Medical Genetics Service, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo

The laboratory offers several molecular diagnosis for more than 160 different genetic diseases (more info here) by classic Sanger sequencing and the most recent high-throughput Next Generations Sequencing and Affymetrix platforms.

Guarnieri’s Research Group is responsible of molecular diagnosis of specific bone dismetabolisms, particularly primary hyperparathyroidism and its endophenotypes such as:

  • Familial Hypercalcemic Hypocalciuria and Neonatal Severe PHPT (CASR, GNA11 and AP2S1 genes);
  • Familial Hypoparathyroidism (CASR, GCM2, GNA11, PTH);
  • Hyperparathyroidism with Jaw Tumour (CDC73 gene);
  • Multiple Endocrine Neoplasia 1, 2 and 4 (MEN1, RET and CDKN1B, respectively), Hypophosphatasia (ALPL gene).

but also of other syndromes such as:

  • Congenital Adrenal Hyperplasia (CYP21A2 gene);
  • Pheochromocitomas/Paragangliomas (SDHx, VHL, RET, TMEM127, MAX genes).

Particular research interest of Guarnieri’s Research Group focuses at the identification of possible biomarkers for unequivocal diagnosis of malignant parathyroid lesions. Instead Primary hyperparathyroidism (pHPT) is caused by parathyroid adenoma (PA, 85%), hyperplasia (HP, 15%), carcinoma (KP, <1%, prevalence of 3-5/million) (1). KP and PA follow different biological pathways and clinical outcomes, but the presurgical suspect in absence of local recurrences/distant metastasis and the pathological diagnosis of KP is difficult. Histological criteria also included the atypical adenoma (AA), a tumour lacking evidence of invasion but with features of malignancy (fibrous bands/capsular invasion/increased mitotic figures) (2) whose biological behavior and natural history is unknown. Before surgery, it is important to know or suspect the type of disease (PA, AA, KP), since in case of KP the en bloc resection (vs local parathyroidectomy in case of PA) is associated with a less local recurrence (8% vs 51%) and a Long Term Overall Survival (LTOS) (89% vs 53%) (3). Moreover, after surgery a correct pathological diagnosis is mandatory for a proper follow up of the patients.

Improvements in Parathyroid Tumours (PTs) diagnosis have been made by molecular screening of 2 genes, CDC73 and MEN1 and the immunohistochemistry (IHC) of the proteins parafibromin and menin. However, these strategies are not always pursued or follow the surgery, thus not fulfilling the need of an unequivocal/prompt diagnosis for the choice of surgery. Genetic/epigenetic (4) factors have been sought by EP/WE (5-7) studies on sporadic cases but the intrinsic variability of different genetic backgrounds (thousands of data/gene variants were detected) made it hard to identify the real causes of PT. At present, a different design based on familial cases (affected/unaffected with the same genetic background) has not been attempted due the rarity of surveys of familial malignant PTs forms (KP and AA). Such an approach could filter and eliminate in a single step all the harmless and confounding variants, finally pinpointing the ultimate genetic factors of this aggressive tumour.

More recently, Dr Guarnieri has been elected as Member of the ECTS (European Calcified Tissues Society) Academy along with other 9 European researchers in the bone field (http://ectsoc.org/ects-academy/ects-academy-members/).

 

References

  • Marx. NEJM 2000; 343: 1863-1865
  • DeLellis. Endocr Pathol 2008; 19: 221-225
  • Koea et al. Surg Oncol 1999; 8: 155-65
  • Starker et al. Genes Chrom Cancer 2011; 9: 735
  • Haven et al. Cancer Res 2004;20: 7405-11
  • Cromer et al. JCEM 2012;9: E1774-81
  • Newey et al. JCEM 2012;10: E1995-2005