PIK3CA Mutational Analysis of Parathyroid Adenomas

Presentation Number: SAT 341
Date of Presentation: April 1st, 2017

Aaliyah Riccardi*1, Justin Bellizzi2, Jessica Costa-Guda1 and Andrew Arnold1
1University of Connecticut School of Medicine, Farmington, CT, 2University of Connecticut School of Medicine

Abstract

Benign parathyroid adenomas are the most common cause of primary hyperparathyroidism while malignant parathyroid carcinomas account for less than 1% of hyperparathyroid cases. Making the distinction between parathyroid adenomas and parathyroid carcinomas on histopathologic examination of a primary tumor can be particularly difficult, and a diagnosis of parathyroid carcinoma may only become clear at a later time, when the rigorous diagnostic criteria of local invasion of surrounding tissues and/or distant metastases are fulfilled. Thus, new insights into their respective molecular bases could result in more precise and efficient diagnostic discrimination between parathyroid adenomas and parathyroid carcinomas. Current understanding of the genetic underpinnings of parathyroid adenomas includes driver mutations in the MEN1 tumor suppressor, the oncogene CCND1 (encoding cyclin D1) and, in small percentages each, EZH2, ZFX, and several cyclin-dependent kinase inhibitor (CDKI) genes, while in parathyroid carcinoma the only established recurrent driver has been inactivating mutation of CDC73/HRPT2. Recently, a gain-of-function mutation in PIK3CA was identified by Kasaian et al. in a single parathyroid carcinoma subjected to whole genome sequencing (1), and by Pandya et al. as a recurrent finding in a subset (<20%) of locally invasive or metastatic parathyroid carcinomas (2). PIK3CA, a recognized driver oncogene in many human malignancies including breast cancer, encodes the p110-alpha subunit of PI3-Kinase, controlling cell proliferation and apoptosis via phosphorylation of AKT. Known PIK3CA mutational hotspots in codons 111, 542/545, and 1047 overlap those in the described parathyroid carcinomas. To assess these mutations’ potential specificity for malignant, as opposed to benign disease, we PCR-amplified and Sanger sequenced those regions of the PIK3CA gene in genomic DNA from 81 typical, sporadic parathyroid adenomas. In 80 of the 81 tumors, there were no known activating hotspot mutations or other mutations in the immediately flanking regions of the amplicons. One parathyroid adenoma (1.2%) had a somatic, heterozygous, activating H1047R mutation. These data suggest that PIK3CA activating mutations in the specified major hotspots are preferentially associated with malignant rather than benign parathyroid neoplasia, but larger sample sizes must be analyzed to assess their potential diagnostic utility. Furthermore, exploration of PIK3CA mutations' role in parathyroid neoplasia could result in insights into pathogenesis and improved therapy through precision targeting.

 

Nothing to Disclose: AR, JB, JC, AA