High Frequency of KRAS Codon 146 and FBXW7 Mutations in Thai Patients with Stage II-III Colon Cancer

Abstract

Background: KRAS, NRAS, and BRAF gene mutations are the most clinically relevant and frequently reported in colorectal cancer (CRC). Although data on these genes are frequently reported in several counties, data specific to these genes among Thai population are scarce. The aim of this study was to investigate and identify molecular alterations associated with colon cancer in Thai population, and to determine the impact of these genetic aberrations on clinical outcome. Methods:DNA from 108 archived formalin-fixed, paraffin-embedded (FFPE) tissue samples that histologically confirmed adenocarcinoma of stage II-III colon cancer between 2010 and 2012 at Siriraj Hospital (Bangkok, Thailand) were extracted. Gene mutational analysis was performed by next-generation sequencing (NGS) using an Oncomine Solid Tumor DNA kit (Thermo Fisher Scientific, Inc., Waltham, MA, USA). Results:A total of 22 somatic gene mutations were detected. The mutation frequency observed in KRAS, NRAS, BRAF, PIK3CA, and FBXW7 mutations was 47.2%, 1.9%, 1.9%, 12%, and 14.8%, respectively. KRAS mutation codon 12, 13, 59, 61, 117, and 146 mutations were identified in 29.6%, 8.3%, 1.8%, 0.9%, 0.0%, and 8.3%, respectively. KRAS Exon 4 had better DFS compared with Exon 2 and 3. Conclusions:This study is the first to comprehensively report hotspot mutations using NGS in Thai colon cancer patients. The most commonly identified gene mutation frequencies among Thai patients (KRAS, NRAS, BRAF, TP53, and PIK3CA) were similar to the gene mutation frequencies reported in Western population, except for subgroup of KRAS codon 146 and FBXW7 mutations that had a slightly higher frequency.

Mutations in the KRAS gene as a predictive biomarker of therapeutic response in patients with colorectal cancer

“…Additionally, similar to the results of other authors [24,25] we noticed that mutations G12D and G12V are the most prevalent in the Serbian population. We found that the frequency of mutations in codons 59, 117 and 146 were 1.5%, which is in concordance with the study of Awidi et al [26] while a higher prevalence of the mutation in codon 146 was observed in patients from Thailand, where 8.3% of them had this mutation [27]. Many authors evaluated correlations between mutations in KRAS, age and sex of patients with clinicopathological characteristics of CRC and some of the results indicate that both tumor location and KRAS status play important roles in the prognosis of CRC patients [19,20,28].…”

KRAS A146 Mutations Are Associated With Distinct Clinical Behavior in Patients With Colorectal Liver Metastases

“…Some studies describe a more favorable clinical outcome in patients with CRC with a KRAS A146-mutated tumor upon anti-EGFR treatment compared with patients with tumors carrying another KRAS mutation. [54][55][56][57] Other studies show that tumors with a KRAS A146 mutation, like other KRAS mutations, are responsible for anti-EGFR resistance. [58][59][60][61] In this study, the homogenous population of initially unresectable liver-only metastatic CRC patients all receiving the same treatment regimen allowed for an unbiased comparison of the clinical features of patients harboring different KRAS tumor mutations.…”

TCGA database analysis of the tumor mutation burden and its clinical significance in colon cancer

“…These results showed that missense mutations, SNP, and C>T mutations are the most common mutations in colon cancer. Former studies (33)(34)(35) have also confirmed that missense mutations are the most common type of colon cancer, and SNPs located in regulatory elements can affect the expression of coding genes through remote regulation, leading to cancer. We found that the four genes with the highest mutation frequency were APC, TP53, TTN, and KRAS, which is consistent with the results of previous studies (36).…”