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Cited by 348Pancreatic and Hepatic Oncology ResearchCancer Genomics and DiagnosticsChromatin Remodeling and Cancer

The DOI matches its Crossref record; 59 of the 60 references it cites were found in a registry or an index.

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

Open access
Singhi, Aatur D., George, Ben, Greenbowe, Joel R., Chung, Jon, Suh, James, Maitra, Anirban, Klempner, Samuel J., Hendifar, Andrew, Milind, Javle M., Golan, Talia, Brand, Randall E., Zureikat, Amer H., Roy, Somak, Schrock, Alexa B., Miller, Vincent A., Ross, Jeffrey S., Ali, Siraj M., Bahary, Nathan·2019·Gastroenterology
DOI 10.1053/j.gastro.2019.02.037
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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.

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Metadata

Authors
Singhi, A. D., George, B., Greenbowe, J. R., Chung, J., Suh, J., Maitra, A., Klempner, S. J., Hendifar, A., Milind, J. M., Golan, T., Brand, R. E., Zureikat, A. H., Roy, S., Schrock, A. B., Miller, V. A., Ross, J. S., Ali, S. M., & Bahary, N.
Affiliations
  • University of Pittsburgh Medical Center (US)
  • Medical College of Wisconsin (US)
  • Foundation Medicine (United States) (US)
  • The University of Texas MD Anderson Cancer Center (US)
  • Cedars-Sinai Medical Center (US)
  • Tel Aviv University (IL)
Corresponding author
Singhi, Aatur D.
ORCID
Venue
Gastroenterology
Publisher
Elsevier BV
Published
2019-06
Volume
156
Issue
8
Pages
2242-2253.e4
ISSN
0016-5085 (ISSN-L)
DOI
10.1053/j.gastro.2019.02.037
OpenAlex
W2919944461
Cited by
348
References
60
Citations by year
2026: 27 · 2025: 43 · 2024: 51 · 2023: 55 · 2022: 56 · 2021: 63 · 2020: 43 · 2019: 9
FWCI
17.87
Type
journal article
Language
en
Open access
Licence
Locations
  • Gastroenterology (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • Pancreatic Cancer Action Network
  • Association for Molecular Pathology
Topics
  • Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
Keywords
pancreatic ductal adenocarcinoma, actionable genomic alterations, KRAS mutation, TP53, CDKN2A, SMAD4, MAPK signaling, gene fusion, gene amplification, microsatellite instability, tumor mutational burden, DNA repair, intraductal papillary mucinous neoplasm, biomarkers, therapeutic target
MeSH terms
Fibroblast Growth Factor-23, Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Adenocarcinoma, Mucinous, Chromosome Mapping, Female, Humans, Male, Middle Aged, Neoplasm Invasiveness, Neoplasm Staging, Pancreatic Neoplasms, Retrospective Studies, Biomarkers, Tumor, Genetic Variation, Cohort Studies, Gene Expression Regulation, Neoplastic, Carcinoma, Pancreatic Ductal, Young Adult, Genomic Structural Variation, Molecular Targeted Therapy, Real-Time Polymerase Chain Reaction

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