Integrated Multiregional Analysis Proposing a New Model of Colorectal Cancer Evolution

Abstract

Understanding intratumor heterogeneity is clinically important because it could cause therapeutic failure by fostering evolutionary adaptation. To this end, we profiled the genome and epigenome in multiple regions within each of nine colorectal tumors. Extensive intertumor heterogeneity is observed, from which we inferred the evolutionary history of the tumors. First, clonally shared alterations appeared, in which C>T transitions at CpG site and CpG island hypermethylation were relatively enriched. Correlation between mutation counts and patients’ ages suggests that the early-acquired alterations resulted from aging. In the late phase, a parental clone was branched into numerous subclones. Known driver alterations were observed frequently in the early-acquired alterations, but rarely in the late-acquired alterations. Consistently, our computational simulation of the branching evolution suggests that extensive intratumor heterogeneity could be generated by neutral evolution. Collectively, we propose a new model of colorectal cancer evolution, which is useful for understanding and confronting this heterogeneous disease.

The PI3K Pathway in Human Disease

“…These same two genes appear to be particularly prone to heterogeneous mutation patterns in primary tumor tissues. Subclonal mutations in PIK3CA were reported in several cancer subtypes, including NSCLC, colorectal cancer, breast cancer, and others (Harbst et al, 2016; de Bruin et al, 2014; McGranahan and Swanton, 2017; Uchi et al, 2016; Yates et al, 2015). Consistent with these findings, a study spanning nine cancer subtypes demonstrated that subclonal mutations in the PI3K-AKT-mTOR pathway were considerably more frequent than subclonal mutations in the RAS-MAPK pathway, which tended to be ubiquitously expressed in all subclones in the tumor (McGranahan et al, 2015).…”

Cancer evolution and heterogeneity

“…Therefore, the dN/dS ratio indicated that positively selected genes might exist under negative selection in advanced CRC. However, our previous study disclosed neutral evolution in advanced CRC with a number of minor (non‐driver) mutations according to our multisampling and sequence data 11. To comprehend this contradiction, we have provided the following possible explanation.…”

“…Neutral evolution along with clonal evolution is a principal cause of ITH and fosters advanced CRC 11. We simulated heterogeneous cancer evolution as “branching evolutionary process (BEP) model” by supercomupter (Figure 1).…”

“…1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 This multiregional analysis (MRA) sequencing approach enabled us not only to observe spatial heterogeneity, but also to calculate temporal alterations and eventually disclose the evolution of tumors. There are two types of somatic aberration in a tumor: ubiquitous aberrations (founder mutations, trunk mutations, or clonal mutations) and scattered aberrations (progressor mutations, branch/leaf mutations, or subclonal mutations).…”

Progression Potential of Ductal Carcinoma in situ Assessed by Genomic Copy Number Profiling

“…Additionally, recent NGS-based approaches to tumor heterogeneity demonstrated that chromosomal CNAs are the principal factor for tumor progression, whereas sequence changes of driver genes as well as chromosomal CNAs are important for the earlier phases of carcinogenesis [30]. In the present chromosome level CNA analysis, our penetrance plot of IDC (invasive part) showed a gain/loss pattern very similar to recent NGS data of 560 breast cancers [29], except for 9q loss, which was observed less frequently in our study.…”