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A very low incidence of BRAF mutations in Middle Eastern colorectal carcinoma.

Siraj AK, Bu R, Prabhakaran S, Bavi P, Beg S, Al Hazmi M, Al-Rasheed M, Alobaisi K, Al-Dayel F, AlManea H, Al-Sanea N, Uddin S, Al-Kuraya KS - Mol. Cancer (2014)

Bottom Line: BRAF mutations were significantly associated with right sided tumors (p = 0.0019), MSI-H status (p = 0.0144), CIMP (p = 0.0017) and a high proliferative index of Ki67 expression (p = 0.0162).Our results highlight the low incidence of BRAF mutations and CIMP in CRC from Saudi Arabia.This could be attributed to ethnic differences and warrant further investigation to elucidate the effect of other environmental and genetic factors.

View Article: PubMed Central - HTML - PubMed

Affiliation: Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, MBC#98-16, P,O, Box 3354 Riyadh 11211, Saudi Arabia. kkuraya@kfshrc.edu.sa.

ABSTRACT

Background: Recent studies emphasize the role of BRAF as a genetic marker for prediction, prognosis and risk stratification in colorectal cancer. Earlier studies have reported the incidence of BRAF mutations in the range of 5-20% in colorectal carcinomas (CRC) and are predominantly seen in the serrated adenoma-carcinoma pathway characterized by microsatellite instability (MSI-H) and hypermethylation of the MLH1 gene in the setting of the CpG island methylator phenotype (CIMP). Due to the lack of data on the true incidence of BRAF mutations in Saudi Arabia, we sought to analyze the incidence of BRAF mutations in this ethnic group.

Methods: 770 CRC cases were analyzed for BRAF and KRAS mutations by direct DNA sequencing.

Results: BRAF gene mutations were seen in 2.5% (19/757) CRC analyzed and BRAF V600E somatic mutation constituted 90% (17/19) of all BRAF mutations. BRAF mutations were significantly associated with right sided tumors (p = 0.0019), MSI-H status (p = 0.0144), CIMP (p = 0.0017) and a high proliferative index of Ki67 expression (p = 0.0162). Incidence of KRAS mutations was 28.6% (216/755) and a mutual exclusivity was noted with BRAF mutations (p = 0.0518; a trend was seen).

Conclusion: Our results highlight the low incidence of BRAF mutations and CIMP in CRC from Saudi Arabia. This could be attributed to ethnic differences and warrant further investigation to elucidate the effect of other environmental and genetic factors. These findings indirectly suggest the possibility of a higher incidence of familial hereditary colorectal cancers especially Hereditary non polyposis colorectal cancer (HNPCC) syndrome /Lynch Syndrome (LS) in Saudi Arabia.

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Impact of KRAS and BRAF mutations in CRC and the Kaplan–Meier. Survival analysis. (A) Colorectal cancer patients with KRAS mutations had reduced overall survival of 63.5% at 5 years compared with 73.5% without KRAS mutations (p = 0.0078). (B) In CRC patients, there was no significance in survival between BRAF mutated and non mutated cases. (p = 0.3310).
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Figure 2: Impact of KRAS and BRAF mutations in CRC and the Kaplan–Meier. Survival analysis. (A) Colorectal cancer patients with KRAS mutations had reduced overall survival of 63.5% at 5 years compared with 73.5% without KRAS mutations (p = 0.0078). (B) In CRC patients, there was no significance in survival between BRAF mutated and non mutated cases. (p = 0.3310).

Mentions: The prognostic significance of KRAS and BRAF mutation was analyzed with the use of the Kaplan–Meier method. Patients with KRAS mutation had poorer survival as compared to CRC with wild type KRAS gene (p = 0.0078) (Figure 2A). In the multivariate analysis using the Cox proportional hazard model (Additional file3: Table S2) for multiple factors such as age, gender, AJCC stage, microsatellite instability and tumor differentiation, the relative risk was 1.75 for CRC with KRAS mutation(95% CI 1.26-2.42; p = 0.0011) and 6.70 for advanced AJCC stage(95% CI 4.78-9.31; p ≤ 0.0001). Thus, KRAS mutation was an independent prognostic marker for poor survival in CRC across all stages. We also assessed the overall survival of KRAS mutation at codon12 and codon13. Amongst the KRAS-mutated cases, mutation in codon 12 was associated with the worst survival (62.8%; p = 0.0230) compared with codon 13 mutations (64.7%) or absence of KRAS mutations (73.5%). BRAF mutation was not associated with any prognostic significance (p = 0.3310; Figure 2B).


