development of flat and depressed-type colorectal neoplasias. Br J Cancer. 2006, 94 (2): 311-317. 10.1038/sj.bjc.6602911PubMedCentralCrossRefPubMed
30.
Jass JR: Classification of colorectal cancer based on correlation of clinical, morphological and molecular features. Histopathology. 2007, 50 (1): 113-130. 10.1111/j.1365-2559.2006.02549.xCrossRefPubMed
31.
Gafa R, Maestri I, Matteuzzi M, Santini A, Ferretti S, Cavazzini L, Lanza G: Sporadic colorectal adenocarcinomas with high-frequency microsatellite instability. Cancer. 2000, 89 (10): 2025-2037. 10.1002/1097-0142(20001115)89:10<2025::AID-CNCR1>3.0.CO;2-SCrossRefPubMed
32.
Risio M, Reato G, di Celle PF, Fizzotti M, Rossini FP, Foa R: Microsatellite instability is associated with the histological features of the tumor in nonfamilial colorectal cancer. Cancer Res. 1996, 56 (23): 5470-5474.PubMed
33.
Jass JR, Do KA, Simms LA, Iino H, Wynter C, Pillay SP, Searle J, Radford-Smith G, Young J, Leggett B: Morphology of sporadic colorectal cancer with DNA replication errors. Gut. 1998, 42 (5): 673-679.PubMedCentralCrossRefPubMed
34.
Fleisher AS, Esteller M, Wang S, Tamura G, Suzuki H, Yin J, Zou TT, Abraham JM, Kong D, Smolinski KN, Shi YQ, Rhyu MG, Powell SM, James SP, Wilson KT, Herman JG, Meltzer SJ: Hypermethylation of the hMLH1 gene promoter in human gastric cancers with microsatellite instability. Cancer Res. 1999, 59 (5): 1090-1095.PubMed
35.
Deng G, Chen A, Hong J, Chae HS, Kim YS: Methylation of CpG in a small region of the hMLH1 promoter invariably correlates with the absence of gene expression. Cancer Res. 1999, 59 (9): 2029-2033.PubMed
36.
Yanagisawa Y, Akiyama Y, Iida S, Ito E, Nomizu T, Sugihara K, Yuasa Y, Maruyama K: Methylation of the hMLH1 promoter in familial gastric cancer with microsatellite instability. Int J Cancer. 2000, 85 (1): 50-53. 10.1002/(SICI)1097-0215(20000101)85:1<50::AID-IJC9>3.0.CO;2-ECrossRefPubMed
37.
Miyakura Y, Sugano K, Konishi F, Ichikawa A, Maekawa M, Shitoh K, Igarashi S, Kotake K, Koyama Y, Nagai H: Extensive methylation of hMLH1 promoter region predominates in proximal colon cancer with microsatellite instability. Gastroenterology. 2001, 121 (6): 1300-1309. 10.1053/gast.2001.29616CrossRefPubMed
38.
Satia JA, Keku T, Galanko JA, Martin C, Doctolero RT, Tajima A, Sandler RS, Carethers JM: Diet, lifestyle, and genomic instability in the North Carolina Colon Cancer Study. Cancer Epidemiol Biomarkers Prev. 2005, 14 (2): 429-436. 10.1158/1055-9965.EPI-04-0486CrossRefPubMed
39.
Slattery ML, Curtin K, Sweeney C, Levin TR, Potter J, Wolff RK, Albertsen H, Samowitz WS: Diet and lifestyle factor associations with CpG island methylator phenotype and BRAF mutations in colon cancer. Int J Cancer. 2007, 120 (3): 656-663. 10.1002/ijc.22342CrossRefPubMed
40.
Longacre TA, Fenoglio-Preiser CM: Mixed hyperplastic adenomatous polyps/serrated adenomas. A distinct form of colorectal neoplasia. Am J Surg Pathol. 1990, 14 (6): 524-537.CrossRefPubMed
41.
Sawhney MS, Farrar WD, Gudiseva S, Nelson DB, Lederle FA, Rector TS, Bond JH: Microsatellite instability in interval colon cancers. Gastroenterology. 2006, 131 (6): 1700-1705. 10.1053/j.gastro.2006.10.022CrossRefPubMed
42.
Tahir MA, Balamurugan K, Tahir UA, Amjad M, Awin MB, Chaudhary OR, Hamby JE, Budowle B, Herrera RJ: Allelic distribution of nine short tandem repeat (STR), HLA-DQA1, and polymarker loci in an Omani sample population. Forensic Sci Int. 2000, 109 (2): 81-85. 10.1016/S0379-0738(99)00227-3CrossRefPubMed
43.
Cheung KH, Osier MV, Kidd JR, Pakstis AJ, Miller PL, Kidd KK: ALFRED: an allele frequency database for diverse populations and DNA polymorphisms. Nucleic Acids Res. 2000, 28 (1): 361-363. 10.1093/nar/28.1.361PubMedCentralCrossRefPubMed
44.
O'Leary CA: The Kurds of Iraq: Recent History, Future Prospects. 2002, 6 (4):
45.
Durroei SR: Kurdish: An Indo-European Language. 1998.
46.
Ko JM, Cheung MH, Wong CM, Lau KW, Tang CM, Kwan MW, Lung ML: Ki-ras codon 12 point mutational activation in Hong Kong colorectal carcinoma patients. Cancer Lett. 1998, 134 (2): 169-176. 10.1016/S0304-3835(98)00257-2CrossRefPubMed
47.
Chang SC, Lin JK, Yang SH, Wang HS, Li AF, Chi CW: Relationship between genetic alterations and prognosis in sporadic colorectal cancer. Int J Cancer. 2006, 118 (7): 1721-1727. 10.1002/ijc.21563CrossRefPubMed
48.
Carethers JM, Chauhan DP, Fink D, Nebel S, Bresalier RS, Howell SB, Boland CR: Mismatch repair proficiency and in vitro response to 5-fluorouracil. Gastroenterology. 1999, 117 (1): 123-131. 10.1016/S0016-5085(99)70558-5PubMedCentralCrossRefPubMed
Metadata
Title
Impact of BRAF, MLH1 on the incidence of microsatellite instability high colorectal cancer in populations based study
Authors
Hassan Brim
Pooneh Mokarram
Fakhraddin Naghibalhossaini
Mehdi Saberi-Firoozi
Mansour Al-Mandhari
Kamla Al-Mawaly
Rayhaneh Al-Mjeni
Abeer Al-Sayegh
Sandy Raeburn
Edward Lee
Francis Giardiello
Duane T Smoot
Alexander Vilkin
C Richard Boland
Ajay Goel
Mitra Hafezi
Mehdi Nouraie
Hassan Ashktorab
Publication date
01-12-2008
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2008
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/1476-4598-7-68

Other articles of this Issue 1/2008

Molecular Cancer 1/2008 Go to the issue

Research

Lymphangiogenesis and lymph node metastasis in breast cancer

Review

Evaluation of cell types for assessment of cytogenetic damage in arsenic exposed population

Research

Insulin-like growth factor-I gene therapy reverses morphologic changes and reduces hyperprolactinemia in experimental rat prolactinomas

Research

Genome-wide screening of copy number alterations and LOH events in renal cell carcinomas and integration with gene expression profile

Research

Prevalence of bortezomib-resistant constitutive NF-kappaB activity in mantle cell lymphoma

Research

Molecular analysis reveals heterogeneity of mouse mammary tumors conditionally mutant for Brca1
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits