Genomic Features and Classification of Homologous Recombination Deficient Pancreatic Ductal Adenocarcinoma

Gastroenterology. 2021 May;160(6):2119-2132.e9. doi: 10.1053/j.gastro.2021.01.220. Epub 2021 Jan 30.


Background and aims: Homologous recombination deficiency (HRD) in pancreatic ductal adenocarcinoma (PDAC), remains poorly defined beyond germline (g) alterations in BRCA1, BRCA2, and PALB2.

Methods: We interrogated whole genome sequencing (WGS) data on 391 patients, including 49 carriers of pathogenic variants (PVs) in gBRCA and PALB2. HRD classifiers were applied to the dataset and included (1) the genomic instability score (GIS) used by Myriad's MyChoice HRD assay; (2) substitution base signature 3 (SBS3); (3) HRDetect; and (4) structural variant (SV) burden. Clinical outcomes and responses to chemotherapy were correlated with HRD status.

Results: Biallelic tumor inactivation of gBRCA or PALB2 was evident in 43 of 49 germline carriers identifying HRD-PDAC. HRDetect (score ≥0.7) predicted gBRCA1/PALB2 deficiency with highest sensitivity (98%) and specificity (100%). HRD genomic tumor classifiers suggested that 7% to 10% of PDACs that do not harbor gBRCA/PALB2 have features of HRD. Of the somatic HRDetecthi cases, 69% were attributed to alterations in BRCA1/2, PALB2, RAD51C/D, and XRCC2, and a tandem duplicator phenotype. TP53 loss was more common in BRCA1- compared with BRCA2-associated HRD-PDAC. HRD status was not prognostic in resected PDAC; however in advanced disease the GIS (P = .02), SBS3 (P = .03), and HRDetect score (P = .005) were predictive of platinum response and superior survival. PVs in gATM (n = 6) or gCHEK2 (n = 2) did not result in HRD-PDAC by any of the classifiers. In 4 patients, BRCA2 reversion mutations associated with platinum resistance.

Conclusions: Germline and parallel somatic profiling of PDAC outperforms germline testing alone in identifying HRD-PDAC. An additional 7% to 10% of patients without gBRCA/PALB2 mutations may benefit from DNA damage response agents.

Keywords: Homologous Recombination Deficiency; Pancreatic Ductal Adenocarcinoma; Whole Genome Sequencing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Alleles
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Carcinoma, Pancreatic Ductal / genetics*
  • Carcinoma, Pancreatic Ductal / therapy
  • Cisplatin / administration & dosage
  • DNA-Binding Proteins / genetics
  • Deoxycytidine / administration & dosage
  • Deoxycytidine / analogs & derivatives
  • Drug Resistance, Neoplasm / genetics
  • Fanconi Anemia Complementation Group N Protein / genetics*
  • Female
  • Fluorouracil / therapeutic use
  • Gemcitabine
  • Genes, BRCA1*
  • Genes, BRCA2*
  • Genomic Instability
  • Germ-Line Mutation
  • Homologous Recombination
  • Humans
  • Irinotecan / therapeutic use
  • Leucovorin / therapeutic use
  • Male
  • Middle Aged
  • Oxaliplatin / therapeutic use
  • Pancreatectomy
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / therapy
  • Prognosis
  • Recombinational DNA Repair*
  • Sensitivity and Specificity
  • Survival Rate
  • Tumor Suppressor Protein p53 / genetics
  • Whole Genome Sequencing


  • DNA-Binding Proteins
  • Fanconi Anemia Complementation Group N Protein
  • PALB2 protein, human
  • RAD51C protein, human
  • RAD51D protein, human
  • Tumor Suppressor Protein p53
  • XRCC2 protein, human
  • folfirinox
  • Oxaliplatin
  • Deoxycytidine
  • Irinotecan
  • Cisplatin
  • Leucovorin
  • Fluorouracil
  • Gemcitabine