Abstract
Purpose
A lack of targeted therapies make parathyroid carcinoma, a diagnostically challenging malignancy, difficult to treat. The rarity of this tumor type necessitates international collaboration to collect a sizable sample set for study. Prior studies have revealed the importance of driver mutations in the CDC73 gene and identified several putative drivers/aberrant pathways including PI3K/mTOR activation and CCND1 (cyclin D1) amplification. In this study, we sought to better understand the prevalence of putative oncogenic drivers in parathyroid carcinoma.
Methods
We subjected an expanded cohort of 71 sporadic parathyroid carcinomas, fulfilling stringent WHO criteria, to next-generation DNA sequencing on a custom 16-gene targeted panel.
Results
One or more variant was detected in 44 tumors (62%) and 27 (38%) had no detectable variant. Consistent with earlier studies, we detected loss-of-function CDC73 mutations in 44% (31/70) of evaluable patients, including germline pathogenic variants in 9 patients (36 patients evaluable for somatic status as matched normal available). Notably, mutations in the PI3K/AKT/mTOR pathway were seen in 12.9% (9/70) of evaluable patients, providing further evidence of this as a key therapeutically actionable pathway in parathyroid carcinoma. Correlating genomic and clinical features revealed that patients harboring CDC73 mutations are more likely suffer from life threatening recurrent/metastatic parathyroid carcinoma (P = 0.024) than those without CDC73 variants.
Conclusions
This genomic characterization of a large parathyroid carcinoma cohort improves understanding of the genomic underpinnings of this rare malignancy, provides novel evidence for genotype-phenotype correlation with recurrent/metastatic disease, and may help to provide a rational basis for individualized treatments.
Supplementary Information
The online version contains supplementary material available at https://doi.org/10.1007/s40618-026-02855-x.
Keywords: Cancer, Disorders of calcium/phosphate metabolism, Parathyroid-related disorders, parathyroid carcinoma, CDC73
Introduction
Parathyroid carcinoma (PC) is a rare, life-threatening endocrine malignancy seen in less than 1% of patients with primary hyperparathyroidism. PC typically has a sporadic/nonfamilial presentation, but can also arise in the heritable hyperparathyroidism-jaw tumor syndrome (HPT-JT) and in familial isolated hyperparathyroidism due to germline mutation of the CDC73 (formerly HRPT2) tumor suppressor gene. Recurrence is seen in more than 50% of patients [1–4] and PC that recurs locally or metastasizes after resection of the primary tumor is typically incurable due to progressive parathyroid hormone (PTH) mediated hypercalcemia, resulting in significant end-organ damage and high mortality [5, 6]. In such advanced cases, hypercalcemia can be partially controlled for variable durations with surgical debulking, bone resorption inhibitors, or calcimimetics. However, neither chemotherapy with traditional agents nor adjuvant radiation have proven effective against PC [7–9]. Identification of new therapies informed by insights into PC’s molecular vulnerabilities would be an important advance [6, 10].
In previous work, mutations / pathogenic variants in the CDC73 tumor suppressor gene were identified as common drivers of PC [11–20] and associated with poorer clinical outcomes [21, 22]. However, no pharmacologic interventions targeting CDC73 have yet been developed. Next-generation sequencing (NGS) techniques have since expanded the listing of putative or possible driver genes in this disease. For example, confirmed findings include PI3K/MTOR activation and CCND1 (cyclin D1) amplification [17–19, 23] in subsets of PC, both of which carry potential therapeutic implications. However, while several genes have been implicated in PC, the rarity of this tumor type makes it difficult to determine how commonly any individual gene is involved. We sought to better understand the molecular mechanisms of oncogenesis in PC by utilizing a custom, PC-informed, targeted, NGS panel [17] to analyze an expanded cohort of PC samples.
Materials and methods
Patients and tumor specimens
We selected a cohort of patients, across multiple international sites, diagnosed with PC according to stringent clinical/pathological criteria: evidence of either local invasion into surrounding tissues, vascular invasion within or beyond the parathyroid tumor capsule, and/or distant metastasis [24]. Diagnoses of primary hyperparathyroidism were made after presentation with hypercalcemia and elevated serum PTH levels; no patient was diagnosed preclinically in a surveillance program for known/suspected carriers of germline CDC73 mutation. Seventy-three patient-derived (surgically treated for primary hyperparathyroidism) primary, locally recurrent, or metastatic PC specimens (tumors PC001T-PC088T), including 24 previously analyzed tumor samples [17], were obtained. Peripheral blood or other uninvolved non-tumor tissue was available from 40 of the patients and provided matched germline control DNA. All samples were obtained with informed consent in concordance with Institutional Review Board approved protocols.
