BRAF(V600E) mutation and the biology of papillary thyroid cancer.
BRAF((V600E)) mutation is the most frequent genetic alteration in papillary thyroid carcinomas (PTCs) that are 80-90% of all thyroid cancers. We evaluated the relationship between BRAF((V600E)) and tumor, host, and environmental factors in PTCs from all geographical areas of Sicily. By PCR, BRAF((V600E)) was investigated in a series of 323 PTCs diagnosed in 2002-2005. The correlation between clinicopathological tumor, host, and environmental characteristics and the presence of BRAF((V600E)) were evaluated by both univariate and multivariate analyses. BRAF((V600E)) was found in 38.6% PTCs, with a 52% frequency in the classical PTCs and 26.4% in the tall cell variant. Univariate analysis indicated that BRAF((V600E)) was associated with greater tumor size (P=0.0048), extra-thyroid invasion (P<0.0001), and cervical lymph nodal metastases (P=0.0001). Multivariate logistic regression analysis confirmed that BRAF((V600E)) was an independent predictor of extra-thyroid invasion (P=0.0001) and cervical lymph nodal metastasis (P=0.0005). The association between BRAF((V600E)) and extra-thyroid invasion was also found in micro-PTCs (P=0.006). In 60 classical PTCs, BRAF((V600E)) was positively correlated with matrix metalloproteinase-9 expression (P=0.0047), suggesting a possible mechanism for BRAF((V600E)) effect on PTC invasiveness. No association was found between BRAF((V600E)) and patient age, gender, or iodine intake. In contrast, a strong association was found with residency in Eastern Sicily (P<0.0001 compared with Western Sicily). These results indicate that BRAF((V600E)) mutation is a marker of aggressive disease in both micro- and macro-PTCs. Moreover, for the first time, a possible link between BRAF((V600E)) mutation and environmental carcinogens is suggested.
Frasca
F
F
Endocrinologia, Dipartimento di Medicina Interna e Medicina Specialistica, University of Catania, PO Garibaldi Nesima, Via Palermo 636, Catania, Italy.
Nucera
C
C
Pellegriti
G
G
Gangemi
P
P
Attard
M
M
Stella
M
M
Loda
M
M
Vella
V
V
Giordano
C
C
Trimarchi
F
F
Mazzon
E
E
Belfiore
A
A
Vigneri
R
R
D002291:Carcinoma, Papillary / Q000235:genetics*; D017931:DNA Primers; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D005843:Geography; D006801:Humans; D007124:Immunoenzyme Techniques; D007834:Lasers; D008207:Lymphatic Metastasis; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D042282:Microdissection; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009361:Neoplasm Invasiveness; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012802:Sicily / Q000453:epidemiology; D013964:Thyroid Neoplasms / Q000235:genetics*
D017931:DNA Primers; D012333:RNA, Messenger; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020780:Matrix Metalloproteinase 9