# Association of distinct mutational signatures with correlates of increased immune activity in pancreatic ductal adenocarcinoma

Source: https://onco.cc/key-papers/paper-connor-mutational-signatures-immune-pancreatic-jama-oncol-2017/  
OnCo record `paper-connor-mutational-signatures-immune-pancreatic-jama-oncol-2017` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Summary

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.

## Fields

- Kind: Key paper
- Last checked: 2026-09-24
- Journal: JAMA Oncology
- Year: 2017
- DOI: 10.1001/jamaoncol.2016.3916
- Authors: Connor AA, Denroche RE, Jang GH, et al.
- Findings: Four signature subtypes: age-related, double-strand break repair, mismatch repair, signature 8.; 45% of double-strand break repair cases had no BRCA1, BRCA2 or PALB2 event.; Repair-defective subtypes express more cytotoxic and checkpoint genes with more neoantigens.
- What it means: Signatures find repair-deficient tumours that gene panels miss, and they mark the minority in which checkpoint drugs have a rationale.
- Caveats: Resected cohort; no immunotherapy outcomes.; Signature calling depends on tumour enrichment.

## Sources

- Connor et al., JAMA Oncol 2017: mutational signatures and immune activity in 160 plus 95 whole genomes: https://doi.org/10.1001/jamaoncol.2016.3916
- PubMed: https://pubmed.ncbi.nlm.nih.gov/27768182/

## Connected records

- biomarkers: [HRD-positive (genomic instability score)](https://onco.cc/biomarkers/hrd-positive/)
- cancers: [Pancreatic ductal adenocarcinoma](https://onco.cc/cancers/pancreatic/)
- technologies: [Whole-exome & whole-genome sequencing](https://onco.cc/technologies/wes-wgs/)
- targets: [BRCA1 / BRCA2 (HRD)](https://onco.cc/targets/brca/), [Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2)](https://onco.cc/targets/mmr/), [PALB2](https://onco.cc/targets/palb2/)
- institutions: [Ontario Institute for Cancer Research](https://onco.cc/institutions/oicr/), [Princess Margaret Cancer Centre](https://onco.cc/institutions/princess-margaret/)
- pathways: [Antigen presentation & immune editing](https://onco.cc/pathways/antigen-presentation-immunoediting/), [Double-strand break repair: HR versus end joining](https://onco.cc/pathways/homologous-recombination-repair/), [Mutagenesis & mutational signatures](https://onco.cc/pathways/mutagenesis-signatures/)
- terms: [Mutational signature](https://onco.cc/terms/mutational-signature/), [Neoantigen](https://onco.cc/terms/neoantigen/)
- journals: [JAMA Oncology](https://onco.cc/journals/jama-oncology/)

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