Frameshift mutations of autophagy‐related genes ATG2B, ATG5, ATG9B and ATG12 in gastric and colorectal cancers with microsatellite instability

Abstract

Mounting evidence indicates that alterations of autophagy processes are directly involved in the development of many human diseases, including cancers. Autophagy-related gene (ATG) products are main players in the autophagy process. In humans there are 16 known ATG genes, of which four (ATG2B, ATG5, ATG9B and ATG12) have mononucleotide repeats with seven or more nucleotides. Frameshift mutations of genes with mononucleotide repeats are features of cancers with microsatellite instability (MSI). It is not known whether ATG genes with mononucleotide repeats are altered by frameshift mutations in gastric and colorectal carcinomas with MSI. For this, we analysed the mononecleotide repeats in ATG2B, ATG5, ATG9B and ATG12 in 32 gastric carcinomas with high MSI (MSI-H), 13 gastric carcinomas with low MSI (MSI-L), 43 colorectal carcinomas with MSI-H and 15 colorectal carcinomas with MSI-L by a single-strand conformation polymorphism (SSCP) analysis. We found ATG2B, ATG5, ATG9B and ATG12 mutations in 10, 2, 13 and 0 cancers, respectively. The mutations were detected in MSI-H cancers but not in MSI-L cancers. Gastric and colorectal cancers with MSI-H harboured one or more ATG mutations in 28.1% and 27.9%, respectively. Our data indicate that frameshift mutations in ATG genes with mononucleotide repeats are common in gastric and colorectal carcinomas with MSI-H, and suggest that these mutations may contribute to cancer development by deregulating the autophagy process.

Nilotinib Induces Autophagy in Hepatocellular Carcinoma through AMPK Activation

“…In contrast, accumulating evidence shows that suppression of the proteins involved in autophagy such as Beclin-1 and Atg-5 may cause acceleration of tumorigenesis. Deletion of one copy of an autophagy-related gene (47), or reduced expression level of such genes has been found in certain types of cancer cells (48). Our present data show that nilotinib induces autophagy which contributes to cytotoxicity, rather than drug-resistance in HCC cells.…”

Autophagy inhibits oxidative stress and tumor suppressors to exert its dual effect on hepatocarcinogenesis

“…5 Frameshift mutations in Atg2B, Atg5, Atg9B and Atg12 autophagy genes are also often found in gastric and colorectal cancers with microsatellite instability. 6 The tumor suppressor role of autophagy is further supported by the studies using mouse models. It has been shown that the monoallelic deletion of the Beclin-1 gene in mice induced tumor lesions in various tissues, 7 Atg4C-knockout (KO) mice had increased susceptibility to carcinogens for the development of fibrosarcomas 8 and the systemic mosaic KO of Atg5 and the liver-specific KO of Atg7 in mice led to the development of benign liver adenomas.…”

Autophagy and genomic integrity

“…16 Further, genes involved in autophagy are monoallelically inactivated in human cancers or occur in genes whose deletion only partially reduces autophagy. Moreover, frameshift mutations were identified in UVRAG, atg2B, atg5 and atg9B in colorectal and in gastric carcinomas with microsatellite instability (MSI), but not in DNA from normal tissues of the same patients, [119][120][121] although the effects of these mutations on autophagic flux were not determined.…”