HMGA2 Expression Predicts Subtype, Survival, and Treatment Outcome in Pancreatic Ductal Adenocarcinoma
Recommended Citation
Yamamoto N, Dobersch S, Loveless I, Samraj AN, Jang GH, Haraguchi M, Kang LI, Ruzinova MB, Vij KR, Mudd JL, Walsh T, Safyan RA, Chiorean EG, Hingorani SR, Bolton NM, Li L, Fields RC, DeNardo DG, Notta F, Crawford HC, Steele NG, and Kugel S. HMGA2 Expression Predicts Subtype, Survival, and Treatment Outcome in Pancreatic Ductal Adenocarcinoma. Clin Cancer Res 2024.
Document Type
Article
Publication Date
2-17-2025
Publication Title
Clinical cancer research
Abstract
PURPOSE: The purpose of this study was to establish HMGA2 as a marker of basal-like disease in pancreatic ductal adenocarcinoma (PDAC) and explore its use as a biomarker for prognosis and treatment resistance.
EXPERIMENTAL DESIGN: We identified high-mobility group A2 (HMGA2) protein expression in basal PDAC cells in a single-cell RNA sequencing (RNA-seq) atlas of 172 patient samples. We then analyzed HMGA2 expression, along with expression of the classic marker GATA-binding factor 6 (GATA6), in a cohort of 580 PDAC samples with multiplex IHC. We further supplemented these data with an additional 30 diverse patient samples and multiple independent single-cell RNA-seq databases.
RESULTS: We found that expression of HMGA2, but not previously described basal markers cytokeratins 5 or 17, predicted overall survival in our cohort. Combining HMGA2 and GATA6 statuses allowed for the identification of two key study groups: an HMGA2+/GATA6- cohort with worse survival, low tumor-infiltrating CD8+ T cells, increased FAP+ fibroblasts, and poorer response to gemcitabine-based chemotherapies (n = 94, median survival = 11.2 months after surgery) and an HMGA2-/GATA6+ cohort with improved survival, increased CD8+ T-cell infiltrate, decreased FAP+ fibroblasts, and improved survival with gemcitabine-based chemotherapy (n = 198, median survival = 21.7 months after surgery). HMGA2 was also prognostic for overall survival in RNA-seq from an independent cohort.
CONCLUSIONS: IHC stratification of primary tumors by HMGA2 and GATA6 statuses in pancreatic cancer is associated with differential outcomes, survival following chemotherapy, and tumor microenvironments. As a nuclear marker for basal disease, HMGA2 complements GATA6 to identify disease subtypes in PDAC.
Medical Subject Headings
Humans; HMGA2 Protein; Carcinoma, Pancreatic Ductal; Biomarkers, Tumor; Prognosis; Pancreatic Neoplasms; Gene Expression Regulation, Neoplastic; Female; Treatment Outcome; Male; GATA6 Transcription Factor; Drug Resistance, Neoplasm; Aged; Gemcitabine; Middle Aged
PubMed ID
39680021
ePublication
ePub ahead of print
Volume
31
Issue
4
First Page
733
Last Page
745