A very low incidence of BRAF mutations in Middle Eastern colorectal carcinoma.

Siraj AK, Bu R, Prabhakaran S, Bavi P, Beg S, Al Hazmi M, Al-Rasheed M, Alobaisi K, Al-Dayel F, AlManea H, Al-Sanea N, Uddin S, Al-Kuraya KS - Mol. Cancer (2014)

Impact of KRAS and BRAF mutations in CRC and the Kaplan–Meier. Survival analysis. (A) Colorectal cancer patients with KRAS mutations had reduced overall survival of 63.5% at 5 years compared with 73.5% without KRAS mutations (p = 0.0078). (B) In CRC patients, there was no significance in survival between BRAF mutated and non mutated cases. (p = 0.3310).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4109832&req=5

Figure 2: Impact of KRAS and BRAF mutations in CRC and the Kaplan–Meier. Survival analysis. (A) Colorectal cancer patients with KRAS mutations had reduced overall survival of 63.5% at 5 years compared with 73.5% without KRAS mutations (p = 0.0078). (B) In CRC patients, there was no significance in survival between BRAF mutated and non mutated cases. (p = 0.3310).
Mentions: The prognostic significance of KRAS and BRAF mutation was analyzed with the use of the Kaplan–Meier method. Patients with KRAS mutation had poorer survival as compared to CRC with wild type KRAS gene (p = 0.0078) (Figure 2A). In the multivariate analysis using the Cox proportional hazard model (Additional file3: Table S2) for multiple factors such as age, gender, AJCC stage, microsatellite instability and tumor differentiation, the relative risk was 1.75 for CRC with KRAS mutation(95% CI 1.26-2.42; p = 0.0011) and 6.70 for advanced AJCC stage(95% CI 4.78-9.31; p ≤ 0.0001). Thus, KRAS mutation was an independent prognostic marker for poor survival in CRC across all stages. We also assessed the overall survival of KRAS mutation at codon12 and codon13. Amongst the KRAS-mutated cases, mutation in codon 12 was associated with the worst survival (62.8%; p = 0.0230) compared with codon 13 mutations (64.7%) or absence of KRAS mutations (73.5%). BRAF mutation was not associated with any prognostic significance (p = 0.3310; Figure 2B).

Bottom Line: BRAF mutations were significantly associated with right sided tumors (p = 0.0019), MSI-H status (p = 0.0144), CIMP (p = 0.0017) and a high proliferative index of Ki67 expression (p = 0.0162).Our results highlight the low incidence of BRAF mutations and CIMP in CRC from Saudi Arabia.This could be attributed to ethnic differences and warrant further investigation to elucidate the effect of other environmental and genetic factors.

View Article: PubMed Central - HTML - PubMed

Affiliation: Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, MBC#98-16, P,O, Box 3354 Riyadh 11211, Saudi Arabia. kkuraya@kfshrc.edu.sa.

ABSTRACT

Background: Recent studies emphasize the role of BRAF as a genetic marker for prediction, prognosis and risk stratification in colorectal cancer. Earlier studies have reported the incidence of BRAF mutations in the range of 5-20% in colorectal carcinomas (CRC) and are predominantly seen in the serrated adenoma-carcinoma pathway characterized by microsatellite instability (MSI-H) and hypermethylation of the MLH1 gene in the setting of the CpG island methylator phenotype (CIMP). Due to the lack of data on the true incidence of BRAF mutations in Saudi Arabia, we sought to analyze the incidence of BRAF mutations in this ethnic group.

Methods: 770 CRC cases were analyzed for BRAF and KRAS mutations by direct DNA sequencing.

Results: BRAF gene mutations were seen in 2.5% (19/757) CRC analyzed and BRAF V600E somatic mutation constituted 90% (17/19) of all BRAF mutations. BRAF mutations were significantly associated with right sided tumors (p = 0.0019), MSI-H status (p = 0.0144), CIMP (p = 0.0017) and a high proliferative index of Ki67 expression (p = 0.0162). Incidence of KRAS mutations was 28.6% (216/755) and a mutual exclusivity was noted with BRAF mutations (p = 0.0518; a trend was seen).

Conclusion: Our results highlight the low incidence of BRAF mutations and CIMP in CRC from Saudi Arabia. This could be attributed to ethnic differences and warrant further investigation to elucidate the effect of other environmental and genetic factors. These findings indirectly suggest the possibility of a higher incidence of familial hereditary colorectal cancers especially Hereditary non polyposis colorectal cancer (HNPCC) syndrome /Lynch Syndrome (LS) in Saudi Arabia.

Show MeSH
Related in: MedlinePlus