The subtypes of duodenal cancer (DC) are complicated and the carcinogenesis process is not well characterized. We present comprehensive characterization of 438 samples from 156 DC patients, covering 2 major and 5 rare subtypes. Proteogenomics reveals LYN amplification at the chromosome 8q gain functioned in the transmit from intraepithelial neoplasia phase to infiltration tumor phase via MAPK signaling, and illustrates the DST mutation improves mTOR signaling in the duodenal adenocarcinoma stage. Proteome-based analysis elucidates stage-specific molecular characterizations and carcinogenesis tracks, and defines the cancer-driving waves of the adenocarcinoma and Brunner’s gland subtypes. The drug-targetable alanyl-tRNA synthetase (AARS1) in the high tumor mutation burden/immune infiltration is significantly enhanced in DC progression, and catalyzes the lysine-alanylation of poly-ADP-ribose polymerases (PARP1), which decreases the apoptosis of cancer cells, eventually promoting cell proliferation and tumorigenesis. We assess the proteogenomic landscape of early DC, and provide insights into the molecular features corresponding therapeutic targets.

十二指肠癌（DC）的亚型复杂，其癌变过程尚不明确。我们对来自 156 名 DC 患者的 438 个样本进行了全面表征，涵盖 2 个主要亚型和 5 个罕见亚型。蛋白质基因组学揭示了染色体 8q 增益处的LYN扩增在通过 MAPK 信号传导从上皮内瘤形成期向浸润性肿瘤期的转变中起作用，并说明DST突变改善了十二指肠腺癌阶段的 mTOR 信号传导。基于蛋白质组的分析阐明了特定阶段的分子特征和致癌轨迹，并定义了腺癌和布伦纳腺亚型的癌症驱动波。高肿瘤突变负荷/免疫浸润中的药物靶向丙氨酰-tRNA合成酶（AARS1）在DC进展中显着增强，并催化聚ADP-核糖聚合酶（PARP1）的赖氨酸-丙氨酰化，从而减少癌症的细胞凋亡细胞，最终促进细胞增殖和肿瘤发生。我们评估了早期 DC 的蛋白质组景观，并提供了对相应治疗靶点的分子特征的见解。