使用具有匹配的基因组转录组分子数据的真实世界数据库，我们试图描述年轻发病胰腺癌（YOPC；小于 50 岁）患者和平均发病胰腺癌患者之间潜在临床差异的不同分子相关性。 AOPC；70 岁及以上）。我们分析了来自 Caris 生命科学数据库（亚利桑那州菲尼克斯）的 2,430 名患者样本（YOPC，n = 292；AOPC，n = 2,138）的匹配全转录组和 DNA 测序数据。使用 quanTIseq 管道执行免疫反卷积。总生存期 (OS) 数据从保险索赔中获得 (n = 4,928)； Kaplan-Meier 估计值是针对年龄和分子定义的队列进行计算的。显着性确定为 FDR 校正 P 值 (Q) < 0.05。与 AOPC 患者相比，YOPC 患者错配修复缺陷/微卫星不稳定性高、BRCA2 突变和 PALB2 突变肿瘤的比例较高，但较少SMAD4、RNF43、CDKN2A 和 SF3B1 突变肿瘤。值得注意的是，与 AOPC 患者相比，YOPC 患者的 KRAS 突变发生率显着降低（81.3% vs 90.9%；Q = 0.004）。在 KRAS 野生型子集中（n = 227），YOPC 肿瘤表现出较少的 TP53 突变，并且更可能由 NRG1 和 MET 融合驱动，而 BRAF 融合仅在 AOPC 患者中观察到。免疫去卷积显示，与 AOPC 患者相比，YOPC 患者的自然杀伤细胞、CD8 T 细胞、单核细胞和 M2 巨噬细胞显着富集，这与 HLA-DPA1 纯合性率较低相对应。与 KRAS 野生型肿瘤的 AOPC 患者相比，YOPC 患者的 OS 改善存在相关性（中位数为 16.2 [YOPC-KRASWT] vs 10.6 [AOPC-KRASWT] 个月；P = .008），但与 KRAS 突变型肿瘤无关肿瘤 (P = .084)。在胰腺导管腺癌中年龄分层分子差异的大型真实世界多组学表征中，YOPC 与具有预后和治疗意义的独特分子景观相关。

Using a real-world database with matched genomic-transcriptomic molecular data, we sought to characterize the distinct molecular correlates underlying clinical differences between patients with young-onset pancreatic cancer (YOPC; younger than 50 years) and patients with average-onset pancreatic cancer (AOPC; 70 years and older).We analyzed matched whole-transcriptome and DNA sequencing data from 2,430 patient samples (YOPC, n = 292; AOPC, n = 2,138) from the Caris Life Sciences database (Phoenix, AZ). Immune deconvolution was performed using the quanTIseq pipeline. Overall survival (OS) data were obtained from insurance claims (n = 4,928); Kaplan-Meier estimates were calculated for age- and molecularly defined cohorts. Significance was determined as FDR-corrected P values (Q) < .05.Patients with YOPC had higher proportions of mismatch repair-deficient/microsatellite instability-high, BRCA2-mutant, and PALB2-mutant tumors compared with patients with AOPC, but fewer SMAD4-, RNF43-, CDKN2A-, and SF3B1-mutant tumors. Notably, patients with YOPC demonstrated significantly lower incidence of KRAS mutations compared with patients with AOPC (81.3% v 90.9%; Q = .004). In the KRAS wild-type subset (n = 227), YOPC tumors demonstrated fewer TP53 mutations and were more likely driven by NRG1 and MET fusions, whereas BRAF fusions were exclusively observed in patients with AOPC. Immune deconvolution revealed significant enrichment of natural killer cells, CD8+ T cells, monocytes, and M2 macrophages in patients with YOPC relative to patients with AOPC, which corresponded with lower rates of HLA-DPA1 homozygosity. There was an association with improved OS in patients with YOPC compared with patients with AOPC with KRAS wild-type tumors (median, 16.2 [YOPC-KRASWT] v 10.6 [AOPC-KRASWT] months; P = .008) but not KRAS-mutant tumors (P = .084).In this large, real-world multiomic characterization of age-stratified molecular differences in pancreatic ductal adenocarcinoma, YOPC is associated with a distinct molecular landscape that has prognostic and therapeutic implications.