Genomic profiling reveals mutational landscape in parathyroid carcinomas

Pandya, Chetanya; Uzilov, Andrew; Bellizzi, Justin; Lau, Chun Yee; Moe, Aye S.; Strahl, Maya; Hamou, Wissam; Newman, Leah; Fink, Marc Y.; Antipin, Yevgeniy; Yu, Willie; Stevenson, Mark; Cavaco, Branca; Teh, Bin Tean; Thakker, Rajesh; Morreau, Hans; Schadt, Eric E.; Sebra, Robert; Li, Shuyu D.; Arnold, Andrew; Chen, Rong

doi:10.1172/jci.insight.92061

Cited by 95 publications

(123 citation statements)

References 68 publications

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“…Interestingly, across the two studies, PIK3CA and CDC73 mutations were mutually exclusive, although the sample sizes were too low to determine statistical significance. Activating mutations of MTOR, also commonly altered in human tumors, were seen in three parathyroid carcinomas in two nextgeneration sequencing studies [11,41] . Functional studies are required to determine if activating mutations of the PI3K/mTOR pathway are indeed capable of driving malignant parathyroid tumorigenesis.…”

Section: Pi3k/mtormentioning

confidence: 99%

“…A heterozygous PIK3CA mutation, resulting in a glutamic acid to lysine change at amino acid 545 (p.E545K), was identified in a parathyroid carcinoma subjected to whole genome sequencing, but interestingly this mutation was absent from two recurrent lesions from the same patient [11] . Whole exome sequencing revealed another established activating PIK3CA mutation (p.K111E) in a parathyroid carcinoma [41] . Targeted sequencing revealed two additional known activating PIK3CA mutations, p.H1047R and p.E545A.…”

Section: Pi3k/mtormentioning

confidence: 99%

“…CCND1 gene amplification [40,41] and cyclin D1 overexpression [40,42] are common in parathyroid carcinoma. Parathyroid-targeted cyclin D1 transgenic mice develop chronic biochemical hyperparathyroidism and parathyroid gland hypercellularity, but parathyroid carcinoma has not been observed [43] .…”

Section: Cyclin D1mentioning

confidence: 99%

“…PRUNE2 has recently been identified as a likely tumor suppressor gene subject to recurrent mutation in parathyroid carcinoma [41,48] . Whole exome sequencing revealed one parathyroid carcinoma with a germline missense PRUNE2 mutation accompanied by allelic loss [48] and two carcinomas harboring biallelic, somatic nonsense mutations [41,48] .…”

Section: Prune2mentioning

confidence: 99%

“…Whole exome sequencing revealed one parathyroid carcinoma with a germline missense PRUNE2 mutation accompanied by allelic loss [48] and two carcinomas harboring biallelic, somatic nonsense mutations [41,48] . Sanger sequencing, limited to exon 8 of PRUNE2, uncovered two additional somatic missense mutations.…”

Section: Prune2mentioning

confidence: 99%

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Parathyroid carcinoma

Costa-Guda¹

2018

JTGG

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Parathyroid carcinoma is a rare but clinically-aggressive tumor. While most cases are sporadic, parathyroid cancer is overrepresented in hyperparathyroidism-jaw tumor syndrome, or rarely other heritable syndromes. Evidence suggests that sporadic parathyroid carcinomas rarely, if ever, evolve through an identifiable benign tumor intermediate. A few genes have been directly implicated in the pathogenesis of sporadic parathyroid cancer; somatic (and less common germline) mutations in the CDC73 tumor suppressor gene are the most frequent finding and the only firmly established molecular drivers of parathyroid cancer. Alterations in other important human cancer genes, including CCND1 /cyclin D1, PIK3CA , MTOR and PRUNE2 have also been described in parathyroid cancer, however their abilities to drive malignant parathyroid tumorigenesis remains to be demonstrated experimentally.

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Section: Pi3k/mtormentioning

confidence: 99%

Section: Pi3k/mtormentioning

confidence: 99%

Section: Cyclin D1mentioning

confidence: 99%

Section: Prune2mentioning

confidence: 99%

Section: Prune2mentioning

confidence: 99%

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Parathyroid carcinoma

Costa-Guda¹

2018

JTGG

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Targeted therapy of advanced parathyroid carcinoma guided by genomic and transcriptomic profiling

et al. 2023

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Parathyroid carcinoma (PC) is an ultra-rare malignancy with a high risk of recurrence after surgery. Tumour-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: (a) immune checkpoint inhibition with pembrolizumab based on high tumour mutational burden and a single-base substitution signature associated with APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) overactivation; (b) multi-receptor tyrosine kinase inhibition with lenvatinib due

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