Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
J Pathol. 2013 Jul;230(3):249-60. doi: 10.1002/path.4203.
Parathyroid carcinoma is a rare endocrine malignancy with an estimated incidence of less than 1 per million population. Excessive secretion of parathyroid hormone, extremely high serum calcium level, and the deleterious effects of hypercalcaemia are the clinical manifestations of the disease. Up to 60% of patients develop multiple disease recurrences and although long-term survival is possible with palliative surgery, permanent remission is rarely achieved. Molecular drivers of sporadic parathyroid carcinoma have remained largely unknown. Previous studies, mostly based on familial cases of the disease, suggested potential roles for the tumour suppressor MEN1 and proto-oncogene RET in benign parathyroid tumourigenesis, while the tumour suppressor HRPT2 and proto-oncogene CCND1 may also act as drivers in parathyroid cancer. Here, we report the complete genomic analysis of a sporadic and recurring parathyroid carcinoma. Mutational landscapes of the primary and recurrent tumour specimens were analysed using high-throughput sequencing technologies. Such molecular profiling allowed for identification of somatic mutations never previously identified in this malignancy. These included single nucleotide point mutations in well-characterized cancer genes such as mTOR, MLL2, CDKN2C, and PIK3CA. Comparison of acquired mutations in patient-matched primary and recurrent tumours revealed loss of PIK3CA activating mutation during the evolution of the tumour from the primary to the recurrence. Structural variations leading to gene fusions and regions of copy loss and gain were identified at a single-base resolution. Loss of the short arm of chromosome 1, along with somatic missense and truncating mutations in CDKN2C and THRAP3, respectively, provides new evidence for the potential role of these genes as tumour suppressors in parathyroid cancer. The key somatic mutations identified in this study can serve as novel diagnostic markers as well as therapeutic targets.
甲状旁腺癌是一种罕见的内分泌恶性肿瘤，估计发病率低于每百万人 1 例。甲状旁腺激素过度分泌、血清钙水平极高以及高钙血症的有害影响是该病的临床表现。多达 60%的患者出现多次疾病复发，尽管姑息性手术可以实现长期生存，但很少能达到永久缓解。散发性甲状旁腺癌的分子驱动因素在很大程度上仍不清楚。先前的研究主要基于该病的家族病例，表明肿瘤抑制因子 MEN1 和原癌基因 RET 可能在良性甲状旁腺瘤发生中起作用，而肿瘤抑制因子 HRPT2 和原癌基因 CCND1 也可能作为甲状旁腺癌的驱动因素。在这里，我们报告了一例散发性和复发性甲状旁腺癌的全基因组分析。使用高通量测序技术分析原发和复发性肿瘤标本的突变景观。这种分子分析有助于鉴定在此恶性肿瘤中从未发现过的体细胞突变。这些突变包括 mTOR、MLL2、CDKN2C 和 PIK3CA 等已明确的癌症基因中的单核苷酸点突变。在患者匹配的原发和复发性肿瘤中比较获得的突变，发现 PIK3CA 激活突变在肿瘤从原发发展到复发的过程中丢失。在单碱基分辨率下鉴定到导致基因融合以及拷贝数缺失和获得的结构变异。第 1 号染色体短臂缺失，以及 CDKN2C 和 THRAP3 中的体细胞错义和截断突变，为这些基因作为甲状旁腺癌肿瘤抑制因子的潜在作用提供了新证据。本研究中鉴定的关键体细胞突变可作为新的诊断标志物和治疗靶点。
