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.
Highlights
Introduction conditions of the Creative CommonsSomatic mitochondrial DNA mutations have been reported in almost all cancer types at variable degrees of mutation load [1,2,3,4,5], their role as modifiers during cancer initiation or progression is still to be elucidated
The two carcinomas were characterized by an expansive growth, well-defined round borders of the capsule and by the growth of dense fibrous tissue at the edge of the tumor, indicative of a desmoplastic reaction causing thickening of the capsule (Figure 1B(b,c)), a process usually associated with malignancy
We report here for the first time the occurrence of oncocytic transformation in several tumors in a family pedigree, associated with Hyperparathyroidism-Jaw Tumor (HPT-JT) syndrome, an inherited cancerpredisposing disorder caused by germline mutations in the CDC73 tumor suppressor gene
Summary
Somatic mitochondrial DNA (mtDNA) mutations have been reported in almost all cancer types at variable degrees of mutation load [1,2,3,4,5], their role as modifiers during cancer initiation or progression is still to be elucidated. Homoplasmic disruptive mutations, such as those affecting respiratory complex I (CI) structural integrity and function, have been long considered hallmarks of oncocytic transformation and are responsible for reduced tumorigenic potential and a less aggressive behavior This indolent phenotype is associated with an impaired metabolism as well as the inability of cancer cells to promptly adapt to hypoxia [10,11,12,13]. Oncocytomas are epithelia-derived human neoplasms characterized by an aberrant accumulation of swollen and deranged mitochondria within the cytoplasm These tumors, found in endocrine and exocrine tissues [14], mainly occur in sporadic forms, albeit rare familial cases have been reported within the phenotypic spectrum of Birt-Hogg-Dubè (BHD; OMIM:135150) [15,16] or Cowden syndrome (CS, OMIM:158350) [17,18], and of Familial. We show an inverse clear-cut correlation between the load of pathogenic mtDNA mutations and the indolent behavior of neoplasms, highlighting the importance of the former in modifying cancer fate
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
