Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Center for Molecular Medicine, University of Connecticut School of Medicine, Farmington, Connecticut, USA.
JCI Insight. 2017 Mar 23;2(6):e92061. doi: 10.1172/jci.insight.92061.
Parathyroid carcinoma (PC) is an extremely rare malignancy lacking effective therapeutic intervention. We generated and analyzed whole-exome sequencing data from 17 patients to identify somatic and germline genetic alterations. A panel of selected genes was sequenced in a 7-tumor expansion cohort. We show that 47% (8 of 17) of the tumors harbor somatic mutations in the tumor suppressor, with germline inactivating variants in 4 of the 8 patients. The PI3K/AKT/mTOR pathway was altered in 21% of the 24 cases, revealing a major oncogenic pathway in PC. We observed amplification in 29% of the 17 patients, and a previously unreported recurrent mutation in putative kinase . We identified the first sporadic PCs with somatic mutations in the Wnt canonical pathway, complementing previously described epigenetic mechanisms mediating Wnt activation. This is the largest genomic sequencing study of PC, and represents major progress toward a full molecular characterization of this rare malignancy to inform improved and individualized treatments.
甲状旁腺癌（PC）是一种极为罕见的恶性肿瘤，缺乏有效的治疗干预措施。我们对 17 名患者的全外显子组测序数据进行了分析，以鉴定体细胞和种系遗传改变。在一个 7 种肿瘤扩展队列中对一组选定的基因进行了测序。我们发现，47%（17 例中的 8 例）的肿瘤存在肿瘤抑制因子的体细胞突变，其中 8 例患者中有 4 例存在种系失活变异。24 例中的 21%存在 PI3K/AKT/mTOR 通路改变，揭示了 PC 的主要致癌途径。我们观察到 17 名患者中有 29%存在 扩增，以及在假定的激酶 中存在一个以前未报道的复发性突变。我们鉴定了首例散发性 PC 中存在 Wnt 经典途径的体细胞突变，补充了先前描述的调节 Wnt 激活的表观遗传机制。这是对 PC 进行的最大规模基因组测序研究，代表着朝着全面分子特征分析这种罕见肿瘤迈出的重要一步，以提供更好的个体化治疗。
