AIM: To examine Krüppel-like factor 6 (KLF6) mutations in nonpolypoid-type tumors and alterations of K-ras, p53,and B-raf in relation between mutation and morphologic type, particularly nonpolypoid-type colorectal carcinomas.METHODS: Fifty-five early nonpolypoid colorectal carcinomas were analyzed. Loss of heterozygosity (LOH) of KLF6 and p53 was determined by microsatellite assay.Mutations of KLF6, K-ras, and B-raf were examined by polymerase chain reaction-single-strand conformation polymorphism followed by direct sequencing. In LOH-positive and/or mutation-positive tumors, multiple (4-7) samples in each tumor were microdissected and examined for genetic alterations, p53 expression was evaluated by immunohistochemistry.RESULTS: LOH of KLF6 and p53 was found in 14 of 29 (48.3%) and 14 of 31 (45.2%) tumors, respectively. In 10 of the 14 (71.4%) KLF6 LOH-positive tumors and 9 of the 14 (64.3%) p53 LOH-positive tumors, LOH was found in all of the microdissected samples. In 1 of the 10 (10.0%) KLF6 LOH-positive tumors, a single missense mutation was identified. K-ras and B-raf mutations were found in 5 of 55 (9.1%) and 6 of 55 (10.9%) tumors,respectively. However, these mutations were detected only in subsets of microdissected tumor samples.CONCLUSION: These data suggest that KLF6 and p53 mutations are involved in the development of nonpolypoid colorectal carcinoma, whereas K-ras and B-raf mutations are not.