甲状旁腺癌（PC）是一种罕见的恶性肿瘤，手术后复发的风险很高。目前尚未建立PC的肿瘤导向性全身治疗。我们利用四个晚期PC患者的全基因组和RNA测序技术，识别分子变化，以指导临床管理。在两个病例中，基因组和转录组图谱提供了试验性治疗靶点，产生了生化反应和持久的疾病稳定：（i）由于高肿瘤突变负荷和与APOBEC（类似脂蛋白B mRNA编辑酶的催化多肽）活化相关的单碱基替代标志，采用免疫检查点抑制剂pembrolizumab；（ii）采用洛伐替尼的多受体酪氨酸激酶抑制剂，由于FGFR1（成纤维细胞生长因子受体1）和RET（Ret Proto-Oncogene）的过度表达，以及在疾病进程后期采用PARP（Poly（ADP-Ribose）聚合酶）抑制剂olaparib，这是由于出现缺陷同源重组DNA修复迹象。此外，我们的数据还提供了关于PC分子景观的新见解，包括特定突变过程和致病性基因突变的全基因组足迹。这些数据强调了全面分子分析对于基于对疾病生物学的洞察力改善罕见肿瘤患者护理的潜力。本文受版权保护。保留所有权利。

Parathyroid carcinoma (PC) is an ultra-rare malignancy with a high risk of recurrence after surgery. Tumor-directed systemic treatments for PC are not established. We used whole-genome and RNA sequencing in four patients with advanced PC to identify molecular alterations that could guide clinical management. In two cases, the genomic and transcriptomic profiles provided targets for experimental therapies that resulted in biochemical response and prolonged disease stabilization: (i) immune checkpoint inhibition with pembrolizumab based on high tumor mutational burden and a single-base substitution signature associated with APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) overactivation; (ii) multi-receptor tyrosine kinase inhibition with lenvatinib due to overexpression of FGFR1 (Fibroblast Growth Factor Receptor 1) and RET (Ret Proto-Oncogene) and, later in the course of the disease, PARP (Poly(ADP-Ribose) Polymerase) inhibition with olaparib prompted by signs of defective homologous recombination DNA repair. In addition, our data provided new insights into the molecular landscape of PC with respect to the genome-wide footprints of specific mutational processes and pathogenic germline alterations. These data underscore the potential of comprehensive molecular analyses to improve care for patients with ultra-rare cancers based on insight into disease biology.This article is protected by copyright. All rights reserved.