Distinct K-ras mutation pattern characterizes signet ring cell colorectal carcinoma

Purpose: Signet ring cell colorectal carcinoma (SRCCC) represents a unique, infrequent, and highly malignant variant of colorectal cancer. To understand the pathogenesis of SRCCC, we investigated its molecular abnormalities and compared them with those of the usual type of colorectal adenocarcinoma. Experimental Design: Microdissected archival paraffin-embedded tissue from 16 SRCCCs and 27 non-SRCCCs was used to determine the frequency and pattern of mutation at codons 12, 13, and 61 of K-ras. A subset of tumors was examined for TP53 mutations at exons 5-8 and allele loss and genetic instability using seven microsatellite and two mononucleotide markers. Results: Comparable data on TP53 mutation, allele loss, and microsatellite instability were found between SRCCC and non-SRCCC. However, SRCCCs demonstrated a distinct pattern of K-ras mutation with a significantly lower frequency of mutations at codons 12 and 13 (13% versus 48%, P = 0.02) as compared with the non-SRCCCs. Four cases (25%) of SRCCC demonstrated the same A:T transversion at the third base position of K-ras codon 61 (CAA to CAT; Gln to His). No such point mutation was detected in non-SRCCCs or in the 30 gastric and 4 urinary bladder signet ring cell carcinomas examined. Conclusions: Our findings suggest that a distinct pattern of K-ras mutation is present in SRCCC, including a specific codon 61 mutation that has rarely been reported in human neoplasms.