High Frequency Of Lman1 Abnormalities In Colorectal Tumors With Microsatellite Instability

Glycosyl epitopes have been identified as tumor-specific markers in colorectal tumors and various lines of evidence indicate the significance of altered synthesis, transport, and secretion of glycoproteins in tumorigenesis. However, aberrant glycosylation has been largely ignored in microsatellite unstable (MSI-H) colorectal tumors. Therefore, we analyzed mutation frequencies of genes of the cellular glycosylation machinery in MSI-H tumors, focusing on frameshift mutations in coding MNRs (cMNRs). Among 28 candidate genes, LMAN1/ ERGIC53, a mannose-specific lectin mediating endoplasmatic reticulum (ER)-to-Golgi transit of glycosylated proteins, showed high mutation frequency in MSI-H colorectal cancer cell tines (52%; 12 of 23), carcinomas (45%; 72 of 161), and adenomas (40%; 8 of 20). Biallelic mutations were observed in 17% (4 of 23) of MSI-H colorectal cancer cell lines. LMAN1 was found to he transcribed but truncated protein remained undetectable in these LMAN1-mutant cell lines. lmmunohistochemical and molecular analysis of LAMNI-mutated carcinomas and adenomas revealed regional loss of LMAN1 expression due to biallelic LAMN1 cMNR frameshift mutations. In LMAN1-deficient colorectal cancer cell lines, secretion of the LMAN1 client protein alpha-1-antitrypsin (A1AT), an inhibitor of angiogenesis and tumor growth, was significantly impaired but could be restored upon LNM1 re-expression. These results suggest that LMAN1 mutational inactivation is a frequent and early event potentially contributing to MSI-H tumorigenesis. [Cancer Res 2009;69(1):292-9]