Different APC genotypes in proximal and distal sporadic colorectal cancers suggest distinct WNT/β-catenin signalling thresholds for tumourigenesis

Abstract

Biallelic protein-truncating mutations in the adenomatous polyposis coli (APC) gene are prevalent in sporadic colorectal cancer (CRC). Mutations may not be fully inactivating, instead producing WNT/β-catenin signalling levels ‘just-right' for tumourigenesis. However, the spectrum of optimal APC genotypes accounting for both hits, and the influence of clinicopathological features on genotype selection remain undefined. We analysed 630 sporadic CRCs for APC mutations and loss of heterozygosity (LOH) using sequencing and single-nucleotide polymorphism microarrays, respectively. Truncating APC mutations and/or LOH were detected in 75% of CRCs. Most truncating mutations occurred within a mutation cluster region (MCR; codons 1282–1581) leaving 1–3 intact 20 amino-acid repeats (20AARs) and abolishing all Ser-Ala-Met-Pro (SAMP) repeats. Cancers commonly had one MCR mutation plus either LOH or another mutation 5′ to the MCR. LOH was associated with mutations leaving 1 intact 20AAR. MCR mutations leaving 1 vs 2–3 intact 20AARs were associated with 5′ mutations disrupting or leaving intact the armadillo-repeat domain, respectively. Cancers with three hits had an over-representation of mutations upstream of codon 184, in the alternatively spliced region of exon 9, and 3′ to the MCR. Microsatellite unstable cancers showed hyper-mutation at MCR mono- and di-nucleotide repeats, leaving 2–3 intact 20AARs. Proximal and distal cancers exhibited different preferred APC genotypes, leaving a total of 2 or 3 and 0 to 2 intact 20AARs, respectively. In conclusion, APC genotypes in sporadic CRCs demonstrate ‘fine-tuned' interdependence of hits by type and location, consistent with selection for particular residual levels of WNT/β-catenin signalling, with different ‘optimal' thresholds for proximal and distal cancers.

Apc Restoration Promotes Cellular Differentiation and Reestablishes Crypt Homeostasis in Colorectal Cancer

“…The reason behind this difference remains unclear, but may reflect differences in the mechanism of Apc disruption and/or the level of Wnt signaling induction. In agreement, analysis of human CRCs reveals selection for particular types of alterations in WNT pathway modulators in different regions of the colon (Albuquerque et al, 2010; Christie et al, 2013), while detailed comparisons between the mouse and human intestine show distinct differences in the expression of Wnt pathway genes (Leedham et al, 2013). Alternatively, the mouse-human differences in previous models may be due to species-specific changes in stem cell behavior (Tomasetti and Vogelstein, 2015).…”

Microbiota impact on the epigenetic regulation of colorectal cancer

“…Approximately 70–80% of sporadic colorectal adenomas and carcinomas have somatic mutations of APC , and nearly all of these mutations result in premature truncation of the APC protein [5]. Inactivation of APC leads to inappropriate and constitutive activation of the Wnt signaling pathway, a general mechanism of CRC development [53]. APC mutations are found in even the earliest lesions, such as microscopic adenomas consisting of a few dysplastic glands [5].…”

Targeted next generation sequencing of pancreatic solid pseudopapillary neoplasms show mutations in Wnt signaling pathway genes

“…We also detected a separate case of SPN with a frameshift deletion affecting the APC gene. This particular variant c.3964delG p.(Glu1322Lysfs*93) is extremely rare, having only been reported once in a colorectal cancer with COSMIC ID COSM4169380 . Our data from the non‐tumoral tissue using Sanger sequencing indicate that the variant is somatic, rather than germline.…”

“…This particular variant c.3964delG p.(Glu1322Lysfs à 93) is extremely rare, having only been reported once in a colorectal cancer with COSMIC ID COSM4169380. 25 Our data from the non-tumoral tissue using Sanger sequencing indicate that the variant is somatic, rather than germline. To the best of our knowledge this is the first report of a potentially pathogenic APC variant found in SPN.…”