title: Complete genomic landscape of a recurring sporadic parathyroid carcinoma.
abstract: 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.
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Katayoon
authors.initials: K
authors.lastname: Kasaian
authors.forename: Sam M
authors.initials: SM
authors.lastname: Wiseman
authors.forename: Nina
authors.initials: N
authors.lastname: Thiessen
authors.forename: Karen L
authors.initials: KL
authors.lastname: Mungall
authors.forename: Richard D
authors.initials: RD
authors.lastname: Corbett
authors.forename: Jenny Q
authors.initials: JQ
authors.lastname: Qian
authors.forename: Ka Ming
authors.initials: KM
authors.lastname: Nip
authors.forename: Ann
authors.initials: A
authors.lastname: He
authors.forename: Kane
authors.initials: K
authors.lastname: Tse
authors.forename: Eric
authors.initials: E
authors.lastname: Chuah
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Varhol
authors.forename: Pawan
authors.initials: P
authors.lastname: Pandoh
authors.forename: Helen
authors.initials: H
authors.lastname: McDonald
authors.forename: Thomas
authors.initials: T
authors.lastname: Zeng
authors.forename: Angela
authors.initials: A
authors.lastname: Tam
authors.forename: Jacquie
authors.initials: J
authors.lastname: Schein
authors.forename: Inanc
authors.initials: I
authors.lastname: Birol
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Mungall
authors.forename: Richard A
authors.initials: RA
authors.lastname: Moore
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Zhao
authors.forename: Martin
authors.initials: M
authors.lastname: Hirst
authors.forename: Marco A
authors.initials: MA
authors.lastname: Marra
authors.forename: Blair A
authors.initials: BA
authors.lastname: Walker
authors.forename: Steven J M
authors.initials: SJ
authors.lastname: Jones
mesh_terms: D000328:Adult; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000235:genetics*; D002118:Calcium / Q000097:blood; D002471:Cell Transformation, Neoplastic; D058534:Class I Phosphatidylinositol 3-Kinases; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000235:genetics; D004273:DNA, Neoplasm / Q000737:chemistry / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D018628:Gene Dosage; D020869:Gene Expression Profiling; D050939:Gene Fusion; D023281:Genomics; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D010281:Parathyroid Hormone / Q000378:metabolism; D010282:Parathyroid Neoplasms / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D000090063:Proto-Oncogene Mas; D012334:RNA, Neoplasm / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D002118:Calcium; D058534:Class I Phosphatidylinositol 3-Kinases; D050763:Cyclin-Dependent Kinase Inhibitor p18; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D010281:Parathyroid Hormone; D019869:Phosphatidylinositol 3-Kinases; D000090063:Proto-Oncogene Mas; D012334:RNA, Neoplasm; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors; C493971:CDKN2C protein, human; C120898:KMT2D protein, human; C000715470:MAS1 protein, human; C475774:THRAP3 protein, human; C546842:MTOR protein, human; C484760:PIK3CA protein, human