Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis of any common solid tumour. Multiple failed clinical trials necessitate newer... Show More
Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis of any common solid 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 disease models that should both recapitulate the molecular heterogeneity of PDAC and validate patient-specific therapeutic sensitivities. To date, deep characterization of PDAC PDX and PDO against their matched human tumour at the whole genome level remains largely unaddressed. We conducted a comprehensive assessment of the genetic landscape of 16 whole-genome pairs of tumours and matched PDX, from primary PDAC and liver metastasis, including a unique cohort of 5 â€˜triosâ€™ of matched primary tumour, PDX, and PDO. We developed a novel pipeline to assess and score concordance of genomic events from PDAC models against their paired human tumours. We applied our method across mutational profiles, structural variation, and copy number variation events to assess agreement between PDAC models and tumours at single-gene and genome-wide levels. Cross-comparison of genomic events emphasizes single-gene agreement of major PDAC driver genes, as well as genome-wide concordance of copy number changes, across both tumours and matching disease models. Genome-wide and chromosome-centric analysis of structural variation events demonstrates high variability of events across the samples, but reveals previously unrecognized concordance across chromosomes that demonstrate large clustering of structural variation (SV) events. Our approach demonstrates that PDX and PDO recapitulate PDAC tumourigenesis with respect to simple somatic mutations and copy number changes, and captures major structural variation events that are found in both resected and metastatic tumours.
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