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This KEGG map shows the order of genetic hits that turn normal pancreatic duct cells into ductal adenocarcinoma: KRAS mutation first, then loss of the p16 brake, then loss of TP53, SMAD4 and BRCA2. It matters because nearly every pancreatic cancer is driven by KRAS, which until recently had no drug.
Infiltrating ductal adenocarcinoma is the most common pancreatic malignancy and progresses from normal duct epithelium through histologically defined precursors (PanINs). KEGG map hsa05212 draws the sequence: HER2 (ERBB2) over-expression and activating KRAS point mutation occur early, inactivation of p16 (CDKN2A) at an intermediate stage, and inactivation of TP53, SMAD4 and BRCA2 relatively late. Activated KRAS engages several effector arms at once: RAF-MEK-ERK, PI3K-AKT and RalGDS. EGFR family receptors sit both upstream of RAS and downstream of it, because RAS induces autocrine EGFR ligands; HER2 also feeds JAK-STAT. Loss of p16 releases CDK4/6 and the G1/S checkpoint; loss of TP53 removes damage-induced arrest; loss of SMAD4 removes the growth-inhibitory arm of TGF-beta signalling. The tumours show extensive genomic instability and aneuploidy, to which telomere attrition and TP53 and BRCA2 mutation contribute.
Kleeff and colleagues, Nature Reviews Disease Primers, 2016 (doi:10.1038/nrdp.2016.22) review the disease: KRAS mutation is found in more than 90 percent of tumours, CDKN2A, TP53 and SMAD4 are the other frequently altered drivers, a dense stroma limits drug delivery, and germline BRCA1/2 and other homologous recombination defects define a subset that responds to platinum and PARP inhibition.
What drugs do about it: direct KRAS inhibition has arrived, with KRAS G12C inhibitors (sotorasib, adagrasib) for the small G12C subset and the pan-RAS(ON) inhibitor daraxonrasib in phase 3 for the common G12D and G12V mutations; olaparib maintenance treats germline BRCA-mutant disease after platinum; erlotinib with gemcitabine (listed by KEGG) gives a small EGFR-directed benefit; larotrectinib and entrectinib treat rare NTRK fusion tumours; pembrolizumab treats the rare MSI-high tumours. Cytotoxic chemotherapy (FOLFIRINOX, gemcitabine with nab-paclitaxel) remains the backbone.
A locked room escape in reverse. KRAS mutation is the first lock picked, and it opens three doors at once (ERK, PI3K, RalGDS). p16, TP53 and SMAD4 are guards posted at later doors, removed one by one. The room is also surrounded by a thick wall of scar-like stroma that keeps rescuers (drugs) out.
It is the reference multi-platform dataset and the reason a KRAS wild-type report is treated as a search for another driver rather than as an absence.
With Moffitt's classical and basal-like split (the squamous and basal-like groups overlap) this fixed the molecular vocabulary of the disease and gave Precision-Panc and the UK's Glasgow group their trial framework.
One pathway page on OnCo cites this paper by its DOI; this record gives the citation a page of its own so a reader can follow it without leaving OnCo. Read the abstract above alongside the citing page listed under Related; the record was created automatically from the Europe PMC entry and its figures have not been checked by hand.
The APGI cohort became the backbone of the QCMG whole-genome and subtype papers; ATM's entry here is the origin of its place on today's germline panels.
It set the frame that every later landscape paper filled in: pancreatic cancer is a disease of a few pathways broken by many different genes, so drugs must aim at pathways or their dependencies rather than one rare mutation.
Shares Solid pseudopapillary neoplasm of the pancreas, Undifferentiated carcinoma of the pancreas with osteoclast-like giant cells, Adenosquamous carcinoma of the pancreas, Colloid (mucinous non-cystic) carcinoma of the pancreas.
Shares Larotrectinib, Daraxonrasib, Entrectinib, Sotorasib.
Shares Pancreatic acinar cell carcinoma, KRAS G12C-mutant pancreatic ductal adenocarcinoma, KRAS wild-type pancreatic ductal adenocarcinoma, BRCA or PALB2-mutant pancreatic ductal adenocarcinoma.
Shares Solid pseudopapillary neoplasm of the pancreas, Undifferentiated carcinoma of the pancreas with osteoclast-like giant cells, Adenosquamous carcinoma of the pancreas, Colloid (mucinous non-cystic) carcinoma of the pancreas.
Shares SMAD4, Adagrasib, TGF-β signalling, Sotorasib.
Shares Solid pseudopapillary neoplasm of the pancreas, Undifferentiated carcinoma of the pancreas with osteoclast-like giant cells, Adenosquamous carcinoma of the pancreas, Classical versus basal-like (squamous) subtypes of pancreatic cancer, and GATA6.
Shares DNA damage response & homologous recombination, CDK4/6, PIK3CA / PI3K-alpha, p53 / RB / cell-cycle checkpoint.
Shares Adenosquamous carcinoma of the pancreas, Invasive carcinoma arising in an intraductal papillary mucinous neoplasm (IPMN-associated carcinoma), KRAS G12C-mutant pancreatic ductal adenocarcinoma, KRAS wild-type pancreatic ductal adenocarcinoma.