Immediately after surgical resection, tumor samples were either frozen in liquid nitrogen for storage at -80 °C until use (N = 17), or were formalin-fixed, paraffin-embedded, sectioned, and mounted on slides, with two or three sections per tumor then grossly dissected from the slides for DNA extraction (N = 59). Genomic DNA was isolated from tumor and non-tumor tissues using either proteinase K digestion followed by phenol-chloroform extraction and ethanol precipitation for frozen tissues and blood, or with the Qiagen supplementary protocol for Purification of genomic DNA from FFPE tissue using the QIAamp DNA FFPE Tissue Kit (Qiagen, Cat. No. 56404) and Deparaffinization Solution (Qiagen, Cat. No. 19093), or the GeneRead DNA FFPE kit (Qiagen, Cat. No. 180134, for formalin-fixed, paraffin-embedded tissues. For a subset of cases, total nucleic acid (undivided DNA and RNA) was isolated from formalin-fixed paraffin-embedded (FFPE) tissue cores (0.6 mm diameter and variable length) or microdissected tissue regions using a fully-automated extraction procedure [25].
Targeted panel sequencing
DNA quality control (QC), sequencing on the 16 gene ParThy panel (958 amplicons covering 97,909 bases of 356 unique genomic regions), and data analysis was performed as described previously [17]. Briefly, Qubit fluorometry (Life Technologies, Grand Island, NY) was used for DNA quantification and Agilent Bioanalyzer was used to assess DNA quality for all samples. Samples that passed quality control were used for library construction using the manufacturer’s (Thermo Fisher Scientific) Ion Torrent Ampliseq library preparation protocol. After library completion and equalization, the Ion Chef was used to concentrate and load the chip using manufacturer’s suggested protocols. The Torrent Chef and run conditions were set up for the ParThy cancer panel and the S5XL configuration was run by manufacturer’s protocol until completion.
Variant calling and classification
Variants from targeted panel sequencing were called using the TorrentSuite variantCaller (https://github.com/iontorrent/TS) module version 5.2.2 using permissive settings (Somatic – Low-Stringency preset; all COSMIC [26] and previously observed variants [17] provided as hotspot file for force calling), exported as VCFs, and loaded into a custom MySQL database schema for analysis. Variants were annotated with SnpEff [27] using RVS [28] and filtered to include SnpEff “moderate” and “high” impact categories. If WES sequencing data were available, concordance analysis was done to ensure the two assays agreed in their somatic variant calls in genomic regions covered by both assays by design. QC statistics and chip type are listed in Supplementary Table 1.
Identification of genetic alterations
Variants observed in a tumor sample with gnomAD (release 2.0.1) [29] population allele frequency exceeding 0.5% in any ethnicity were discarded assuming that they are any combination of: contamination, a variant present but missed in normal sample, a low-level technical artifact, or unlikely to be a cancer driver owing to common frequency in the general population. All variant calls were manually reviewed in IGV [30] and the UCSC Genome Browser [31] to inspect supporting alignment quality and alignability of the genomic region in the hg19 human genome assembly [30]. Due to the relatively sparse genome coverage of this panel & few normal diploid samples, a robust baseline for copy number variant calling could not be generated and thus, copy number status of genes on the panel could not be determined for this study.
Statistics
To determine mutual exclusivity of genetic alternations in gene pairs, one-sided Fisher’s exact test was performed, and for determining correlation between clinical variables and genes two-sided Fisher’s exact test was performed. Multiple hypothesis correction was performed using the Benjamini-Hochberg (also known as FDR) method to generated adjusted P-values. All calculations were performed using in-built functions in the R statistical computing software. P-value < 0.05 was considered significant.
Results
Clinical information summary
A total of 71 patients with sporadic PC, according to stringent clinical/pathological criteria (summarized in Tables 1 and 2; detailed information in Supplementary Table 2 [32, 33]), were selected. Four samples were removed from further study post-QC (Supplementary Table 1), resulting in 70 patients with evaluable specimens (71 tumors). Patient-derived tumor samples analyzed here originated from either primary (59.2%, N = 42/71), locally recurrent (14.1%, N = 10/71) or metastatic tumors (26.8%, N = 19/71). For only one patient (PC083), paired samples were available for both primary tumor plus a recurrence/metastasis. For the 42 primary tumor samples, 11 patients developed locally recurrent disease and 12 patients developed metastatic disease. Patients whose tumors exhibited those overtly malignant clinical behaviors of local recurrence or distant metastasis are defined here as having “life-threatening disease”.
Table 1.
Characteristics of Cohort
| Characteristics | Number (%) of patients (N=70) |
|---|---|
| Sequenced tumor specimen type | |
| Primary | 42 (59.2%) |
| Locally recurrent | 10 (14.1%) |
| Metastatic | 19 (26.8%) |
| Primary disease progressed? (avail N=42) | |
| No | 19 (45.2%) |
| Yes, local recurrence | 11 (26.2%) |
| Yes, metastasis | 12 (28.6%) |
Targeted panel sequencing
Previously, we developed an amplicon-based (Ion AmpliSeq) targeted cancer gene panel (“ParThy” panel; Supplemental Fig. 1) covering all coding exons of 16 genes implicated in PC based on our findings and the literature [17]. The genes to be included in the panel were chosen at that time based upon recurrence of variants in our discovery cohort, biological significance, and literature review. We employed the ParThy panel to study the present expanded cohort of PC samples. Briefly, DNA was extracted from all patient samples, sequenced using the ParThy panel, and the sequencing data were analyzed as described in Materials and Methods.
