HMGA2 Predicts Treatment Outcome in Pancreatic Cancer
Recommended Citation
Yamamoto N, Dobersch S, Loveless I, Samraj AN, Jang G, Haraguchi M, Kang L, Ruzinova MB, Vij KR, Mudd JL, Walsh T, Safyan RA, Chiorean E, Hingorani SR, Bolton NM, Li L, Fields RC, DeNardo DG, Notta F, Crawford HC, Steele NG, Kugel S. HMGA2 Predicts Treatment Outcome in Pancreatic Cancer. Cancer Res 2025; 85(18):B112.
Document Type
Conference Proceeding
Publication Date
9-28-2025
Publication Title
Cancer Res
Abstract
The recognition of distinct transcriptional subtypes in pancreatic ductal adenocarcinoma (PDAC) has defined a group of poorly differentiated tumors with worse prognosis, but these findings have yet to reach clinical application. These tumors, termed “basal,” are unique for their loss of epithelial identity and relative chemoresistance compared to “classical” tumors. To develop a prognostic biomarker for the basal subtype, we have identified that the chromatin architectural protein HMGA2 is highly expressed in this subset of cancers. Using a tumor microarray of 580 primary biopsies from a diverse set of PDAC patients undergoing surgical resection, we performed multiplex immunohistochemistry for HMGA2, previously published markers of basal and classical disease, and immune subsets. We then associated patient outcome and known clinical data from 491 of these samples to staining patterns. We found that expression of HMGA2, but not published basal markers CK5 or CK17, predicted overall survival in our cohort. Combination of HMGA2 status with GATA6 status allowed for identification of two key study groups: an HMGA2+/GATA6- cohort with worse survival, decreased CD8+ T cells, and poorer response to gemcitabine-based chemotherapies (n=94, median survival = 11.2 months post-surgery); and an HMGA2-/GATA6+ cohort with improved survival, increased CD8+ T cell infiltrate, and improved survival with gemcitabine-based chemotherapy (n=198, median survival = 21.7 months post-surgery). Importantly, these findings were also true for Black patients, who have been underrepresented in previous subtyping studies. HMGA2 was also predictive of overall survival in RNA sequencing from metastatic tumors in an independent cohort. As a positive nuclear marker for basal disease, HMGA2 complements GATA6 as a dual-indicator test for disease subtype in PDAC. We aim to introduce this novel biomarker in a prospective multi-center clinical trial to further validate its use in selecting chemotherapy regimens and across other under-represented racial groups.
Volume
85
Issue
18
First Page
B112
