Multiclonal colorectal cancers with divergent histomorphological features and RAS mutations: one cancer or separate cancers?
Journal
Human Pathology
Journal Volume
98
Pages
120-128
Date Issued
2020
Author(s)
Abstract
Detection of coexisting mutations within the same signal transduction pathway, which are expected to be mutually exclusive, raises a concern of laboratory errors. We have previously confirmed the presence of different RAS (KRAS and NRAS) mutations in the adenoma and/or adenocarcinoma subpopulations of colorectal cancers (CRCs). In this study, multiregional analyses by next-generation sequencing were conducted to elucidate the mechanisms underlying multiple RAS mutations seen in 5 CRC specimens. Multiregional analyses were initially conducted in a single tissue block originally submitted for mutational profiling. In 2 specimens, mutational status of the APC gene was not identical, indicating collisional adenoma and adenocarcinoma. In 3 specimens, the same APC mutation was present in different subpopulations with divergent RAS mutations, indicating a common clonal origin. Subsequent comprehensive multiregional analyses of additional adenoma and adenocarcinoma components revealed multiclonal CRCs with divergent histomorphological features and RAS mutations originating from a common APC-mutated founder lineage of adenoma, but from different RAS-mutated founder lineages of adenocarcinoma. These findings are consistent with the stepwise model of colorectal tumorigenesis along with parallel evolution, which affects RAS genes within the mitogen-activated protein kinase pathway and occurs during the progression from adenomas to adenocarcinomas. Evaluation of tumor subpopulations with divergent histomorphological features by pathologists may help identify multiclonal CRCs. Further studies are warranted to evaluate the incidence of multiclonality in CRCs and its impact on clinical outcomes. Perhaps, multiclonal CRCs originating from the same APC-mutated founder lineage of adenoma but from different RAS-mutated founder lineages of adenocarcinomas should be defined and managed as separate CRCs. ? 2020 Elsevier Inc.
Subjects
Colorectal cancer; KRAS; Multiclonality; NRAS; Parallel evolution
SDGs
Other Subjects
protein kinase; APC protein; APC protein, human; guanosine triphosphatase; KRAS protein, human; membrane protein; NRAS protein, human; protein p21; tumor marker; Article; cancer growth; cancer tissue; clonal variation; colon carcinogenesis; colorectal adenoma; colorectal carcinoma; gene mutation; high throughput sequencing; human; human tissue; major clinical study; oncogene; oncogene apc; oncogene ras; pyrosequencing; adenocarcinoma; adenoma; cell lineage; cell transformation; colorectal tumor; disease exacerbation; genetic predisposition; genetics; mutation; pathology; phenotype; tumor invasion; Adenocarcinoma; Adenoma; Adenomatous Polyposis Coli Protein; Biomarkers, Tumor; Cell Lineage; Cell Transformation, Neoplastic; Colorectal Neoplasms; Disease Progression; Genetic Predisposition to Disease; GTP Phosphohydrolases; Humans; Membrane Proteins; Mutation; Neoplasm Invasiveness; Phenotype; Proto-Oncogene Proteins p21(ras)
Publisher
W.B. Saunders
Type
journal article