Resulting sequencing data achieved an average of 1.6 × 106 mapped reads (range = 2.3 × 104-1.0 × 107), 93.9% on-target accuracy (range = 68.4%-99.4%), 1.8 × 103 mean depth (range = 2.2 × 101-1.3 × 104) and 93.1% uniformity (range = 56.9%-97.2%) across the cohort (metrics as calculated by TorrentSuite software). A summary of per-sample sequencing QC metrics is available as Supplementary Table 1. Next, we performed variant calling and filtering (detailed in Materials and Methods) on the sequencing reads. Based on variant QC and manual inspection of data using IGV, we removed 4 samples from further analysis (Supplementary Table 1). For the resulting evaluable patients (N = 70) in the cohort, 86 variants were observed with 20 samples having 1 or more variant (Fig. 1; Table 2). The majority of observed variants were missense (40/86, 46.5%), while the rest were truncations − 22/86 (25.6%) frameshift and 24/86 (27.9%) stop gain.
Fig. 1.
Mutational landscape of PC: Custom OncoPrint/Waterfall plot [50] showing the distribution of tumor variants across patients (N = 43; X-axis) in genes on the ParThy panel (N = 14; Y-axis). Clinical information associated with each patient are also shown. For clarity, patients (X-axis) and genes (Y-axis) with no observed tumor mutations have not been included. Patient PC083 (sole case with both a primary and a metastasis lesion sequenced) is shown only once because mutations in the two tumors were identical
Table 2.
Clinical and Sequence Variant Information
| Patient ID | Sex | Local recurrence | Metastasis | Life-threatening disease | Specimen/lesion that was sequenced? | Specimen ID | Gene symbol | Chromosome | Position | Reference allele | Alternate allele | Amino acid change | Variant status | Allelic fraction | COSMIC ID |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| PC001 | F | yes | yes | yes | primary | PC001T | CDC73 | 1 | 193,094,267 | G | T | p.Glu53* | likely somatic | 48.3% | |
| CDC73 | 1 | 193,094,286 | C | T | p.Ser59Phe | germline | 47.2% | ||||||||
| FAT3 | 11 | 92,613,978 | G | A | p.Arg4070Gln | likely somatic | 46.2% | ||||||||
| MTOR | 1 | 11,190,617 | G | A | p.Thr1861Ile | likely somatic | 5.5% | ||||||||
| PC002 | F | yes | no | yes | normal | PC002N | no notable variants found | ||||||||
| recurrence | PC002T | CDC73 | 1 | 193,091,415 | G | T | p.Glu29* | somatic | 13.7% | ||||||
| PC003 | F | yes | yes | yes | primary | PC003T | TNRC6A | 16 | 24,802,347 | C | A | p.Ser795Tyr | likely somatic | 9.2% | |
| PC004 | M | no | no | no | normal | PC004N | no notable variants found | ||||||||
| primary | PC004T | KDM5C | X | 53,224,526 | C | T | p.Val1063Met | somatic | 4.4% | COSM1169517 | |||||
| PC005 | F | no | no | no | normal | PC005N | no notable variants found | ||||||||
| primary | PC005T | ||||||||||||||
| PC006 | M | no | yes | yes | normal | PC006N | no notable variants found | ||||||||
| primary | PC006T | ||||||||||||||
| PC007 | M | yes | yes | yes | metastasis | PC007T | CDC73 | 1 | 193,094,274 | AC | A | p.Tyr55fs | likely somatic | 34.4% | COSM26047 |
| PC008 | F | n/a | n/a | no | normal | PC008N | no notable variants found | ||||||||
| primary | PC008T | MTOR | 1 | 11,188,177 | T | A | p.Ile1973Phe | somatic | 9.1% | COSM423441 | |||||
| PC009 | M | yes | no | yes | primary | PC009T | FAT3 | 11 | 92,085,687 | G | A | p.Asp137Asn | likely somatic | 5.4% | |
| FAT3 | 11 | 92,531,391 | C | T | p.Gln1738* | likely somatic | 5.6% | ||||||||
| FBXO4 | 5 | 41,925,487 | G | A | p.Ala26Thr | likely somatic | 7.1% | ||||||||
| MTOR | 1 | 11,199,411 | G | A | p.Pro1694Ser | likely somatic | 6.3% | ||||||||
| PRUNE2 | 9 | 79,325,103 | C | T | p.Arg696Lys | likely somatic | 4.9% | ||||||||
| PC010 | M | no | no | no | normal | PC010N | no notable variants found | ||||||||
| primary | PC010T | ||||||||||||||
| PC011 | F | yes | yes | yes | metastasis | PC011T | no notable variants found | ||||||||
| PC012 | M | yes | yes | yes | metastasis | PC012T | CDC73 | 1 | 193,094,272 | C | G | p.Tyr54* | likely somatic | 10.7% | COSM26051 |
