未知原发癌（CUP）是一种无法追溯到其原发部位的癌症，占所有癌症的3-5%。CUP缺乏成熟的靶向治疗方法，导致疗效普遍不佳。我们开发了OncoNPC，一种机器学习分类器，它通过对来自三个机构的22种癌症类型中36,445个肿瘤的有针对性下一代测序（NGS）数据进行训练。肿瘤学NGS基于原发癌类型的分类器（OncoNPC）对保留的肿瘤样本进行高置信度预测，加权F1分数为0.942（[Formula: see text]）。这些保留样本占所有保留样本的65.2%。在应用于丹纳-法伯癌症研究所收集的971个CUP肿瘤时，OncoNPC对41.2%的肿瘤的原发癌类型进行了高置信度预测。OncoNPC还确定了CUP亚组，其具有预测癌症类型较高的多基因遗传风险和明显不同的生存结果。值得注意的是，CUP患者如果接受了与其OncoNPC预测的癌症类型一致的第一次姑息治疗，其疗效显著更好（风险比（HR）= 0.348；95%可信区间（CI）= 0.210-0.570；P = [Formula: see text]）。此外，OncoNPC使得接受基因组引导治疗的CUP患者数量增加了2.2倍。因此，OncoNPC证实了不同的CUP亚组，并为管理CUP患者提供了临床决策支持的潜力。© 2023. 作者，在Springer Nature America, Inc.的独家许可下发布。

Cancer of unknown primary (CUP) is a type of cancer that cannot be traced back to its primary site and accounts for 3-5% of all cancers. Established targeted therapies are lacking for CUP, leading to generally poor outcomes. We developed OncoNPC, a machine-learning classifier trained on targeted next-generation sequencing (NGS) data from 36,445 tumors across 22 cancer types from three institutions. Oncology NGS-based primary cancer-type classifier (OncoNPC) achieved a weighted F1 score of 0.942 for high confidence predictions ([Formula: see text]) on held-out tumor samples, which made up 65.2% of all the held-out samples. When applied to 971 CUP tumors collected at the Dana-Farber Cancer Institute, OncoNPC predicted primary cancer types with high confidence in 41.2% of the tumors. OncoNPC also identified CUP subgroups with significantly higher polygenic germline risk for the predicted cancer types and with significantly different survival outcomes. Notably, patients with CUP who received first palliative intent treatments concordant with their OncoNPC-predicted cancers had significantly better outcomes (hazard ratio (HR) = 0.348; 95% confidence interval (CI) = 0.210-0.570; P = [Formula: see text]). Furthermore, OncoNPC enabled a 2.2-fold increase in patients with CUP who could have received genomically guided therapies. OncoNPC thus provides evidence of distinct CUP subgroups and offers the potential for clinical decision support for managing patients with CUP.© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.