# Whole genomes redefine the mutational landscape of pancreatic cancer

Source: https://onco.cc/key-papers/paper-waddell-whole-genomes-pancreatic-nature-2015/  
OnCo record `paper-waddell-whole-genomes-pancreatic-nature-2015` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

The 2015 whole-genome study of 100 pancreatic cancers that sorted them by how broken their chromosomes were and noticed that the most unstable tumours, often with BRCA-type defects, responded to platinum chemotherapy.

## Summary

Waddell and colleagues of the Australian Pancreatic Cancer Genome Initiative performed whole-genome sequencing and copy number analysis of 100 pancreatic ductal adenocarcinomas. Chromosomal rearrangements disrupting known genes (TP53, SMAD4, CDKN2A, ARID1A, ROBO2) and new candidates (KDM6A, PREX2) were prevalent. Patterns of structural variation classified the tumours into four subtypes: stable, locally rearranged, scattered and unstable. Focal amplifications containing druggable oncogenes (ERBB2, MET, FGFR1, CDK6, PIK3R3, PIK3CA) were found at low individual prevalence. Genomic instability co-segregated with inactivation of BRCA1, BRCA2 or PALB2 and a DNA damage repair deficiency signature; of eight patients who received platinum, four of five with these measures of defective DNA maintenance responded.

## Fields

- Kind: Key paper
- Last checked: 2026-09-24
- Tags: pancreatic-evidence
- Journal: Nature
- Year: 2015
- DOI: 10.1038/nature14169
- Authors: Waddell N, Pajic M, Patch AM, et al.
- Findings: 100 whole genomes; four structural subtypes: stable, locally rearranged, scattered, unstable.; Druggable focal amplifications (ERBB2, MET, FGFR1, CDK6, PIK3R3, PIK3CA) at low individual prevalence.; Unstable genomes co-segregated with BRCA1, BRCA2 or PALB2 inactivation; 4 of 5 such patients responded to platinum.
- What it means: The genomic case for platinum in BRCA-type pancreatic cancer, four years before POLO built a maintenance strategy on top of it.
- Caveats: Eight platinum-treated patients; the response observation is a hint, not a trial.; Whole-genome sequencing was not routine clinical practice in 2015 and is not routine in the NHS pathway now.

## Sources

- Nature 2015: https://doi.org/10.1038/nature14169
- PubMed: https://pubmed.ncbi.nlm.nih.gov/25719666/

## Connected records

- key papers: [Genomic analyses identify molecular subtypes of pancreatic cancer](https://onco.cc/key-papers/paper-bailey-molecular-subtypes-pancreatic-nature-2016/), [POLO: maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer](https://onco.cc/key-papers/paper-polo-olaparib-maintenance-gbrca-pancreatic-nejm-2019/)
- cancers: [BRCA or PALB2-mutant pancreatic ductal adenocarcinoma](https://onco.cc/cancers/brca-palb2-pdac/), [Pancreatic ductal adenocarcinoma](https://onco.cc/cancers/pancreatic/)
- technologies: [HRD & BRCA testing](https://onco.cc/technologies/hrd-testing/), [Platinum agents](https://onco.cc/technologies/platinum/), [Whole-exome & whole-genome sequencing](https://onco.cc/technologies/wes-wgs/)
- targets: [BRCA1 / BRCA2 (HRD)](https://onco.cc/targets/brca/), [CDKN2A](https://onco.cc/targets/cdkn2a/), [HER2](https://onco.cc/targets/her2/), [KDM6A](https://onco.cc/targets/kdm6a/), [PALB2](https://onco.cc/targets/palb2/), [SMAD4](https://onco.cc/targets/smad4/), [TP53](https://onco.cc/targets/tp53/)
- institutions: [Garvan Institute of Medical Research / Kinghorn Cancer Centre](https://onco.cc/institutions/garvan-institute/)
- pathways: [Chromosomal instability & aneuploidy](https://onco.cc/pathways/chromosomal-instability/), [DNA damage response & homologous recombination](https://onco.cc/pathways/ddr/), [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: [Germline BRCA mutation (gBRCA)](https://onco.cc/terms/gbrca-mutation/), [Homologous recombination deficiency (HRD)](https://onco.cc/terms/hrd/), [Mutational signature](https://onco.cc/terms/mutational-signature/), [Platinum-sensitive / platinum-resistant](https://onco.cc/terms/platinum-sensitivity/)
- journals: [Nature](https://onco.cc/journals/nature/)
- roadmaps: [Pancreatic cancer roadmap: from Whipple's operation to gemcitabine, FOLFIRINOX, adjuvant chemotherapy, PARP inhibition, KRAS inhibition, vaccines and the surveillance question](https://onco.cc/roadmaps/pancreatic-roadmap/)
- biomarkers: [HRD-positive (genomic instability score)](https://onco.cc/biomarkers/hrd-positive/)

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