| FAT3 | 11 | 92,577,271 | A | G | p.Met3580Val | likely somatic | 28.3% | ||||||||
| PARK2 | 6 | 161,969,928 | C | G | p.Gln347His | likely somatic | 13.7% | COSM450871 | |||||||
| PC013 | F | no | yes | yes | normal | PC013N | no notable variants found | ||||||||
| primary | PC013T | ||||||||||||||
| PC014 | F | no | no | no | primary | PC014T | CDC73 | 1 | 193,094,272 | C | G | p.Tyr54* | likely somatic | 99.2% | COSM26051 |
| PC015 | F | no | yes | yes | normal | PC015N | no notable variants found | ||||||||
| primary | PC015T | no notable variants found | |||||||||||||
| PC017 | M | no | yes | yes | normal | PC017N | CDC73 | 1 | 193,111,157 | A | AT | p.Trp231_Arg232fs | germline | 47.4% | |
| metastasis | PC017T | CDC73 | 1 | 193,091,458 | G | A | p.Trp43* | somatic | 40.5% | COSM26046 | |||||
| PIK3CA | 3 | 178,936,091 | G | A | p.Glu545Lys | somatic | 39.6% | COSM763 | |||||||
| PRUNE2 | 9 | 79,322,647 | C | T | p.Val1515Ile | somatic | 4.6% | ||||||||
| PC018 | M | yes | yes | yes | metastasis | PC018T | no notable variants found | ||||||||
| metastasis | PC019T | ||||||||||||||
| PC020 | M | n/a | n/a | no | primary | PC020T | SETD1B | 12 | 122,254,983 | C | G | p.Asp920Glu | likely somatic | 47.6% | COSM5574222 |
| PC021 | M | no | no | no | primary | PC021T | ADCK1 | 14 | 78,353,525 | C | T | p.Thr172Met | likely somatic | 47.6% | COSM2249317 |
| SETD1B | 12 | 122,248,314 | C | A | p.Ser488Tyr | likely somatic | 47.2% | ||||||||
| PC024 | F | yes | yes | yes | normal | PC024N | CDC73 | 1 | 193,111,145 | CAG | C | p.Arg227fs | germline | 43.1% | |
| recurrence | PC024T | no notable variants found | |||||||||||||
| PC025 | M | no | no | no | primary | PC025T | no notable variants found | ||||||||
| PC026 | M | yes | n/a | yes | normal | PC026N | no notable variants found | ||||||||
| primary | PC026T | ||||||||||||||
| PC027 | F | yes | yes | yes | normal | PC027N | QC fail | ||||||||
| metastasis | PC027T | CDC73 | 1 | 193,091,390 | GA | G | p.Lys21fs | somatic | 80.7% | ||||||
| CEP152 | 15 | 49,048,132 | G | C | p.Leu1105Val | somatic | 49.9% | ||||||||
| PC028 | F | n/a | n/a | no | primary | PC028T | no notable variants found | ||||||||
| PC029 | M | no | no | no | primary | PC029T | CDC73 | 1 | 193,091,417 | GT | G | p.Phe30fs | likely somatic | 84.4% | |
| PC030 | M | no | no | no | primary | PC030T | CDC73 | 1 | 193,111,006 | A | AA | p.Ile182fs | germline | 34.8% | |
| TNRC6A | 16 | 24,818,075 | C | G | p.Pro1504Ala | likely somatic | 4.3% | ||||||||
| PC031 | F | no | no | no | normal | PC031N | no notable variants found | ||||||||
| primary | PC031T | no notable variants found | |||||||||||||
| PC032 | F | yes | no | yes | metastasis | PC032T | PIK3CA | 3 | 178,936,091 | G | A | p.Glu545Lys | likely somatic | 47.3% | COSM763 |
| PC033 | F | no | no | no | primary | PC033T | PARK2 | 6 | 162,206,909 | G | A | p.Arg256Cys | likely somatic | 35.2% | |
| PC034 | F | n/a | n/a | no | primary | PC034T | no notable variants found | ||||||||
| PC035 | M | n/a | n/a | no | primary | PC035T | no notable variants found | ||||||||
| PC036 | M | n/a | n/a | no | primary | PC036T | CDC73 | 1 | 193,091,411 | CG | C | p.Gly28fs | likely somatic | 27.2% | COSM26069 |
| CDC73 | 1 | 193,117,027 | C | T | p.Gln254* | likely somatic | 36.6% | COSM4507949 | |||||||
| PC037 | M | yes | yes | yes | normal | PC037N | no notable variants found | ||||||||
| recurrence | PC037T | ||||||||||||||
| PC038 | F | no | no | no | primary | PC038T | no notable variants found | ||||||||
| PC039 | F | yes | n/a | yes | recurrence | PC039T | SETD1B | 12 | 122,257,478 | T | A | p.Val1153Glu | likely somatic | 49.4% | |
| PC040 | F | yes | yes | yes | metastasis | PC040T | no notable variants found | ||||||||
| PC041 | F | no | no | no | normal | PC041N | no notable variants found | ||||||||
| primary | PC041T | ||||||||||||||
| PC042 | M | yes | no | yes | normal | PC042N | no notable variants found | ||||||||
