Abstract
Accumulation of allelic variants in genes that regulate cellular proliferation, differentiation, and apoptosis may result in expansion of the aberrant intestinal epithelium, generating adenomas. Herein, we compared the mutation profiles of conventional colorectal adenomas (CNADs) across stages of progression towards early carcinoma. DNA was isolated from 17 invasive adenocarcinomas (ACs) and 58 large CNADs, including 19 with low-grade dysplasia (LGD), 21 with LGD adjacent to areas of high-grade dysplasia and/or carcinoma (LGD-H), and 28 with high-grade dysplasia (HGD). Ion AmpliSeq Comprehensive Cancer Panel libraries were prepared and sequenced on the Ion Proton. We identified 956 unique allelic variants; of these, 499 were considered nonsynonymous variants. Eleven genes (APC, KRAS, SYNE1, NOTCH4, BLNK, FBXW7, GNAS, KMT2D, TAF1L, TCF7L2, and TP53) were mutated in at least 15% of all samples. Out of frequently mutated genes, TP53 and BCL2 had a consistent trend in mutation prevalence towards malignancy, while two other genes (HNF1A and FBXW7) exhibited the opposite trend. HGD adenomas had significantly higher mutation rates than LGD adenomas, while LGD-H adenomas exhibited mutation frequencies similar to those of LGD adenomas. A significant increase in copy number variant frequency was observed from LGD through HGD to malignant samples. The profiling of advanced CNADs demonstrated variations in mutation patterns among colorectal premalignancies. Only limited numbers of genes were repeatedly mutated while the majority were altered in single cases. Most genetic alterations in adenomas can be considered early contributors to colorectal carcinogenesis.
Highlights
IntroductionPolygenic disorders that arise in multistep microevolutionary processes involving the selection of successive cellular clones that occur in response to specific environmental factors, as well as genetic influences
Cancers are highly heterogeneous, polygenic disorders that arise in multistep microevolutionary processes involving the selection of successive cellular clones that occur in response to specific environmental factors, as well as genetic influences
19 samples were from adenomas containing only low-grade dysplasia (LGD, benign adenomas), 21 were from adenomas with LGD associated with synchronous high-grade dysplasia adenoma and/or carcinoma components (LGD-H), 28 were from high-grade dysplasia (HGD) adenomas, and 17 were from submucosal invasive adenocarcinoma (AC)
Summary
Polygenic disorders that arise in multistep microevolutionary processes involving the selection of successive cellular clones that occur in response to specific environmental factors, as well as genetic influences. Colorectal cancer (CRC) is a common epithelial neoplasia worldwide and a leading cause of cancer-related morbidity and mortality [1]. There are multiple colorectal neoplastic pathways, including the chromosomal instability (CIN) pathway, the microsatellite instability (MSI) pathway, and the CpG island methylator pathway (CIMP, referred to as the serrated neoplasia pathway) [3]. Most CRCs are sporadic, with only 5–10% tumors developing as part of highly penetrant hereditary syndromes, mediated by rare germline mutations in genes involved in DNA mismatch repair or the adenomatous polyposis coli (APC) gene [4].
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