Abstract
Although gene-to-gene analyses identified genetic alterations such as APC, KRAS and TP53 mutations in colon adenomas, it is largely unknown whether there are any others in them. Mutational profiling of high-grade colon adenoma (HGCA) that just precedes colon carcinoma might identify not only novel adenoma-specific genes but also critical genes for its progression to carcinoma. For this, we performed whole-exome sequencing (WES) of 12 HGCAs and identified 11 non-hypermutated and one hypermutated (POLE-mutated) cases. We identified 22 genes including APC, KRAS, TP53, GNAS, NRAS, SMAD4, ARID2, and PIK3CA with non-silent mutations in the cancer Census Genes. Bi-allelic and mono-allelic APC alterations were found in nine and one HGCAs, respectively, while the other two harbored wild-type APC. Five HGCAs harbored either mono-allelic (four HGCAs) or bi-allelic (one HGCA) SMAD4 mutation or 18q loss that had been known as early carcinoma-specific changes. We identified MTOR, ACVR1B, GNAQ, ATM, CNOT1, EP300, ARID2, RET and MAP2K4 mutations for the first time in colon adenomas. Our WES data is largely matched with the earlier ‘adenoma-carcinoma model’ (APC, KRAS, NRAS and GNAS mutations), but there are newly identified SMAD4, MTOR, ACVR1B, GNAQ, ATM, CNOT1, EP300, ARID2, RET and MAP2K4 mutations in this study. Our findings provide resource for understanding colon premalignant lesions and for identifying genomic clues for differential diagnosis and therapy options for colon adenomas and carcinomas.
Highlights
Colorectal cancer (CRC) is the third most common cancer in males, and the second most common in females worldwide [1]
The C: G->T: A transitions were the most significant changes in the high-grade colon adenoma (HGCA) samples (Figure 1B and Supplementary Table 2), which was consistent with a previous report that analyzed a colon adenoma [13]
We attempted to disclose the genomic profiles of HGCAs to find the mutational abundance compared to that of CRC especially with respect to the driver mutations
Summary
Colorectal cancer (CRC) is the third most common cancer in males, and the second most common in females worldwide [1]. The www.impactjournals.com/oncotarget multistep model in the adenoma-to-carcinoma sequence is well recognized in CRC development [3]. According to this model, most CRCs are considered to arise from pre-existing adenomas. Conventional colorectal adenomas are classified on the basis of their architectural phenotype as either tubular or villous or tubulovillous type. According to the cellular atypia, they are classified as either low- or high-grade colon adenoma (HGCA) [4]. SMAD4 mutation is rarely detected in colon adenomas but occurs in intramucosal carcinoma and more commonly in invasive carcinomas with metastases [8, 9]
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