title: RAS/BRAFmutational status in familial non-medullary thyroid carcinomas: A retrospective study.
abstract: There are contrasting views on whether familial non-medullary thyroid carcinomas (FNMTCs) are characterized by aggressive behavior, and limited evidence exists on the prognostic value ofBRAFandRASmutations in these tumors. Thus, in the present study, clinicopathological features were analyzed in 386 non-medullary thyroid carcinomas (NMTCs), subdivided in 82 familial and 304 sporadic cases. Furthermore, theRASandBRAFmutational statuses were investigated in a subgroup of 34 FNMTCs to address their clinical and biological significance. The results demonstrated that, compared with sporadic NMTCs, FNMTCs are characterized by significantly higher rates of multicentricity and bilaterality and are more frequently associated with chronic autoimmune thyroiditis. Notably, a statistically significant difference in the rates of multicentricity was observed by subgrouping familial tumors according to the number of relatives involved; those with ≥3 affected relatives were more likely to be multicentric. Furthermore, the FNMTC cohort exhibited higher rates of tumors >4 cm in size with extrathyroidal or lymph node involvement. However, no significant difference was observed. Similarly, no differences were observed with respect to the age of onset or the patient outcome. The mutational profiling exhibited a rate of 58.8% forBRAFV600E mutations in familial tumors, which is at the upper limit of the mutational frequency observed in historical series of sporadic thyroid cancer. A high rate ofNRASmutations (17.6%) was also observed, mostly in the follicular variant histotype. Notably, compared withBRAF/RAS-wild type FNMTCs, the familial carcinomas bearingBRAForNRASmutations exhibited slightly higher rates of bilaterality and multicentricity, in addition to increased frequency of locally advanced stage or lymph node involvement. The present data support the theory that FNMTCs are characterized by clinicopathological features that resemble a more aggressive phenotype and suggest thatRAS/BRAFmutational analysis deserves to be further evaluated as a tool for the identification of FNMTCs with a potentially unfavorable prognosis.
authors.affiliation: Medical Oncology Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Foggia I-71100, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Landriscina
authors.affiliation: Molecular Biology Laboratory, Riuniti Hospital, Foggia, Foggia I-71100, Italy.
authors.forename: Maria Iole
authors.initials: MI
authors.lastname: Natalicchio
authors.affiliation: Endocrinology Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Foggia I-71100, Italy.
authors.forename: Olga
authors.initials: O
authors.lastname: Lamacchia
authors.affiliation: Endocrinology Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Foggia I-71100, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Conserva
authors.affiliation: Medical Oncology Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Foggia I-71100, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Piscazzi
authors.affiliation: Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari, Bari I-70124, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Ciampolillo
authors.affiliation: Azienda Sanitaria Locale Foggia, Foggia, Foggia I-71100, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Zingrillo
authors.affiliation: Pathology Unit, Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Foggia I-71100, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Pennella
authors.affiliation: Pathology Unit, Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Foggia I-71100, Italy.
authors.forename: Pantaleo
authors.initials: P
authors.lastname: Bufo
authors.affiliation: Pathology Unit, IRCCS, Referral Cancer Center of Basilicata, Rionero in Vulture, Potenza I-85028, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Vita
authors.affiliation: Molecular Biology Laboratory, Riuniti Hospital, Foggia, Foggia I-71100, Italy.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Antonetti
authors.affiliation: Section of Pathology, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Bari I-70124, Italy.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Maiorano
authors.affiliation: Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari, Bari I-70124, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Giorgino
authors.affiliation: Endocrinology Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Foggia I-71100, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Cignarelli
keywords: BRAF; RAS; bilaterality; familial non-medullary thyroid carcinomas; multicentricity; thyroiditis