The earliest stages of colorectal neoplastic transformation

The succession of somatic genetic events associated with the conversion of a normal colorectal epithelial cell into a colorectal carcinoma constitutes a paradigmatic model of cancer development. To investigate the earliest stages of the progression, we microdissected and individually whole genome sequenced 279 histologically normal and abnormal colorectal crypts from 15 individuals with Familial Adenomatous Polyposis in whom one inherited APC gene allele carries an inactivating mutation. Histologically normal crypts generally exhibited similar mutation burdens and mutational signatures to normal crypts from wild-type individuals of the same age, and 1/110 such crypts carried a somatic inactivating APC mutation. By contrast, 9/17 aberrant crypt foci carried somatic APC mutations and these showed modestly increased burdens of some mutational signatures found in normal crypts. 16/16 diminutive adenomatous polyps (<5mm diameter) showed somatic APC mutations and carried substantially increased mutation loads of most mutational signatures present in normal crypts. Phylogenetic trees of crypts from aberrant crypt foci and adenomatous polyps revealed that some had acquired their initiating somatic APC mutations decades previously during the first few years of life. The results catalogue the changes in somatic mutation rates, mutational processes and “driver” mutations in cancer genes during very early stages of colorectal neoplastic transformation and highlight the long periods of clonal evolution required for a cancer to develop.

• DAC: EGAC00001000000
• Technologies: HiSeq X Ten, Illumina NovaSeq 6000