| primary | PC042T | CDC73 | 1 | 193,091,411 | CG | C | p.Gly28fs | somatic | 16.5% | COSM26069 | |||||
| CDC73 | 1 | 193,111,152 | A | T | p.Arg229* | somatic | 12.5% | ||||||||
| PC043 | F | yes | yes | yes | normal | PC043N | no notable variants found | ||||||||
| metastasis | PC043T | ||||||||||||||
| PC044 | M | no | no | no | normal | PC044N | no notable variants found | ||||||||
| primary | PC044T | ||||||||||||||
| PC045 | M | no | no | no | normal | PC045N | no notable variants found | ||||||||
| primary | PC045T | CDC73 | 1 | 193,091,355 | C | T | p.Arg9* | somatic | 37.5% | COSM26056 | |||||
| PC046 | M | yes | no | yes | normal | PC046N | CDC73 | 1 | 193,117,012 | AT | A | p.Ile249fs | germline | 17.9% | |
| primary | PC046T | no notable variants found | |||||||||||||
| PC047 | F | no | no | no | normal | PC047N | no notable variants found | ||||||||
| primary | PC047T | ||||||||||||||
| PC048 | F | yes | no | yes | normal | PC048N | no notable variants found | ||||||||
| primary | PC048T | CDC73 | 1 | 193,091,415 | G | T | p.Glu29* | somatic | 19.5% | ||||||
| CDC73 | 1 | 193,104,668 | C | CA | p.Lys125_Arg126fs | somatic | 48.7% | ||||||||
| FBXL7 | 5 | 15,936,973 | G | A | p.Gly385Asp | somatic | 10.3% | ||||||||
| MTOR | 1 | 11,217,299 | A | G | p.Leu1460Pro | somatic | 12.6% | COSM462618 | |||||||
| ZEB1 | 10 | 31,809,662 | C | G | p.Gln467Glu | somatic | 8.2% | ||||||||
| PC049 | M | yes | no | yes | normal | PC049N | CDC73 | 1 | 193,111,145 | C | CAG | p.Arg227_Glu228fs | germline | 13.1% | |
| recurrence | PC049T | CDC73 | 1 | 193,094,272 | C | G | p.Tyr54* | somatic | 29.1% | COSM26051 | |||||
| PC050 | M | yes | no | yes | normal | PC050N | no notable variants found | ||||||||
| recurrence | PC050T | FAT3 | 11 | 92,086,105 | T | A | p.Leu276* | somatic | 16.7% | ||||||
| PC051 | M | yes | yes | yes | normal | PC051N | no notable variants found | ||||||||
| metastasis | PC051T | CDC73 | 1 | 193,091,368 | TC | T | p.Ile13fs | somatic | 80.1% | COSM26064 | |||||
| TNRC6A | 16 | 24,801,018 | C | G | p.Ser352* | somatic | 12.2% | ||||||||
| PC052 | M | no | no | no | normal | PC052N | no notable variants found | ||||||||
| primary | PC052T | ||||||||||||||
| PC053 | M | no | yes | yes | normal | PC053N | no notable variants found | ||||||||
| metastasis | PC053T | CDC73 | 1 | 193,091,352 | CTGC | CGT | p.Leu8fs | somatic | 17.1% | COSM26065 | |||||
| KDM5C | X | 53,231,065 | C | T | p.Glu613Lys | somatic | 10.1% | ||||||||
| ZEB1 | 10 | 31,803,576 | G | A | p.Glu244Lys | somatic | 8.5% | ||||||||
| PC054 | F | yes | yes | yes | normal | PC054N | no notable variants found | ||||||||
| metastasis | PC054T | ||||||||||||||
| PC055 | F | yes | yes | yes | normal | PC055N | no notable variants found | ||||||||
| metastasis | PC055T | CDC73 | 1 | 193,111,131 | C | T | p.Arg222* | somatic | 23.4% | ||||||
| FAT3 | 11 | 92,568,041 | A | G | p.Ile3293Val | somatic | 15.4% | ||||||||
| SETD1B | 12 | 122,260,548 | CT | C | p.Leu1312fs | somatic | 8.3% | ||||||||
| PC056 | M | yes | no | yes | normal | PC056N | QC fail | ||||||||
| recurrence | PC056T | PIK3CA | 3 | 178,916,944 | A | G | p.Lys111Glu | somatic | 52.4% | COSM13570 | |||||
| PC057 | M | no | no | no | primary | PC057T | CDC73 | 1 | 193,091,459 | G | A | p.Trp43* | likely somatic | 36.1% | COSM26046 |
| CDC73 | 1 | 193,111,159 | G | A | p.Trp231* | likely somatic | 33.2% | ||||||||
| FAT3 | 11 | 92,523,182 | C | T | p.Ser1470Phe | likely somatic | 2.6% | ||||||||
| PC058 | F | no | yes | yes | normal | PC058N | CDC73 | 1 | 193,111,152 | A | T | p.Arg229* | germline | 15.4% | |
| primary | PC058T | QC fail | |||||||||||||
| PC059 | M | yes | yes | yes | metastasis | PC059T | QC fail | ||||||||
| PC060 | F | yes | yes | yes | metastasis | PC060T | PIK3CA | 3 | 178,952,085 | A | G | p.His1047Arg | likely somatic | 12.2% | COSM775 |
| PC061 | F | no | no | no | primary | PC061T | no notable variants found | ||||||||
