Mills Jamie N, Gunchick Valerie, McGue Jake, Qin Zhaoping, Kumar-Sinha Chandan, Bednar Filip, Brown Noah, Shi Jiaqi, Udager Aaron M, Frankel Timothy, Zalupski Mark M, Sahai Vaibhav
Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA.
JNCI Cancer Spectr. 2025 Jan 3;9(1). doi: 10.1093/jncics/pkae097.
Undifferentiated carcinoma (UC) is a rare subtype of pancreatic cancer distinguished from UC with osteoclast-like giant cells (UC-OGC) in 2019, affecting interpretation of literature that does not distinguish these subtypes. We sought to identify translationally relevant differences between these 2 variants and compared with pancreatic ductal adenocarcinoma.
We characterized clinical and multiomic differences between UC (n = 32) and UC-OGC (n = 15) using DNA sequencing, RNA sequencing, and multiplex immunofluorescence and compared these findings with pancreatic ductal adenocarcinoma.
Characteristics at diagnosis were similar between UC and UC-OGC, though the latter was more resectable (P = .009). Across all stages, median overall survival was shorter for UC than for UC-OGC (0.4 years vs 10.8 years, respectively; P = .003). This shorter survival was retained after stratification by resection, albeit without statistical significance (1.8 years vs 11.9 years, respectively; P = .08). In a subset of patients with available tissue, the genomic landscape was similar among UC (n = 9), UC-OGC (n = 5), and pancreatic ductal adenocarcinoma (n = 159). Bulk RNA sequencing was deconvoluted and, along with multiplex immunofluorescence in UC (n = 13), UC-OGC (n = 5), and pancreatic ductal adenocarcinoma (n = 16), demonstrated statistically significantly increased antigen-presenting cells, including M2 macrophages and natural killer cells, and decreased cytotoxic and regulatory T cells in UC and UC-OGC vs pancreatic ductal adenocarcinoma. Findings were similar between UC and UC-OGC , except for decreased regulatory T cells in UC-OGC (P = .04).
In this series, UC was more aggressive than UC-OGC, with these variants having more antigen-presenting cells and fewer regulatory T cells than pancreatic ductal adenocarcinoma, suggesting potential for immune-modulating therapies in the treatment of these pancreatic cancer subtypes.
未分化癌（UC）是胰腺癌的一种罕见亚型，2019年从伴有破骨细胞样巨细胞的未分化癌（UC-OGC）中区分出来，这影响了未区分这些亚型的文献解读。我们试图确定这两种变体之间与转化相关的差异，并与胰腺导管腺癌进行比较。
我们使用DNA测序、RNA测序和多重免疫荧光对UC（n = 32）和UC-OGC（n = 15）之间的临床和多组学差异进行了表征，并将这些结果与胰腺导管腺癌进行比较。
UC和UC-OGC在诊断时的特征相似，尽管后者更可切除（P = 0.009）。在所有阶段，UC的中位总生存期均短于UC-OGC（分别为0.4年和10.8年；P = 0.003）。按切除情况分层后，这种较短的生存期仍然存在，尽管无统计学意义（分别为1.8年和11.9年；P = 0.08）。在有可用组织的一部分患者中，UC（n = 9）、UC-OGC（n = 5）和胰腺导管腺癌（n = 159）的基因组格局相似。对批量RNA测序进行了反卷积分析，并结合UC（n = 13）、UC-OGC（n = 5）和胰腺导管腺癌（n = 16）中的多重免疫荧光显示，与胰腺导管腺癌相比，UC和UC-OGC中抗原呈递细胞（包括M2巨噬细胞和自然杀伤细胞）在统计学上显著增加，而细胞毒性T细胞和调节性T细胞减少。UC和UC-OGC之间的结果相似，但UC-OGC中的调节性T细胞减少（P = 0.04）。
在本系列研究中，UC比UC-OGC更具侵袭性，与胰腺导管腺癌相比，这些变体具有更多的抗原呈递细胞和更少的调节性T细胞，提示免疫调节疗法在治疗这些胰腺癌亚型方面具有潜力。
