Abstract
Advanced colorectal cancer harbors extensive intratumor heterogeneity shaped by neutral evolution; however, intratumor heterogeneity in colorectal precancerous lesions has been poorly studied. We perform multiregion whole-exome sequencing on ten early colorectal tumors, which contained adenoma and carcinoma in situ. By comparing with sequencing data from advanced colorectal tumors, we show that the early tumors accumulate a higher proportion of subclonal driver mutations than the advanced tumors, which is highlighted by subclonal mutations in KRAS and APC. We also demonstrate that variant allele frequencies of subclonal mutations tend to be higher in early tumors, suggesting that the subclonal mutations are subject to selective sweep in early tumorigenesis while neutral evolution is dominant in advanced ones. This study establishes that the evolutionary principle underlying intratumor heterogeneity shifts from Darwinian to neutral evolution during colorectal tumor progression.
Highlights
Advanced colorectal cancer harbors extensive intratumor heterogeneity shaped by neutral evolution; intratumor heterogeneity in colorectal precancerous lesions has been poorly studied
We found that multiple precancerous lesions of colorectal cancers (PCRCs) cases have evolutionary trees of forked tree-like shapes, which were not observed for advanced CRC (ACRC)
More direct evidence of Darwinian evolution was the observation that a significantly higher proportion of driver mutations accumulated as heterogeneous mutations in PCRC than in ACRC. (For simplicity, we discuss all results of the ubiquitous-heterogeneous categorization since analyses of the trunk-branch categorization produced similar results.) In particular, heterogeneous mutations in APC and KRAS were noteworthy; these mutations were completely recognized as ubiquitous events in ACRC13,14
Summary
Advanced colorectal cancer harbors extensive intratumor heterogeneity shaped by neutral evolution; intratumor heterogeneity in colorectal precancerous lesions has been poorly studied. Multiregion sequencing has revealed the landscapes of ITH for renal[1,2], breast[3], esophageal[4,5], lung[6,7], ovarian[8], prostate[9,10], pancreatic[11], and other types of cancer These studies have presented evidence that Darwinian evolution shapes at least part of ITH: there exist one or more subclonal driver events within distinct subclones of a tumor (hereafter, this evidence will be referred to as branched evolution). In contrast to our previous report about ACRC13, our multiregion analysis of the ten early colorectal tumors strongly suggests that Darwinian evolution plays a critical role in shaping ITH in the early phase of colorectal tumorigenesis
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