| PC062 | M | yes | yes | yes | metastasis | PC062T | FAT3 | 11 | 92,531,077 | C | T | p.Thr1633Met | likely somatic | 27.7% | COSM2223537 |
| PC063 | F | yes | n/a | yes | recurrence | PC063T | CDC73 | 1 | 193,091,345 | TA | T | p.Ser6fs | likely somatic | 35.0% | |
| CDC73 | 1 | 193,202,197 | AC | A | p.Asp410fs | likely somatic | 38.7% | ||||||||
| PC064 | M | yes | no | yes | recurrence | PC064T | CDC73 | 1 | 193,091,415 | G | T | p.Glu29* | likely somatic | 43.5% | |
| FAT3 | 11 | 92,532,819 | G | A | p.Glu2214Lys | likely somatic | 9.3% | ||||||||
| TNRC6A | 16 | 24,800,831 | G | A | p.Gly290Ser | likely somatic | 51.2% | ||||||||
| PC065 | M | no | yes | yes | primary | PC065T | FBXO4 | 5 | 41,929,906 | G | A | p.Arg178Gln | likely somatic | 54.2% | COSM3393590 |
| PIK3CA | 3 | 178,936,092 | A | C | p.Glu545Ala | likely somatic | 12.8% | COSM12458 | |||||||
| PC066 | M | no | yes | yes | primary | PC066T | no notable variants found | ||||||||
| PC067 | M | yes | no | yes | recurrence | PC067T | CDC73 | 1 | 193,091,389 | TGAAGGGAGAC | T | p.Val20fs | likely somatic | 12.0% | |
| CDC73 | 1 | 193,111,167 | C | T | p.Arg234* | likely somatic | 45.2% | COSM26077 | |||||||
| PC080 | F | yes | yes | yes | normal | PC080N | CDC73 | 1 | 193,111,167 | C | T | p.Arg234* | germline | 48.8% | COSM26077 |
| metastasis | PC080T | FAT3 | 11 | 92,531,143 | C | T | p.Ala1655Val | somatic | 3.6% | ||||||
| PC081 | M | n/a | yes | yes | normal | PC081N | no notable variants found | ||||||||
| primary | PC081T | CDC73 | 1 | 193,094,292 | T | A | p.Leu61* | somatic | 77.4% | COSM1732628 | |||||
| FAT3 | 11 | 92,565,132 | C | T | p.Arg3276Trp | somatic | 2.7% | ||||||||
| TNRC6A | 16 | 24,800,831 | G | A | p.Gly290Ser | somatic | 3.2% | ||||||||
| PC082 | M | yes | yes | yes | normal | PC082N | no notable variants found | ||||||||
| primary | PC082T | CDC73 | 1 | 193,094,302 | T | TA | p.Asn65_Asn66fs | somatic | 52.0% | COSM26058 | |||||
| PC083 | M | yes | yes | yes | normal | PC083N | no notable variants found | ||||||||
| primary | PC083T | CDC73 | 1 | 193,094,304 | A | AT | p.Asn65_Asn66fs | somatic | 72.3% | COSM26058 | |||||
| metastasis | PC084T | CDC73 | 1 | 193,094,304 | A | AT | p.Asn65_Asn66fs | somatic | 75.2% | COSM26058 | |||||
| PC085 | F | yes | yes | yes | normal | PC085N | CDC73 | 1 | 193,104,711 | C | T | p.Arg139* | germline | 30.5% | |
| primary | PC085T | CDC73 | 1 | 193,094,272 | C | G | p.Tyr54* | somatic | 12.1% | COSM26051 | |||||
| PC086 | F | yes | yes | yes | normal | PC086N | no notable variants found | ||||||||
| metastasis | PC086T | CEP152 | 15 | 49,081,074 | A | G | p.Leu366Pro | somatic | 6.0% | ||||||
| PC087 | M | n/a | yes | yes | normal | PC087N | no notable variants found | ||||||||
| primary | PC087T | CDC73 | 1 | 193,091,355 | C | T | p.Arg9* | somatic | 57.5% | COSM26056 | |||||
| PC088 | M | yes | n/a | yes | normal | PC088N | no notable variants found | ||||||||
| primary | PC088T | CDC73 | 1 | 193,091,392 | AG | A | p.Lys21fs | somatic | 29.8% | ||||||
| CDC73 | 1 | 193,111,040 | TAAGAA | T | p.Lys192fs | somatic | 38.5% | ||||||||
Mutational landscape in PC
Inactivation of the CDC73 gene is the earliest discovered and the only fully established driver event for PC [34, 35]. In our cohort, we observed loss of function (stop gain or frameshift) CDC73 variants in 31/70 (44%) patients, which is consistent with earlier studies. In 12 patients (38.7%) biallelic CDC73 variants were found, with 4 patients harboring a inactivating germline variant plus a somatic variant and 8 having two somatic variants. In addition 5 patients carried a heterozygous germline CDC73 variant with no second hit detected in the tumor, for a total of 9 (29.0%) patients harboring a germline inactivating variant. It is important to note our approach was not able to detect certain types of inactivating mutations such as large genomic deletions or variants in cis-regulatory or non-coding regions. All observed CDC73 variants are detailed in Table 2.
