Complete genomic landscape of a recurring sporadic parathyroid carcinoma. Issue 3 (7th June 2013)

• Record Type: Journal Article
• Authors: Kasaian, Katayoon; Wiseman, Sam M; Thiessen, Nina; Mungall, Karen L; Corbett, Richard D; Qian, Jenny Q; Nip, Ka Ming; He, Ann; Tse, Kane; Chuah, Eric; Varhol, Richard J; Pandoh, Pawan; McDonald, Helen; Zeng, Thomas; Tam, Angela; Schein, Jacquie; Birol, Inanc; Mungall, Andrew J; Moore, Richard A; Zhao, Yongjun; Hirst, Martin; Marra, Marco A; Walker, Blair A; Jones, Steven JM
• Is Part Of: Journal of pathology. Volume 230:Issue 3(2013)
• Page Start: 249
• Page End: 260
• Publication Date: 2013-06-07
• Subjects: Pathology -- Periodicals; 616.07
• DOI: 10.1002/path.4203
• Languages: English
• ISSNs: 0022-3417

Abstract

<abstract abstract-type="main" id="path4203-abs-0001"> <title>Abstract</title> <p id="path4203-para-0001"> <bold>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 <italic>MEN1</italic> and proto‐oncogene <italic>RET</italic> in benign parathyroid tumourigenesis, while the tumour suppressor <italic>HRPT2</italic> and proto‐oncogene <italic>CCND1</italic> 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 <italic>mTOR</italic>, <italic>MLL2</italic>, <italic>CDKN2C</italic>, and <italic>PIK3CA</italic>. Comparison of acquired mutations in patient‐matched primary and recurrent tumours revealed loss of <italic>PIK3CA</italic> 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 <italic>CDKN2C</italic> and <italic>THRAP3</italic>, 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. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.</bold> </p> </abstract>