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Reading the mutation patterns in 255 whole genomes sorted pancreatic cancers into four types, and the two with broken DNA repair carried more mutations, more neoantigens and more signs of an immune response, suggesting who might respond to immunotherapy.
Retrospective ICGC cohort of resected pancreatic ductal adenocarcinoma: a discovery set of 160 tumour-enriched cases (154 patients) with whole-genome and RNA sequencing and a replication set of 95 bulk cases. Non-negative matrix factorisation measured signature contributions; hierarchical clustering gave five predominant mutational signatures in four subtypes: age-related, double-strand break repair, mismatch repair and unknown aetiology (signature 8), replicated and stable from primaries to matched metastases. Twelve of 27 (45%) double-strand break repair cases lacked germline or somatic events in BRCA1, BRCA2 or PALB2. Double-strand break repair and mismatch repair subtypes showed increased antitumour immunity expression (GZMA, PRF1) and regulatory molecules (CTLA-4, PD-1, IDO1), corresponding to higher somatic mutation and neoantigen frequency.
Signatures find repair-deficient tumours that gene panels miss, and they mark the minority in which checkpoint drugs have a rationale.
Shares HRD-positive (genomic instability score), PALB2, Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), Mutagenesis & mutational signatures.
Shares HRD-positive (genomic instability score), PALB2, Mutagenesis & mutational signatures, Mutational signature.
Shares HRD-positive (genomic instability score), PALB2, Mutational signature, Double-strand break repair: HR versus end joining.
Shares Ontario Institute for Cancer Research, Princess Margaret Cancer Centre, Whole-exome & whole-genome sequencing, Pancreatic ductal adenocarcinoma.
Shares HRD-positive (genomic instability score), Mutational signature, Whole-exome & whole-genome sequencing, BRCA1 / BRCA2 (HRD).
Shares Ontario Institute for Cancer Research, Princess Margaret Cancer Centre, Whole-exome & whole-genome sequencing, Pancreatic ductal adenocarcinoma.
Shares Antigen presentation & immune editing, Neoantigen, Whole-exome & whole-genome sequencing, Pancreatic ductal adenocarcinoma.
Shares Ontario Institute for Cancer Research, Princess Margaret Cancer Centre.