Clonal origins and parallel evolution of regionally synchronous colorectal adenoma and carcinoma

Abstract

Although the colorectal adenoma-to-carcinoma sequence represents a classical cancer progression model, the evolution of the mutational landscape underlying this model is not fully understood. In this study, we analyzed eight synchronous pairs of colorectal high-grade adenomas and carcinomas, four microsatellite-unstable (MSU) and four -stable (MSS) pairs, using whole-exome sequencing. In the MSU adenoma-carcinoma pairs, we observed no subclonal mutations in adenomas that became fixed in paired carcinomas, suggesting a ‘parallel’ evolution of synchronous adenoma-to-carcinoma, rather than a ‘stepwise’ evolution. The abundance of indel (in MSU and MSS pairs) and microsatellite instability (in MSU pairs) was noted in the later adenoma- or carcinoma-specific mutations, indicating that the mutational processes and functional constraints operative in early and late colorectal carcinogenesis are different. All MSU cases exhibited clonal, truncating mutations in ACVR2A, TGFBR2, and DNA mismatch repair genes, but none were present in APC or KRAS. In three MSS pairs, both APC and KRAS mutations were identified as both early and clonal events, often accompanying clonal copy number changes. An MSS case uniquely exhibited clonal ERBB2 amplification, followed by APC and TP53 mutations as carcinoma-specific events. Along with the previously unrecognized clonal origins of synchronous colorectal adenoma-carcinoma pairs, our study revealed that the preferred sequence of mutational events during colorectal carcinogenesis can be context-dependent.

Mutation heterogeneity between primary gastric cancers and their matched lymph node metastases

“…This suggests that the subclonal structures of somatic mutations, at least for the common mutations, are relatively conserved between two separate regional biopsies. This evolutionary pattern is also consistent with the paralleled evolution of multiple regional biopsies we have proposed for the development of synchronous colorectal adenomas and carcinomas [7].…”

“…These studies along with our previous works [7,8] have shown the potential of highthroughput sequencing-based multi-region analysis to identify the genomic aberrations associated with specific cellular events, such as the acquisition of malignant potential. For example, sequencing-based inference of subclonal architecture of cancer genomes using the burdens of mutant alleles may reveal the subclones arising during the progression or relapse of cancers as well as their evolutionary relationship with primary tumors [7,8]. In addition, the sequencing of multiple regional biopsies in given individuals and the mutation-based inference of phylogenetic trees have been used in elucidating the evolutionary relationship of regional biopsies (e.g., primary and metastatic genomes) [9,10].…”

“…Comparative studies have been published for primary GC genomes and peritoneal ascitic metastatic genomes [5,6]. These studies along with our previous works [7,8] have shown the potential of highthroughput sequencing-based multi-region analysis to identify the genomic aberrations associated with specific cellular events, such as the acquisition of malignant potential. For example, sequencing-based inference of subclonal architecture of cancer genomes using the burdens of mutant alleles may reveal the subclones arising during the progression or relapse of cancers as well as their evolutionary relationship with primary tumors [7,8].…”

“…In addition, we performed joint calling of somatic mutations so as not to overestimate the extent of heterogeneity. For this, the mutations called in either primary or LN genomes were reexamined for the presence of sequencing reads supporting the mutations in the other biopsy of the given case [7,10]. In the five cases with three matched LNs were examined, primary-and LN-specific mutations were also identified as those exclusive to primary or LN genomes.…”

Understanding intratumor heterogeneity by combining genome analysis and mathematical modeling

“…Furthermore, in multiregion sequencing, local heterogeneity can be evaluated by obtaining a sufficient number of reads for each of the multiregion samples. Multiregion sequencing has been reported in various types of tumors, so far including brain tumors, breast cancers, colorectal cancers, esophageal cancers, head and neck cancers, hepatocellular carcinomas, lung cancers, melanomas, ovarian cancers, pancreatic cancers, prostate cancers and urothelial carcinomas, as summarized comprehensively in a previous review . We also performed whole exome multiregion sequencing in 9 cases of colorectal cancers to identify founder and progressor mutations in each case .…”