Real-Time Targeted Genome Profile Analysis of Pancreatic Ductal Adenocarcinomas Identifies Genetic Alterations That Might Be Targeted With Existing Drugs or Used as Biomarkers.

Abstract

BACKGROUND & AIMS:

It has been a challenge to select treatment for patients with pancreatic ductal adenocarcinomas (PDACs) based on genome alterations. We performed targeted genomic profile analyses of a large number of PDACs to assess the full spectrum of actionable genomic alterations.

METHODS:

We performed targeted genomic profile analyses of 3594 PDAC samples from an international cohort, including capture-based targeted genomic profiling of as many as 315 cancer-associated genes and intron regions of 28 genes that are rearranged in cancer cells. Tumor mutation burden (TMB) and microsatellite instability (MSI) status were also assessed. TMB was calculated across a 1.14-megabase region; TMB-high was defined as ≥20 mutations/megabase. MSI-high status was assigned based on analysis of 114 intron homopolymer loci.

RESULTS:

KRAS, TP53, CDKN2A, and SMAD4 were the most frequently altered genes in PDAC. We found KRAS mutations in 88% of samples. Among PDACs without mutations in KRAS, we found alterations in genes whose products are in the mitogen-activated protein kinase signaling pathway and are candidate drug targets (actionable targets, n = 132; 4%), as well as gene fusions (n = 51), gene amplifications (n = 35), genes with missense mutations (n = 30), and genes that contain deletions (n = 16). Many of these encode proteins in receptor tyrosine kinase, RAS, or mitogen-activated protein kinase signaling pathways. Aside from TP53, alterations in genes encoding DNA damage repair proteins (BRCA and FANC) were detected in 14% of PDACs. Among PDACs evaluated for MSI (n = 2563) and TMB (n = 1021), MSI-high and/or TMB-high phenotypes were detected in 0.5% of samples. Alterations in FGF23, CCND2, PIK3CA, and FGF6 were more commonly detected in intraductal papillary mucinous neoplasm-associated PDACs.

CONCLUSIONS:

In targeted genomic profile analyses of 3594 PDACs, we found 17% to contain genomic alterations that might make the tumor cells susceptible to currently used anticancer agents. We identified mutations in genes that could contribute to progression of intraductal papillary mucinous neoplasms into malignancies. These alterations might be used as biomarkers for early detection.

• Authors: Aatur D Singhi, Ben George, Joel R Greenbowe, Jon Chung, James Suh, Anirban Maitra, Samuel J Klempner, Andrew Hendifar, Javle M Milind, Talia Golan, Randall E Brand, Amer H Zureikat, Somak Roy, Alexa B Schrock, Vincent A Miller, Jeffrey S Ross, Siraj M Ali, Nathan Bahary
• Journal: Gastroenterology (Gastroenterology) Vol. 156 Issue 8 Pg. 2242-2253.e4 (06 2019) ISSN: 1528-0012 [Electronic] United States
• PMID: 30836094 (Publication Type: Journal Article, Multicenter Study)
• Copyright: Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Biomarkers, Tumor
• FGF23 protein, human
• Fibroblast Growth Factor-23

Topics

• Adenocarcinoma, Mucinous (diagnosis, epidemiology, genetics)
• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (administration & dosage)
• Biomarkers, Tumor (analysis)
• Carcinoma, Pancreatic Ductal (drug therapy, epidemiology, genetics)
• Chromosome Mapping (methods)
• Cohort Studies
• Female
• Fibroblast Growth Factor-23
• Gene Expression Regulation, Neoplastic
• Genetic Variation (drug effects)
• Genomic Structural Variation
• Humans
• Male
• Middle Aged
• Molecular Targeted Therapy (methods)
• Neoplasm Invasiveness (pathology)
• Neoplasm Staging
• Pancreatic Neoplasms (drug therapy, epidemiology, genetics)
• Real-Time Polymerase Chain Reaction (methods)
• Retrospective Studies
• Young Adult