KRAS G>A mutation favors poor tumor differentiation but may not be associated with prognosis in patients with curatively resected duodenal adenocarcinoma

Abstract

KRAS mutations have been found in duodenal adenocarcinomas and may have prognostic significance. The purpose of this study was to classify clinicopathological characteristics, microsatellite instability, and KRAS mutations and identify possible prognostic role of KRAS mutations in duodenal adenocarcinomas. Demographics, tumor characteristics and survival were recorded for 78 patients with duodenal adenocarcinomas (stages I to III). KRAS mutations were detected in 27 (34.6%) cases, of which the majority (74.1%) were G>A transitions. Multivariate logistic regression analysis showed that KRAS G>A mutation was significantly associated with late stage (p = 0.025) and poor tumor differentiation (p = 0.035), when compared with wild-type and other than G>A mutations. KRAS G>A mutation carriers were at increased risk for distant relapse (p = 0.022) and had significantly shorter overall survival (OS; log-rank p = 0.045) and a trend toward shorter relapse-free survival (RFS; log-rank p = 0.062) when compared with those who did not carry the KRAS G>A mutation. In multivariate analyses, there was a significant correlation between ≥ 3 positive lymph nodes and poor OS (p < 0.001) and RFS (p = 0.001) and KRAS G>A mutation carriers demonstrated no effect on clinical outcome. In conclusion, KRAS G>A mutation correlates significantly with late stage and poor tumor differentiation in duodenal adenocarcinoma. Among patients who undergo a curative resection of duodenal adenocarcinoma, KRAS G>A mutation carriers will more likely experience distant relapse but may not exhibit a poor prognosis. Number of positive lymph nodes should be incorporated in future staging systems.

Clinicopathologic and prognostic associations of KRAS and BRAF mutations in small intestinal adenocarcinoma

“…Previous studies from Japan with homogeneous ethnic groups showed a wide range of frequencies of KRAS mutation (9-71%), [13][14][15]19 and other studies with heterogeneous ethnic groups, such as studies from USA, also reported various frequencies of KRAS mutation (14-83%). 10,17,18,20 Various KRAS mutation frequencies in the previous studies may be related with different detection methods rather than diverse ethnic background. Several different techniques for detecting KRAS and/or BRAF mutation were used, including restriction fragment length polymorphism, allele-specific oligonucleotide hybridization, PCR-single-strand conformation polymorphism, allele discrimination assay and Sanger sequencing.…”

“…Although a few previous studies of small intestinal adenocarcinomas have examined KRAS and/or BRAF mutations, which are well-known oncogenes in colorectal cancer, most of these analyses were performed on small numbers of patients (Table 9). 1,3,[10][11][12][13][14][15][16][17][18][19][20] The frequency of KRAS mutations among small intestinal adenocarcinomas ranged from 9 to 83% in the previous studies. Previous studies from Japan with homogeneous ethnic groups showed a wide range of frequencies of KRAS mutation (9-71%), [13][14][15]19 and other studies with heterogeneous ethnic groups, such as studies from USA, also reported various frequencies of KRAS mutation (14-83%).…”

“…Several different techniques for detecting KRAS and/or BRAF mutation were used, including restriction fragment length polymorphism, allele-specific oligonucleotide hybridization, PCR-single-strand conformation polymorphism, allele discrimination assay and Sanger sequencing. 1,3,[10][11][12][13][14][15][16][17][18][19][20] In addition to different detection techniques, differences in sample size may contribute to the wide range of KRAS mutation frequencies observed. The overall prevalence of KRAS mutations in the previous studies was 38% (150/400).…”

“…There has been considerable controversy regarding the prognostic significance of KRAS/BRAF mutations. 3,10 Many studies have investigated the prognostic value of KRAS/BRAF mutations on retrospectively collected cohorts of colorectal cancers patients, with conflicting results. 23,[28][29][30][31][32] Initially, KRAS was found to be an important prognostic indicator, but this finding was later restricted to G12V mutations.…”

“…1,3,[10][11][12][13][14][15][16][17][18][19][20] In addition, because most of these few analyses were performed on only small numbers of small intestinal adenocarcinoma patients, they need to be validated.…”