title: Correlation between B-RAFV600E mutation and clinico-pathologic parameters in papillary thyroid carcinoma: data from a multicentric Italian study and review of the literature.
abstract: Recently, a somatic point mutation of the B-RAF gene (V600E) has been identified as the most common genetic event in papillary thyroid carcinoma (PTC), with a prevalence variable among different series. Since discordant data on the clinico-pathologic features of B-RAF mutated PTC are present in the literature, the aim of the present co-operative study was to establish the prevalence of this genetic alteration and to perform a genotype-phenotype correlation in a large cohort of patients with PTC. To this purpose, a series of 260 sporadic PTCs with different histological variants were included in the study. The mutational analysis of the B-RAF gene was performed either by RT-PCR followed by single-stranded conformational polymorphism or by PCR and direct sequencing. Statistical analyses were obtained by means of chi2/Fisher's exact test and t-test. Overall, a heterozygous T > A transversion at nucleotide 1799 (V600E) was found in 99 out of 260 PTCs (38%). According to the histological type of the tumor, the B-RAF (V600E) mutation was present in 48.3% of cases of classic PTCs (85 out of 176), in 17.6% (nine out of 51) of follicular variants of PTCs, in 21.7% (five out of 23) in other PTC variants and in none of the ten poorly differentiated tumors. B-RAF (V600E) was significantly associated with the classic variant of PTC (P = 0.0001) and with an older age at diagnosis (P = 0.01). No statistically significant correlation was found among the presence of B-RAF (V600E) and gender, tumor node metastasis (TNM), multicentricity of the tumor, stage at diagnosis and outcome. In conclusion, the present study reports the prevalence of B-RAF (V600E) (38%) in the largest series of sporadic PTCs, including 260 cases from three different Italian referring centers. This prevalence is similar to that calculated by pooling together all data previously reported, 39.6% (759 out of 1914 cases), thus indicating that the prevalence of this genetic event lies around 38-40%. Furthermore, B-RAF (V600E) was confirmed to be associated with the papillary growth pattern, but not with poorer differentiated PTC variants. A significant association of B-RAF mutation was also found with an older age at diagnosis, the mutation being very rare in childhood and adolescent PTCs. Finally, no correlation was found with a poorer prognosis and a worse outcome after a median follow-up of 72 months.
authors.affiliation: Institute of Endocrine Sciences, University of Milan and Fondazione Policlinico IRCCS, Milan, Italy. l.fugazzola@policlinico.mi.it
authors.forename: L
authors.initials: L
authors.lastname: Fugazzola
authors.forename: E
authors.initials: E
authors.lastname: Puxeddu
authors.forename: N
authors.initials: N
authors.lastname: Avenia
authors.forename: C
authors.initials: C
authors.lastname: Romei
authors.forename: V
authors.initials: V
authors.lastname: Cirello
authors.forename: A
authors.initials: A
authors.lastname: Cavaliere
authors.forename: P
authors.initials: P
authors.lastname: Faviana
authors.forename: D
authors.initials: D
authors.lastname: Mannavola
authors.forename: S
authors.initials: S
authors.lastname: Moretti
authors.forename: S
authors.initials: S
authors.lastname: Rossi
authors.forename: M
authors.initials: M
authors.lastname: Sculli
authors.forename: V
authors.initials: V
authors.lastname: Bottici
authors.forename: P
authors.initials: P
authors.lastname: Beck-Peccoz
authors.forename: F
authors.initials: F
authors.lastname: Pacini
authors.forename: A
authors.initials: A
authors.lastname: Pinchera
authors.forename: F
authors.initials: F
authors.lastname: Santeusanio
authors.forename: R
authors.initials: R
authors.lastname: Elisei
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002291:Carcinoma, Papillary / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology*; D004252:DNA Mutational Analysis; D005260:Female; D018698:Glutamic Acid / Q000737:chemistry / Q000235:genetics; D006801:Humans; D007558:Italy / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D017720:Molecular Epidemiology; D017354:Point Mutation; D015995:Prevalence; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology*; D014633:Valine / Q000737:chemistry / Q000235:genetics
chemical_list: D018698:Glutamic Acid; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D014633:Valine