Enhanced rate of acquisition of point mutations in mouse intestinal adenomas compared to normal tissue?

The genomes of thousands of human cancers have been sequenced, revealing a largenumber of single nucleotide substitutions (SNSs) per cancer. The SNSs present incancer conform to distinct mutation signatures, the most prevalent of which comprisesC to T substitutions in the context of CpG motifs. It has been suggested that the SNSsbelonging to this signature arise during organismal aging, before transformation of anormal cell to a cancer cell. However, our previous study of human colon adenomasshowed that the number of SNSs in each tumor correlates with tumor size and notpatient age, arguing that SNSs arise after cellular transformation. To resolve the twoviewpoints, we sequenced organoids derived from single intestinal normal or cancercells of APC-mutant mice. SNSs were at least ten times more frequent in the tumorthan in the normal cells, even though both cell types were derived from the same mice.We propose that most mutations in intestinal cancers arise after a normal cell istransformed into a cancer cell, contrary to the current view that mutations are acquiredduring organismal aging.