title: 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.
authors.affiliation: 1] Ludwig Colon Cancer Initiative Laboratory, Ludwig Institute for Cancer Research, Royal Melbourne Hospital, Parkville, Victoria, Australia [2] Department of Surgery, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Royal Melbourne Hospital, Parkville, Victoria, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Christie
authors.forename: R N
authors.initials: RN
authors.lastname: Jorissen
authors.forename: D
authors.initials: D
authors.lastname: Mouradov
authors.forename: A
authors.initials: A
authors.lastname: Sakthianandeswaren
authors.forename: S
authors.initials: S
authors.lastname: Li
authors.forename: F
authors.initials: F
authors.lastname: Day
authors.forename: C
authors.initials: C
authors.lastname: Tsui
authors.forename: L
authors.initials: L
authors.lastname: Lipton
authors.forename: J
authors.initials: J
authors.lastname: Desai
authors.forename: I T
authors.initials: IT
authors.lastname: Jones
authors.forename: S
authors.initials: S
authors.lastname: McLaughlin
authors.forename: R L
authors.initials: RL
authors.lastname: Ward
authors.forename: N J
authors.initials: NJ
authors.lastname: Hawkins
authors.forename: A R
authors.initials: AR
authors.lastname: Ruszkiewicz
authors.forename: J
authors.initials: J
authors.lastname: Moore
authors.forename: A W
authors.initials: AW
authors.lastname: Burgess
authors.forename: D
authors.initials: D
authors.lastname: Busam
authors.forename: Q
authors.initials: Q
authors.lastname: Zhao
authors.forename: R L
authors.initials: RL
authors.lastname: Strausberg
authors.forename: A J
authors.initials: AJ
authors.lastname: Simpson
authors.forename: I P M
authors.initials: IP
authors.lastname: Tomlinson
authors.forename: P
authors.initials: P
authors.lastname: Gibbs
authors.forename: O M
authors.initials: OM
authors.lastname: Sieber
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D003062:Codon / Q000235:genetics; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D017491:Genes, APC; D005838:Genotype; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D009154:Mutation; D009928:Organ Specificity; D012004:Rectal Neoplasms / Q000235:genetics / Q000473:pathology; D017384:Sequence Deletion; D012811:Sigmoid Neoplasms / Q000235:genetics / Q000473:pathology; D060449:Wnt Signaling Pathway / Q000235:genetics
chemical_list: D003062:Codon