Amongst other genes screened using the ParThy panel, we observed no sequence variants in PCMTD1 or CCND1. After CDC73, FAT3 (10/70, 14.3%), TNRC6A (5/70, 7.14%) and PIK3CA (5/70, 7.14%) are the top mutated genes, harboring primarily missense variants. Several genes on the panel are longer than average (> 3,000 bp) which might confound this observation.
To determine oncogenic driver events in the cohort, we cross-referenced the list of observed variants with the COSMIC database v81 (Supplementary Table 3). As expected, several CDC73 loss-of-function (LOF) variants have been observed in published studies and included in COSMIC. Importantly, four PIK3CA missense variants observed in our cohort are highly recurrent in COSMIC in multiple tumor types, as highlighted in Supplementary Fig. 1, providing supporting evidence for their role as drivers. Additionally, variants in FBXO4 (N = 1), KDM5C (N = 1), MTOR (N = 3), and PARK2 (N = 1) are also present in COSMIC. This suggests that the observed gene variants may act as potential drivers in specific subsets of PC patients.
Clinical significance of observed variants
Figure 1 shows a OncoPrint plot providing a comprehensive view of the mutational landscape of the cohort. Notably, the PI3K/AKT/mTOR pathway was altered in 12.9% (9/70) patients, primarily in tumors without CDC73 mutations. Observed mutations in PIK3CA (p. K111E, p.E545K, p.E545A, and p. H1047R) all occurred in known oncogenic hotspots. MTOR mutations included p.T1861I, p.P1694S, and known oncogenic mutations p.L1460P and p.I1973F.
Statistical significance (p-value and odds-ratio) of disease progression with mutated genes was computed. We noted that patients with germline or somatic pathogenic CDC73 variants were significantly more likely to suffer from life threatening recurrent/metastatic PC (p-value = 0.024, odds ratio = 3.51, CI = [1.08–12.7]). Of the 31 PC patients with CDC73 mutations, 25 (81%) progressed to life threatening disease, compared with only 54% (21/39) of patients with no CDC73 variant. This trend toward life-threatening disease in the CDC73-mutation group was similarly distributed across patients with germline vs. somatic CDC73 mutation (8/9, 88.9% vs. 17/22, 77.3% respectively), or across those with a single allele mutation (15/19, 78.9%) vs. biallelic CDC73 mutations (10/12, 83.3%).
Discussion
Given the dearth of effective, non-surgical therapies for PC, the identification of genetic/molecular aberrations that might serve as “actionable targets” for pharmacologic intervention in patients whose disease is no longer surgically curable remains a high priority for ongoing research. Especially important for a rare disease, international cooperation has enabled us to examine a sizeable cohort of PC samples and thereby better understand the frequency of alterations in key established and candidate driver genes [34, 35]. Most notably, our observations expand and strengthen the genetic evidence that oncogenic variants in PIK3CA and other PI3K/AKT/MTOR pathway genes are recurrently identified in PC and thus likely contribute to a selective advantage in the neoplastic cell. These features, and their occurrence in patients across multiple international sites, have important implications for future therapeutic interventions.
