Whole Genomes Define Concordance in Matched Primary, Xenograft, and Organoid Models of Pancreas Cancer

Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis of any common solid epithelial tumour. Multiple failed clinical trials necessitate newer approaches to understand the molecular etiology of this disease. Patient-derived xenografts (PDX) and patient-derived organoids (PDO) may serve as pre-clinical disease models; however, characterization remains largely unaddressed at the whole genome level. We conducted a comprehensive assessment of the genetic landscape of tumours and matched PDX and PDO from patients with PDAC. Our data show that PDX and PDO recapitulate PDAC tumourigenesis with respect to simple somatic mutations and copy number changes, and capture major structural variation events.

Type: Other
Archiver: European Genome-Phenome Archive (EGA)

4 Datasets 1 Publication

Click on a Dataset ID in the table below to learn more, and to find out who to contact about access to these data

Dataset ID	Description	Samples
EGAD00001003586	Whole Genomes Define Concordance in Matched Primary, Xenograft, and Organoid Models of Pancreas Cancer - WGS mapped reads	54
EGAD00001006152	Bam files from WGS of PDAC samples described in: Transcription phenotypes of pancreatic cancer are driven by genomic events events during tumour evolution	-
EGAD00001006262	Bam files from WGS of PDAC samples used in the PCSI mismatch repair study	-
EGAD00001007571	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 g_BRCA_ and PALB2. HRD classifiers were applied to the dataset and included: 1) the genomic instability score (GIS) used by Myriad 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 tumour inactivation of g_BRCA_ or PALB2 was evident in 43/49 germline carriers identifying HRD-PDAC. HRDetect (score ?0.7) predicted gBRCA1/PALB2 deficiency with highest sensitivity (98%) and specificity (100%). HRD genomic tumour classifiers suggested that 7-10% of PDAC that do not harbor g_BRCA/PALB2_ have features of HRD. Of the somatic HRDetect 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 to BRCA2-associated HRD-PDAC. HRD status was not prognostic in resected PDAC. However in advanced disease the GIS (p=0.02), SBS3 (p=0.03) and HRDetect score (p=0.005) were predictive of platinum response and superior survival. PVs in g_ATM_ (n=6) or g_CHEK2_ (n=2) did not result in HRD-PDAC by any of the classifiers. In four 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 7-10% of patients without gBRCA/PALB2 mutations may benefit from DNA damage response agents.	-

Publications	Citations
Whole genomes define concordance of matched primary, xenograft, and organoid models of pancreas cancer. Gendoo DMA, Denroche RE, Zhang A, Radulovich N, Jang GH, Lemire M, Fischer S, Chadwick D, Lungu IM, Ibrahimov E, Cao PJ, Stein LD, Wilson JM, Bartlett JMS, Tsao MS, Dhani N, Hedley D, Gallinger S, Haibe-Kains B. PLoS Comput Biol 15: 2019 e1006596	38