DR-454 The genomic landscapes of MLH1-mutated and/or CTNNB1-mutated colorectal carcinomas

Colorectal cancer (CRC) is a heterogeneous disease comprising subtypes with distinct clinical and/or molecular characteristics. Roughly, two major categories of sporadic CRCs are discerned i.e. ‘classical’ chromosomal instable (85%) and microsatellite-instable (MSI) CRCs (15%), the latter being characterized by erroneous replication of nucleotide-repeat sequences and significantly higher mutation frequencies than classical CRCs and therefore  also denoted as hypermutated CRCs. In the vast majority of CRCs, the Wnt route is constitutively active due to deletion of and/or loss-of-function mutations in the APC gene. In 1-5% of all sporadic CRCs however the Wnt pathway is unleashed by activating CTNNB1 mutations. 

We studied MSI CRCs lacking MLH1 and PMS2 expression as due to bi-allelic inactivating MLH1 gene mutations, either somatic or in germline. Interestingly, we found that in 60% of sporadic and 40% of MLH1-Lynch-associated MSI CRCs the WNT pathway is driven by activating CTNNB1 mutations instead of APC mutations.  Based on these findings, we define a subgroup of MSI CRCs potentially derived of yet unidentified precursor lesions.

Carel Van Noesel, Amsterdam UMC, the Netherlands