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GATA6 is the transcription factor that separates the two pancreatic cancer subtypes that survive every re-analysis: classical tumours express it, basal-like (squamous) tumours have lost it. A GATA6 stain on a biopsy can therefore call the subtype that predicts how a tumour answers first-line chemotherapy, although no guideline yet acts on the result.
In the COMPASS study of advanced pancreatic ductal adenocarcinoma, real-time whole-genome and RNA sequencing of biopsies classed tumours as classical or basal-like; basal-like tumours were 20% of 195 patients, responded to first-line chemotherapy in 10% against 33% of classical tumours, progressed on modified FOLFIRINOX in 60% against 15%, and had median overall survival of 5.9 against 9.3 months (O'Kane 2020). GATA6 expression by RNA in situ hybridisation separated the two with sensitivity 89% and specificity 83%, so a single stain can stand in for sequencing. GATA6 amplification marks the classical lineage (15 to 17% of tumours in the molecular table), and loss of GATA6 sits on a continuum with mutant KRAS dosage: purified whole genomes show classical and basal-like states as the two ends of a spectrum with about 12% of tumours hybrid and intermediate in survival (Chan-Seng-Yue 2020). The earlier COMPASS report (Aung 2018) had already shown that sequencing in the time frame of a treatment decision was feasible in 63 patients. What follows for care: no prospective subtype-directed trial has changed a guideline, so basal-like patients still receive the regimen they resist; GATA6 or a subtype classifier is used where a trial requires it (the record's open problems).
In plain words · KRAS is the most commonly mutated cancer gene, called 'undruggable' for 40 years until 2021.
Showing the target this term concerns: KRAS.
It is the number behind 'basal-like is chemoresistant' and the validation of the GATA6 stain that lets a pathology laboratory call the subtype without RNA sequencing.
It explains why single-sample classifiers disagree on about one tumour in eight and why KRAS allelic imbalance and GATA6 copy number are being read alongside expression.
COMPASS is the prospective evidence that transcriptional subtype predicts chemotherapy response, and it produced the practical GATA6 test that trials now use to stratify.
Shares Pancreatic ductal adenocarcinoma and the tag pancreatic-molecular.
Shares Pancreatic ductal adenocarcinoma and the tag pancreatic-molecular.
Shares Pancreatic ductal adenocarcinoma and the tag pancreatic-molecular.
Shares Pancreatic ductal adenocarcinoma and the tag pancreatic-molecular.
Shares KRAS allelic imbalance and mutant KRAS dosage in pancreatic cancer, Transcription phenotypes of pancreatic cancer are driven by genomic events during tumor evolution, Pancreatic ductal adenocarcinoma.
Shares Genomics-driven precision medicine for advanced pancreatic cancer: early results from the COMPASS trial, GATA6 expression distinguishes classical and basal-like subtypes in advanced pancreatic cancer, Transcription phenotypes of pancreatic cancer are driven by genomic events during tumor evolution, Pancreatic ductal adenocarcinoma.
Shares Locally advanced unresectable pancreatic ductal adenocarcinoma, KRAS, Metastatic pancreatic ductal adenocarcinoma, Pancreatic ductal adenocarcinoma.
Shares RNA sequencing & expression profiling, KRAS, Pancreatic ductal adenocarcinoma.