Multiomic Characterization Reveals a Distinct Molecular Landscape in Young-Onset Pancreatic Cancer

• Type of Material: Article
• Authors: Ifeanyichukwu Ogobuiro, University of Miami; Yasmine Baca, Caris Life Sciences; Jennifer R. Ribeiro, Caris Life Sciences; Phillip Walker, Caris Life Sciences; Gregory C. Wilson, University of Cincinnati; Prateek Gulhati, The Cancer Institute of NJ; John L. Marshall, Georgetown University; Rachna T. Shroff, University of Arizona, Tucson; David Spetzler, Caris Life Sciences; Matthew J. Oberley, Caris Life Sciences; Daniel E. Abbott, University of Wisconsin, Madison; Hong Jin Kim, University of North Carolina, Chapel Hill; David A Kooby, Emory University; Shishir Kumar Maithel, Emory University; Syed A. Ahmad, University of Cincinnati; Nipun B. Merchant, University of Miami; Joanne Xiu, Caris Life Sciences; Peter J. Hosein, University of Miami; Jashodeep Datta, University of Miami
• Language: English
• Date: 2023-11-09
• Publisher: American Society of Clinical Oncology Journal
• Publication Version: Final Published Version
• Copyright Statement: © 2023 by American Society of Clinical Oncology
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): https://doi.org/10.1200/PO.23.00152
• Title of Journal or Parent Work: Precision Oncology
• Volume: 7
• Start Page: e2300152
• Grant/Funding Information: Supported by KL2 career development grant from the Miami Clinical and Translational Science Institute under National Institutes of Health (NIH) Award UL1TR002736, American College of Surgeons Franklin H. Martin Research Fellowship, Association for Academic Surgery Joel J. Roslyn Faculty Award, Society of Surgical Oncology Young Investigator Award, and Elsa U. Pardee Foundation Award (to J.D.). I.O. was supported by NIH/National Cancer Institute (NCI) T32 (to N.B.M.). Research reported in this publication was supported by the NCI/NIH Award P30CA240139 to the Sylvester Comprehensive Cancer Center.
• Keywords: PALB2-mutant tumors; young-onset pancreatic cancer; BRCA2-mutant; average-onset pancreatic cancer
• Research Categories: Health Sciences, Oncology; Biology, Molecular; Biology, Bioinformatics

Abstract

PURPOSE Using a real-world database with matched genomic-transcriptomic molecular data, we sought to characterize the distinct molecular correlates underlying clinical differences between patients with young-onset pancreatic cancer (YOPC; younger than 50 years) and patients with average-onset pancreatic cancer (AOPC; 70 years and older). METHODS We analyzed matched whole-transcriptome and DNA sequencing data from 2,430 patient samples (YOPC, n = 292; AOPC, n = 2,138) from the Caris Life Sciences database (Phoenix, AZ). Immune deconvolution was performed using the quanTIseq pipeline. Overall survival (OS) data were obtained from insurance claims (n = 4,928); Kaplan-Meier estimates were calculated for age- and molecularly defined cohorts. Significance was determined as FDR-corrected P values (Q) < .05. RESULTS Patients with YOPC had higher proportions of mismatch repair–deficient/microsatellite instability-high, BRCA2-mutant, and PALB2-mutant tumors compared with patients with AOPC, but fewer SMAD4-, RNF43-, CDKN2A-, and SF3B1-mutant tumors. Notably, patients with YOPC demonstrated significantly lower incidence of KRAS mutations compared with patients with AOPC (81.3% v 90.9%; Q = .004). In the KRAS wild-type subset (n = 227), YOPC tumors demonstrated fewer TP53 mutations and were more likely driven by NRG1 and MET fusions, whereas BRAF fusions were exclusively observed in patients with AOPC. Immune deconvolution revealed significant enrichment of natural killer cells, CD8+ T cells, monocytes, and M2 macrophages in patients with YOPC relative to patients with AOPC, which corresponded with lower rates of HLA-DPA1 homozygosity. There was an association with improved OS in patients with YOPC compared with patients with AOPC with KRAS wild-type tumors (median, 16.2 [YOPC-KRASWT] v 10.6 [AOPC-KRASWT] months; P = .008) but not KRAS-mutant tumors (P = .084). CONCLUSION In this large, real-world multiomic characterization of age-stratified molecular differences in pancreatic ductal adenocarcinoma, YOPC is associated with a distinct molecular landscape that has prognostic and therapeutic implications.