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Wnt/β-catenin is a developmental pathway hijacked by colorectal cancer. Normally a destruction complex keeps β-catenin low; losing APC lets it flood the nucleus and drive growth genes.
Without Wnt, β-catenin is phosphorylated by the destruction complex (APC, AXIN, GSK3β, CK1) and degraded. Wnt binding to Frizzled/LRP5/6 disables the complex; β-catenin accumulates, enters the nucleus, and with TCF/LEF drives MYC, cyclin D1, LGR5, AXIN2. APC loss initiates ~80% of colorectal cancers; CTNNB1 mutations occur in HCC, endometrial, and desmoid tumours; RNF43/RSPO alterations define a ligand-dependent subset. Wnt is also immunosuppressive (excludes dendritic cells). Drugs have been hard: porcupine inhibitors for RSPO/RNF43 tumours, tankyrase inhibitors, and nirogacestat (gamma-secretase, desmoid) are the closest.
β-catenin is a messenger constantly being shredded by a committee (APC and friends). A Wnt signal tells the committee to stand down. Colorectal cancer fires the committee (APC loss), so the messenger runs unchecked into the nucleus.
Molecular confirmation that the visible precursor is not always the parent of the cancer beside it, which tempers hopes that finding and removing dysplasia catches every tumour, and puts Wnt signalling through CTNNB1 at the start of the raised route.
It gives surveillance a target and a timetable: catch high-grade dysplasia and there are about three years before invasion, and TGF-beta pathway loss is the event to detect.
A three-continent cohort from high-incidence countries, and the origin of the idea that a shared frameshift (ELF3) could be a vaccine target in a cancer with few targets. CTNNB1 and STK11 from this list recur in the MSK data.
It fills the gap between the primary-tumour atlases and the castration-resistant series by describing the disease at the moment most treatment decisions are actually made, and it identifies SPOP as a favourable marker rather than a neutral one.
It links the molecular route to the practical failure mode: interval cancers after a clear colonoscopy are disproportionately serrated, so detection quality is a molecular problem as much as a technical one.
It turned sidedness from an epidemiological curiosity into a mechanistic statement, and it is the reason a wild-type mitogenic report on a left-sided tumour is read as ligand dependence rather than as an absence.
It gives a genetic account of both immunotherapy failures: why some mismatch repair deficient tumours resist, and why the microsatellite-stable majority has no T cells in it to begin with.
It is the study that justified using plasma instead of a bone biopsy in this disease, with the honest caveat attached: the concordance holds only above a tumour fraction threshold, and below it the test is uninformative rather than negative.
Shares Macrocyclic peptides to cover protein surfaces that pills cannot, Terminology, molecular features, epidemiology, and management of serrated colorectal neoplasia, Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets, Signalling pathway.
Shares Hallmark: evading growth suppressors, Oncogenic genomic alterations, clinical phenotypes and outcomes in metastatic castration-sensitive prostate cancer, Endometrial cancer (KEGG map), Thyroid cancer (KEGG map).
Shares Nirogacestat, Genomic analyses identify molecular subtypes of pancreatic cancer, Hedgehog signalling, Cancer stem cell theory and phenotypic plasticity.
Shares Genomic characterization of malignant progression in neoplastic pancreatic cysts, Clinical sequencing defines the genomic landscape of metastatic colorectal cancer, Genetic alterations during colorectal-tumor development, Genomic analyses identify molecular subtypes of pancreatic cancer.
Shares The consensus molecular subtypes of colorectal cancer, Consensus molecular subtypes (CMS1-4), Endometrial cancer (KEGG map), Gastric cancer (KEGG map).
Shares Eric R. Fearon, Genetic alterations during colorectal-tumor development, APC, Colorectal cancer (KEGG map).
Shares Hallmark: evading growth suppressors, Adenoma-carcinoma sequence, Oncogenic genomic alterations, clinical phenotypes and outcomes in metastatic castration-sensitive prostate cancer, Concordance of circulating tumour DNA and matched metastatic tissue biopsy in prostate cancer.
Shares Clinical sequencing defines the genomic landscape of metastatic colorectal cancer, Endometrial cancer (KEGG map), Proteoglycans in cancer, Gastric cancer (KEGG map).