Pathogenic Mitochondrial DNA Mutation Load Inversely Correlates with Malignant Features in Familial Oncocytic Parathyroid Tumors Associated with Hyperparathyroidism-Jaw Tumor Syndrome

Abstract

While somatic disruptive mitochondrial DNA (mtDNA) mutations that severely affect the respiratory chain are counter-selected in most human neoplasms, they are the genetic hallmark of indolent oncocytomas, where they appear to contribute to reduce tumorigenic potential. A correlation between mtDNA mutation type and load, and the clinical outcome of a tumor, corroborated by functional studies, is currently lacking. Recurrent familial oncocytomas are extremely rare entities, and they offer the chance to investigate the determinants of oncocytic transformation and the role of both germline and somatic mtDNA mutations in cancer. We here report the first family with Hyperparathyroidism-Jaw Tumor (HPT-JT) syndrome showing the inherited predisposition of four individuals to develop parathyroid oncocytic tumors. MtDNA sequencing revealed a rare ribosomal RNA mutation in the germline of all HPT-JT affected individuals whose pathogenicity was functionally evaluated via cybridization technique, and which was counter-selected in the most aggressive infiltrating carcinoma, but positively selected in adenomas. In all tumors different somatic mutations accumulated on this genetic background, with an inverse clear-cut correlation between the load of pathogenic mtDNA mutations and the indolent behavior of neoplasms, highlighting the importance of the former both as modifiers of cancer fate and as prognostic markers.

Insights into Hyperparathyroidism–Jaw Tumour Syndrome: From Endocrine Acumen to the Spectrum of CDC73 Gene and Parafibromin-Deficient Tumours

“…We identified 17 original studies regarding the spectrum of CDC73-associated HJT or HJT-PHP, having as a starting point either the HJT population or subjects with PHP who underwent genetic assays or screening within one family [30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46] (Table 1). Table 1.…”

“…Table 1. Original human studies (N ≥ four subjects/article) addressing HJT and CDC73 pathogenic variants-associated clinical considerations amid past decade according to our mentioned methods (starting with the most recent publication date) [30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46].…”

“…Most of the enrolled patients were diagnosed before the age of 40 years, with the youngest subject being 10 [31] and the oldest 71 [35]. While some studies found that males were more affected than females [31,34,46], others identified quite the opposite results [35,41] or a similar sex ratio [30,32,43].…”

“…Most of the enrolled patients were diagnosed before the age of 40 years, with the youngest subject being 10 [31] and the oldest 71 [35]. While some studies found that males were more affected than females [31,34,46], others identified quite the opposite results [35,41] or a similar sex ratio [30,32,43]. Overall, no specific sex distribution was confirmed (of note, the type of studied population varied among individuals, such as initial admission for HJT/PHP or one family screening).…”

“…For example, Tora et al [31] studied a retrospective cohort (N = 68) with an age at first admission between 10 and 30 years, and 71% (N = 36) of them being women [31]. Iacobone et al [35] identified an older age at diagnosis of HJT-related PHP (a median of 38, ranging between 11 and 71 years; female-to-male ratio of 14/8) [35]. Figueiredo et al [30] showed an average age of 33.3 ± 13.1 years at HJT diagnosis and a mean of 35.1 ± 13.6 years with respect to PHP onset, also identifying an equal distribution among women and men [30].…”