Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P31749 (AKT)
 22,954 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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 CDC73 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 CCND1 amplification in 29% of the 17 patients, and a previously unreported recurrent mutation in putative kinase ADCK1. 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.
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PMID:Genomic profiling reveals mutational landscape in parathyroid carcinomas. 2835 68

Parathyroid carcinoma (PC) is a rare neoplasia difficult to diagnose preoperatively. It mainly occurs as a sporadic disease but also as part of familial PHPT. At variance with patients with the benign counterpart, the phenotype of these patients is characterized by a severe primary hyperparathyroidism (PHPT). The clinical features are mostly due to the effects of the excessive secretion of PTH by the functioning tumor and hypercalcemia rather than to the tumor burden. The prognosis is poor and unmanageable hypercalcemia accounts for death in the majority of cases. The best chance of cure is surgery, although persistent or recurrent disease occurs in about 50% of patients. Somatic loss-of-function mutations of CDC73 gene, encoding parafibromin, are the most frequent genetic alterations occurring in PCs. Mutations of the PRUNE2 gene, alterations of the PI3K/AKT/mTOR pathway and amplification of the CCND1 gene have been recently detected in PCs. Alteration of microRNA profile and methylation pattern have been identified in PCs. The recent studies have better defined the genomic landscape of PCs and represent major progress toward a full molecular characterization of this neoplasia and development of novel therapeutic options.
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PMID:Parathyroid carcinoma: a clinical and genetic perspective. 2894 21

Parathyroid carcinoma (PC) is a rare endocrine malignancy with poor outcomes. Although some mutations such as CDC73 have been found in patients, the molecular mechanism of PC still needs extensive data to clarify. Whole-genome sequencing (WGS) was performed with frozen samples from 23 PC patients. Peripheral leukocytes were collected from 14 patients and served as controls. Somatic and germline gene alterations, copy number abnormalities and structural variants were detected. Inactivating CDC73 mutations were identified in 39.1% of patients, but only one germline inactivating mutation was found. Other cancer-related mutations identified in more than one case were MAF (2/23), NEB (6/23), NCOR1 (2/23), TTK (2/23), GRIN3A (4/23), TRIO (2/23), MAP1B (2/23), TJP2 (2/23) and FAM20A (2/23). In the seven wild-type CDC73 samples, the mutated genes were enriched in pathways involving antigen presentation, allograft rejection or autoimmune disease. More copy number variants were found in patients with cancer recurrence (P = .006) and CDC73 mutations (P = .022) than in those without these characteristics. PIK3CA loss was found in one sample, which also harboured a CDC73 mutation. Gene alterations in the PI3K/AKT/mTOR pathway were found in 78.3% (18/23) of tumours. The most prominent cancer-predisposing mutations were PDE4DIP (15/23), MAP3K1 (13/23) and CDC42EP1 (10/23). In conclusion, the PI3K/AKT/mTOR pathway may be pivotal in PC. CDC73 mutation correlated with an increased mutational burden and tumour relapse. PC patients with wild-type CDC73 harboured mutations relevant to antigen presentation and autoimmune diseases. A molecular classification based on the CDC73 mutation may help to manage follow-up and therapy for PC patients.
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PMID:The genomic profile of parathyroid carcinoma based on whole-genome sequencing. 3257 88