Whole-exome sequencing identified mutational profiles of high-grade colon adenomas

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.

Genetic alterations related to endoscopic treatment of colorectal tumors

“…31 In CRC patients, SMAD4 alterations in advanced stage cancers reportedly contributed to tumor metastasis. 32 In our study, SMAD4 alterations occurred during carcinogenesis, but the frequency of SMAD4 alterations was not high in advanced CRCs. 32 In our study, SMAD4 alterations occurred during carcinogenesis, but the frequency of SMAD4 alterations was not high in advanced CRCs.…”

WRN Helicase is a Synthetic Lethal Target in Microsatellite Unstable Cancers

“…Polymerase epsilon (POLE) exonuclease domain mutational classifications: POLE exonuclease domain mutational classifications were determined by compiling the previously described functional POLE exonuclease domain mutations from these reports 30,31,45 . Specifically, the following were considered proofread-impairing POLE exonuclease domain mutations: Differential dependency analysis: Genes that were preferentially dependent in MSI compared to MSS cell lines were identified using linear modeling performed in parallel across genes using the R package Limma 46 .…”

Smad4/DPC4

“…Smad4 mutation is rarely detected in colon adenomas, with 0.8% (2/246) of smad4 mutations in the Catalogue Of Somatic Mutations In Cancer database being reported in colon adenomas 29. However, recently, Lee and colleagues performed whole exome sequencing of 12 high-grade colonic adenomas (HGCAs) and found that five HGCAs harboured either monoallelic (four HGCAs) or biallelic (one HGCA) smad4 mutation or 18q loss 29.…”

“…However, recently, Lee and colleagues performed whole exome sequencing of 12 high-grade colonic adenomas (HGCAs) and found that five HGCAs harboured either monoallelic (four HGCAs) or biallelic (one HGCA) smad4 mutation or 18q loss 29. The authors suggest that monoallelic inactivation of smad4 either by mutation or copy loss may rarely occur in HGCAs and that it may require an additional hit during or after the progression to invasive or metastatic CRC 29…”