Parathyroid carcinoma (PCa) is a rare endocrine disease representing <1% of the parathyroid gland’s tumors, which may led to elevated parathyroid hormone (PTH) secretion, hypercalcemic crisis, bone disorders, renal failure and a consequent fatal hyperparathyroidism (1). Opposite to other endocrine tumors, it occurs with an equal frequency in men and women (2). Further, in about half of the cases the current clinical approach, i.e. surgery followed by adjuvant therapies, is not curative and tumor relapse often occurs. This results in a poor survival rate, with 85% of the patients dying within 5 years (3). Moreover, the presence of a metastatic lesion at diagnosis and the tumor size are worse prognostic factor (4, 5).

Current diagnosis of parathyroid carcinoma is made intra- and post-operatively and it is based on advanced histopathologic criteria of an invasive phenotype, like vascular invasion or distant metastasis (6). Histologically, the absence of the Cell Division Cycle 73 (CDC73), amplification of the Cyclin D1 (CCND1) gene and CCND1 overexpression, are the most common molecular features distinguishing PCas from benign parathyroid adenomas (PAds). In addition, the mutational status of APC, RB, E-cadherin, MDM2 and p53 overexpression are considered useful biomarkers for parathyroid carcinomas’ diagnosis (7). Nevertheless, some PCas have an indolent growth and mimic benign lesions making their diagnosis more challenging (8). This clinical scenario is further complicated by the absence of accurate molecular markers supporting the differential diagnosis between parathyroid adenomas and carcinomas. We previously showed that non-coding RNAs play important roles in parathyroid tumorigenesis, acting both as oncogenes (9) and as biomarkers (10, 11).

In particular, long non-coding RNAs (lncRNAs) actively participate in endocrine tumors by promoting cancer cell proliferation, migration and metastasis (12, 13). Moreover, lncRNAs are involved in drug resistance and correlate with patient’s prognosis and overall survival (14); hence the evidence of lncRNAs as prognostic and diagnostic biomarkers. In recent years, lncRNAs became a crucial topic in parathyroid tumors field, with the purpose of identifying biomarkers able to distinguish malignant from benign glands (11, 15–17). Recently, we profiled 90 lncRNAs in a cohort of 24 PAds, 9 PCas and 4 normal glands, and we identified Brain Cytoplasmic RNA 1 BC200 (BCYRN1) as the most upregulated lncRNA in PCas compared to the other histotypes (11). BC200 is the shortest and neuronal-specific lncRNA whose aberrant expression was originally associated to neurodegenerative disorders, but its deregulation has been described also in cancer (18). Particularly, its expression is dramatically increased in gastric, colorectal and breast cancers, where it positively correlates with tumor size and clinical stage. In these contexts, BC200 affects cancer cells motility, promoting in vitro cell migration and proliferation (19–21). Interestingly, BC200 was detected in the circulation of patients with invasive breast cancer compared to healthy donors, suggesting its possible role as a non-invasive tumor biomarker (22).

The identification of biomarkers, especially non-invasive ones, in parathyroid tumors is key for their correct diagnosis, prognosis and patients’ follow-up. Based on our preliminary evidence, here we aimed to get further insights on the possible use of BC200 as a biomarker of parathyroid tumor malignancy.

Here, we report novel observations about the lncRNA BC200 relevance in parathyroid tumors. Particularly, we found that pre-surgery circulating BC200 levels are higher in patients with parathyroid carcinomas than in those with benign adenomas. Importantly, BC200 expression in patients’ circulation drops decrease after the successful surgical removal of the cancer. Further, in PAd patients BC200 expression is directly correlated with increased serum calcium levels, a clinical parameter of active disease. Therefore, these results indicate that serological BC200 can be accurately measured in the circulation of patients with parathyroid tumors, and can be used to complement the clinical algorithm to correctly diagnose and follow subjects affected by parathyroid carcinoma.

Then, we tested the hypothesis of BC200 correlation with tumor aggressiveness by measuring its mRNA levels in non-metastatic and metastatic parathyroid carcinomas’ tissues. In line with its supposed oncogenic role, BC200 is more expressed in the lesions from metastatic PCas than in non-metastatic carcinomas, suggesting a possible involvement of BC200 in PCas’ metastatic process and invasiveness.

We previously reported that BC200, measured in parathyroid tissues, was able to discriminate benign from malignant parathyroid lesions. Now we extend this information providing novel evidence of the use of BC200 as a non-invasive biomarker of PCa. Despite the limited sample series, our results confirm the positive correlation of BC200 expression with disease severity. The use of a highly accurate methodology such as the digital PCR may rapidly translate, if confirmed in a larger cohort, these results into a point-of-care test to support the clinical and histological diagnosis of PCa versus PAd, and the follow-up of PCa patients. This could be crucial in the management of patients affected by parathyroid tumors, a complex class of diseases that lacks accurate biomarkers, especially of the non-invasive kind (24).

PCas are one of the rarest endocrine malignancies, representing <1% of parathyroid tumors (25). They are frequently characterized by markedly PTH hypersecretion and some patients experience hypercalcemia-related symptoms, with renal and bone involvement. The preoperatively diagnosis of this tumor is complicated and could be misleading since PCas often show clinical and molecular features shared by benign lesions and they are often indolent. The histological diagnosis of PCa is made on the presence of mitotic figures, capsular invasion, parenchyma gross infiltration, vascular invasion and, less frequently, distant metastasis (26). The complete resection of the tumor is the best treatment, even if it may not be curative. At the molecular level, mutations in few cell cycle-related genes such as CDC73, Rb and PRAD1, have been proposed as crucial in promoting parathyroid cells malignancy, but their role as PCas biomarkers is still uncertain. As a results, more than 50% of PCas recur at local or distant sites (27). Hence, there is an unmet need for a sensitive biomarker able to discriminate PCas from PAds and to stratify patients according to tumor aggressiveness and severity.

Epigenetic alterations represent a hallmark of cancer, mainly related to DNA methylation and histone post-translational modifications (28). These alterations, together with non-coding RNAs, make a great contribution to endocrine tumor development (29, 30). In parathyroid tumors, the hypermethylation of the tumor-suppressor HIC1, together with RASSF1A, CDKN2B and APC genes, were described in PCas and could be an early event in parathyroid tumor development (31, 32). Our previous study reported a lncRNA signature able to distinguish parathyroid carcinomas from adenomas and normal glands. Particularly, we found the lncRNA BC200 as the most upregulated one in PCas compared to other parathyroid tumour histotypes (11). Consistently with our findings, several works have reported a BC200 increase in many cancer types, where its overexpression promoted cell proliferation, metastasis formation and cancer aggressiveness (19, 33, 34). In addition, BC200 was detected in the peripheral blood of patients with invasive or metastatic breast cancer compared to disease-free patients (22).

Overall, our novel findings and previous data extend the knowledge on BC200 relevance in parathyroid tumors, supporting its role as a novel candidate biomarker in PCas diagnosis and follow-up.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors.

The studies involving human participants were reviewed and approved by Ethical Committee of Scientific Institute San Raffaele Hospital (#CE40/2019). The patients/participants provided their written informed consent to participate in this study.

AM and VV studied concept and design. AM and GP performed experiments. AM, SC, and VV analyzed and interpreted data. AM and GP acquired data and technical material. FC, SB, EP, VG, CV, GT, LV, CB, and SC provided tumor specimens and clinical information. AM and VV drafted the manuscript. SF and SC obtained funding. All authors critically revised and approved the final version of the manuscript.

This work is supported by the Ricerca Corrente Program 2021 (from the Italian Ministry of Health) to SF and SC.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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