The PI3K/AKT/MTOR pathway has central roles in regulation of cell growth and survival, and cell cycle progression. Pathway members are frequently subject to mutation in human tumors. PIK3CA encodes the p110 alpha catalytic subunit of phosphatidylinositol 3-kinase (PI3K), which when activated, converts PIP2 to PIP3, in turn activating AKT to subsequently activate mTOR, ultimately leading to cellular growth, increased survival and angiogenesis [36]. The PIK3CA pathogenic variants observed in the present study, p.K111E, p.E545A, p.E545K and p.H1047R, are all known, activating, hot spot mutations, previously shown to be involved in other human cancers, including breast, lung, ovarian and colorectal cancers [37]. PIK3CA variants have been reported in other studies of PC [18, 19, 23, 38]. Two of the MTOR variants observed in this study, p.L1460P and p.I1973F, are also known and established pathogenic activating variants [39, 40]. Pathogenic or likely pathogenic variants have been reported in other PI3K/AKT/MTOR genes, including PTEN [18, 19], TSC1 [19, 20, 38] and TSC2 [18], suggesting the involvement of this pathway in 11.5% of PCs across the literature [18–20, 23, 38, 41, 42]. Several drugs inhibiting the PI3K/AKT/MTOR pathway are already approved for treating human cancers, with other drugs still being evaluated. For example, alpelisib, a PI3K inhibitor, is approved for the treatment of PIK3CA-mutated advanced breast cancer [43] and certain MTOR mutations, including p.I1973F, confer increased sensitivity to everolimus [44, 45], a drug approved for renal cell and other cancers. Given the availability of drugs to target this pathway, patients with advanced PC should be strongly considered for tumor sequencing, including PI3K/AKT/MTOR pathway genes, and treatment, as clinically appropriate.
Methodologically, a key advantage of using a targeted, amplicon-based panel is the ability to sequence to a significantly greater depth at lower cost compared to typically used genome- or exome-wide methods. This enables identification of variants at lower allelic fractions. Since this method requires lower DNA input, smaller tissue samples can be analyzed, or additional, multi-omic analyses can be performed on the same tumor [46], further enhancing insight into personalized therapeutic strategies. On the other hand, the present analysis was limited at its inception by the prior selection of specific genes for inclusion on the ParThy panel, plus the more general limitations of such panels for detecting larger genomic alterations and robustly detecting copy number variations. While this study is unable to speak to the potential role of some additional genes of interest, it would be worthwhile in the future to design an analogous panel whose content is informed by additional candidates [6, 47].
CCND1/cyclin D1 has long been established as a parathyroid tumor oncogene, activated by somatic gene rearrangement in a subset of common benign parathyroid adenomas [34]. More recently, it has been demonstrated that cyclin D1-driven parathyroid neoplasia, in contrast to other tumor types, depends strongly on the ability of cyclin D1 to bind to and activate its partner cdks [48], suggesting that cyclin D1-overexpressing parathyroid tumor cells may be more sensitive to alterations in cdk-mediated proliferation control, and thus may be highly responsive to cdk4/6 inhibitor therapy. Additional data have implicated cyclin D1 in parathyroid malignancies, with gene amplification being the major observed activating mechanism [49]. Specifically, using NGS we previously found CCND1 amplification in 29% of PCs [17]. While the present study was unable to evaluate CCND1 copy number due to the inability to obtain a robust reference for detecting somatic copy number alterations, a renewed effort to examine cyclin D1 copy number in a large set of PCs should be considered.
Finally, we observed a significant association between CDC73 variant status and clinically-determined life-threatening disease, as described above in Results/Clinical significance of observed variants. This raises the question of whether a subset of primary parathyroid tumors, despite fulfilling currently accepted histopathologic criteria for diagnosis of PC (and generally with intact CDC73), may not share an equally high potential for truly malignant clinical behavior, i.e. local recurrence after primary resection or distant metastasis, with CDC73-mutant tumors. A prospective study would be needed to rigorously test this hypothesis, and meanwhile we consider it important for clinicians and pathologists, and authors of future studies, to specify the precise criteria used to support a diagnosis of PC in any individual case, including any evidence for clinically advanced or surgically incurable disease.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
This work was supported in part through the computational resources and staff expertise provided by the Department of Scientific Computing at the Icahn School of Medicine at Mount Sinai; Murray-Heilig Fund in Molecular Medicine (AA); National Institute for Health Research (NIHR) Oxford (UK) Biomedical Research Centre Programme (RVT & MS); Wellcome Trust Senior Investigator award (RVT); NIHR Senior Investigator Award (RVT); Fundação para a Ciência e a Tecnologia (FCT), Ministério da Ciência, Tecnologia e Ensino Superior (MCTES), Portugal, through national funds to the iNOVA4Health R&D Unit (UIDB/04462/2020, UIDP/04462/2020), the Associated Laboratory LS4FUTURE (LA/P/0087/2020) (BMC). The authors are thankful for the collaboration of the Endocrinology and Pathology Departments from Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG).
Data availability
Somatic variant calls are available publicly via COSMIC (cancer.sanger.ac.uk) under accession ID COSP53916.
Declarations
Competing Interests
The authors have no competing interests to declare that are relevant to the content of this article.
Footnotes
The original online version of this article was revised due to Table 2 was incorrect in the article.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rong Chen and Andrew Arnold contributed equally to this work.
Change history
6/24/2026
The original online version of this article was revised: due to Table 2 was incorrect in the article.
Change history
8/6/2026
A Correction to this paper has been published: https://doi.org/10.1007/s40618-026-02959-4
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Somatic variant calls are available publicly via COSMIC (cancer.sanger.ac.uk) under accession ID COSP53916.