Characteristics of Advanced- and Non Advanced Sporadic Polypoid Colorectal Adenomas: Correlation to KRAS Mutations

Abstract

The malignant potential of colorectal adenomas highly correlates with their pathological characteristics, such as size, histology and grade of dysplasia. Currently, based on these parameters, adenomas are characterized as "non-advanced or advanced" and patient surveillance is adjusted accordingly. The aim of this study was to investigate the correlation between the KRAS mutations and characteristics of non-advanced and advanced colorectal adenomas for predicting the risk of increased malignant potential of adenomas that may influence the decision to offer follow-up endoscopic surveillance. We used a mutagenic polymerase chain reaction - restriction fragment length polymorphism method to determine KRAS mutations in 164 colorectal sporadic polypoid adenomas (51 non-advanced-, 113 advanced adenomas) and in 40 early colorectal carcinomas. The method of mutation detection was validated according to recommendation for KRAS mutation testing in colorectal carcinoma of the European Quality Assurance Program. The limit of detection of the assay was 3 % mutated DNA with a good reproducibility. Evaluation of pathological characteristics was performed according to European Guidelines for Quality Assurance in Colorectal Cancer Screening and Diagnosis. The morphological parameters of the adenoma such as size, histology, grade of dysplasia are highly correlated with one another: an increasing adenoma size raised the proportion of villous histology and degree of dysplasia (all p < 0.0001). KRAS mutations were detected in 31 % of the non-advanced adenomas, in 57.5 % of the advanced adenomas and in 62.5 % of the early carcinomas. Most mutations occurred at codon 12 rather than at codon 13 (72 %, 82 %, 76 % versus 22 %, 17 %, 24 %, respectively). There was no significant difference in association of KRAS mutation with age, gender, location among non-advanced-, and advanced adenomas and early carcinomas. KRAS mutation was found more often in tubulovillous and villous adenomas, whereas wild-type KRAS was observed more frequently in tubular adenomas (P < 0.0001) and there was an increased prevalence of KRAS mutations in larger adenomas (P < 0.0001). In this study KRAS mutation occurred with the same frequency in adenomas with low-grade (48 %) and high-grade (50 %) dysplasia. KRAS mutation is very strongly associated with a villous architecture and through villous component expansion, KRAS mutations may increase risk of tumor progression in sporadic colorectal polypoid adenomas.

KRAS and BRAF mutations and MSI status in precursor lesions of colorectal cancer detected by colonoscopy

“…This Our results indicated that BRAF is a prevalent marker in the serrated pathway. We observed BRAF mutation in ~40% of SAs and this is in line with previous studies that demonstrated a frequency of BRAF mutations (v600E) ranging from 32 to 82.9% (33). Collectively, our findings, as well as those of others, are in agreement with a recent study using BRAF V600E knock-in murine models that demonstrate the pivotal role of BRAF mutations in the initiation of the serrated pathway (35).…”

“…KRAS mutations were significantly associated with advanced adenomas, which have a greater risk of developing into malignant tumors than non-advanced adenomas. Yadamsuren et al demonstrated that 57.5% of advanced adenomas harbored KRAS mutations compared with 31.0% of non-advanced adenomas in a series of 164 sporadic adenomas (33). These findings are in agreement with the Fearon and vogelstein model where KRAS mutation is responsible for the intermediate stage of adenoma progression (33).…”

“…Yadamsuren et al demonstrated that 57.5% of advanced adenomas harbored KRAS mutations compared with 31.0% of non-advanced adenomas in a series of 164 sporadic adenomas (33). These findings are in agreement with the Fearon and vogelstein model where KRAS mutation is responsible for the intermediate stage of adenoma progression (33). At variance, we did not observe KRAS mutations in SAs, contrasting with some studies that report the presence of KRAS mutations, yet at lower frequencies (8-16,5%) (24,34).…”

K-ras Mutations as the Earliest Driving Force in a Subset of Colorectal Carcinomas

“…Thus, K-ras mutation does not confer to the metastatic potential of colorectal carcinomas. v. K-ras mutation does not confer to the formation of early adenomas (confirming other researchers) (32,55,82), but it rather aids the evolution of the non-advanced adenoma to the advanced one (data not shown).…”

“…It is among the earliest genetic events of the process (51) although it is well known that it can occur at any stage (52). Its mutations are present in 50-95% of dysplastic ACF (34,53), in 15-78% of colorectal adenomas (54,55) and in 36-42% of CRCs (56). K-ras mutations on codons 12/13 of exon 2 and on codon 61 of exon 3 are de novo mutations whose presence depends on the random "activation" of the protooncogene K-ras during the life-span of healthy individuals either due to carcinogen exposure or to sporadic replication errors (57).…”