Multi-omic molecular comparison of primary versus metastatic pancreatic tumours

Abstract

BACKGROUND: Molecular profiling is increasingly used to match patients with metastatic cancer to targeted therapies, but obtaining a high-quality biopsy specimen from metastatic sites can be difficult. METHODS: Patient samples were received by Perthera to coordinate genomic, proteomic and/or phosphoproteomic testing, using a specimen from either the primary tumour or a metastatic site. The relative frequencies were compared across specimen sites to assess the potential limitations of using a primary tumour sample for clinical decision support. RESULTS: No significant differences were identified at the gene or pathway level when comparing genomic alterations between primary and metastatic lesions. Site-specific trends towards enrichment of MYC amplification in liver lesions, STK11 mutations in lung lesions and ATM and ARID2 mutations in abdominal lesions were seen, but were not statistically significant after falsediscovery rate correction. Comparative analyses of proteomic results revealed significantly elevated expression of ERCC1 and TOP1 in metastatic lesions. CONCLUSIONS: Tumour tissue limitations remain a barrier to precision oncology efforts, and these real-world data suggest that performing molecular testing on a primary tumour specimen could be considered in patients with pancreatic adenocarcinoma who do not have adequate tissue readily available from a metastatic site.

Whole genome sequencing identifies rare germline variants enriched in cancer related genes in first degree relatives of familial pancreatic cancer patients

“…Mutational and transcriptional changes in some of the significant genes in Table 2 have previously been shown to be associated with PDAC. Brar et al (2019) 34 found that LRP1B (low-density lipoprotein receptor-related protein 1B) mutations are more frequent in metastatic lesions than in primary pancreatic tissue suggesting that mutation in this tumor suppressor gene may promote PDAC metastasis.…”

Accurate Prognosis Prediction of Pancreatic Ductal Adenocarcinoma Using Integrated Clinico-Genomic Data of Endoscopic Ultrasound-Guided Fine Needle Biopsy

“…Integration of genomic and transcriptional features in pancreatic cancer revealed that cell cycle progression was increased in PDAC metastases with driver gene ( KRAS , TP53 , CDKN2A , SMAD4 ) loss [ 28 ]. Moreover, mutations in known driver genes in the metastases of individual patients with PDAC were remarkably uniform [ 29 ], and no significant differences were identified at the gene or pathway level when comparing genomic alterations between primary and metastatic pancreatic tumors [ 30 ]. Many studies have reported some genes which may be involved in tumor metastasis, such as KAI1 and nm23-H1 in pancreatic cancer [ 31 ].…”

Diagnostic, Predictive and Prognostic Molecular Biomarkers in Pancreatic Cancer: An Overview for Clinicians

“…Moreover, other organ-specific diseases, such as chronic pancreatitis, pancreatic duct obstruction, jaundice, and diabetes, may confound the performance of a protein biomarker in pancreatic cancer detection. Composite markers or scores, focusing on multi-omics approaches [ 147 ] with the concomitant application of computational biology and artificial intelligence principles, can enhance detection accuracy and provide a better robustness. These panels of markers can be initially tested in high-risk patients (smokers, chronic pancreatitis, mucinous neoplasms of the pancreas, and genetic predisposition) before being validated in lower risk patients [ 148 , 149 , 150 ].…”