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

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.

Análisis molecular del cáncer de colon esporádico

“…En el presente trabajo, los tumores con mutaciones en BRAF se asociaron significativamente a MSI alta y localización en el colon derecho, lo cual es consistente con reportes previos 33,34 . Aun más, ha sido reportado que la mutación activante en BRAF fue encontrada entre 10-18% de pacientes con CC y que este porcentaje se incrementa a 27-45% en quienes presentan tumores MSI alta 35,36 , en concordancia nosotros observamos 9% de mutación en BRAF en nuestra población de estudio y que alcanza a 27% en aquellos con MSI alta.…”

Molecular Biomarkers of Colorectal Cancer: A Review of Published Articles From Iran

“…The basic tests identify five markers (NR-21, BAT-26, BA T -25, NR-27 and NR-24) to devise the simplest diagnostic assay (9). Previous reports have shown significant diversity regarding the most common marker for microsatellite testing; BAT 25, BAT26 and NR21 have been reported in HNPCC and sporadic CRCs (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28). Table 1 shows the reports from Iran that studied the frequency of MMR genes in both hereditary and sporadic colorectal cancers.…”

“…Table 1 shows the reports from Iran that studied the frequency of MMR genes in both hereditary and sporadic colorectal cancers. As it shows, the frequency of MSI in patients with HNPCC has been 29% -62.5% (9-25), there are not so many studies about the frequency of MSI in sporadic CRC from Iran; however, the reported frequencies of MMR have been from 19.4% to 66.6% (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25).…”

“…There are very few studies from Iran. Table 3 shows previous studies from Iran with BRAF mutation prevalence from 0 to 3.7% (18,30,48,49).…”

Effect of classification based on combination of mutation and methylation in colorectal cancer prognosis

“…The frequency of BRAF mutation in CRC patients differs among ethnic groups. Brim et al (28) analyzed BRAF mutation in CRC patients of different ethnic groups, African American, Omani and Iranian. Among these CRC patients, BRAF mutation was detected in 10% of the African Americans, 19% of the Omanis, and 2% of the Iranians.…”