TY - JOUR
T1 - The primary occurrence of BRAFV600E is a rare clonal event in papillary thyroid carcinoma
AU - Guerra, Anna
AU - Sapio, Maria Rosaria
AU - Marotta, Vincenzo
AU - Campanile, Elisabetta
AU - Rossi, Stefania
AU - Forno, Irene
AU - Fugazzola, Laura
AU - Budillon, Alfredo
AU - Moccia, Tania
AU - Fenzi, Gianfranco
AU - Vitale, Mario
PY - 2012/2
Y1 - 2012/2
N2 - Context: BRAFV600E is considered a primary event, a negative prognostic marker, and a site for pharmacological intervention in papillary thyroid carcinoma (PTC). We asked whether BRAFV600Ecan occur as a subclonal event in PTC and whether this and other oncogenes can coexist in the same tumor. Study Design: We determined by pyrosequencing the percentage of mutant BRAF, NRAS, and KRAS alleles in a series of conventional PTC. We also analyzed the BRAF mutation status in PTC cell clones in culture. Results: BRAFV600E alleles were present in 41 of 72 PTC (56.9%) in the range 44.7 to 5.1% of total BRAF alleles. In four PTC samples, mutant BRAF alleles were about 50%, being therefore compatible with a clonal heterozygous mutation. In 27 PTC samples, BRAFV600E alleles were in the range of 25 to 5.1%. This finding was confirmed after exclusion of the presence of a large contamination by lymphoreticular cells and by the analysis of PTC cells selected by laser capture. Analysis of clones derived from a single cell confirmed the presence of two distinct PTC populations with wild-type or mutated BRAF. Simultaneous subclonal BRAF and KRAS mutations were demonstrated in two PTC. Conclusions: These data demonstrate that clonal BRAFV600E is a rare occurrence in PTC, although frequently this cancer consists of a mixture of tumor cells with wild-type and mutant BRAF. These results suggest that BRAF mutation in PTC is a later subclonal event, its intratumoral heterogeneity may hamper the efficacy of targeted pharmacotherapy, and its association with a more aggressive disease should be reevaluated.
AB - Context: BRAFV600E is considered a primary event, a negative prognostic marker, and a site for pharmacological intervention in papillary thyroid carcinoma (PTC). We asked whether BRAFV600Ecan occur as a subclonal event in PTC and whether this and other oncogenes can coexist in the same tumor. Study Design: We determined by pyrosequencing the percentage of mutant BRAF, NRAS, and KRAS alleles in a series of conventional PTC. We also analyzed the BRAF mutation status in PTC cell clones in culture. Results: BRAFV600E alleles were present in 41 of 72 PTC (56.9%) in the range 44.7 to 5.1% of total BRAF alleles. In four PTC samples, mutant BRAF alleles were about 50%, being therefore compatible with a clonal heterozygous mutation. In 27 PTC samples, BRAFV600E alleles were in the range of 25 to 5.1%. This finding was confirmed after exclusion of the presence of a large contamination by lymphoreticular cells and by the analysis of PTC cells selected by laser capture. Analysis of clones derived from a single cell confirmed the presence of two distinct PTC populations with wild-type or mutated BRAF. Simultaneous subclonal BRAF and KRAS mutations were demonstrated in two PTC. Conclusions: These data demonstrate that clonal BRAFV600E is a rare occurrence in PTC, although frequently this cancer consists of a mixture of tumor cells with wild-type and mutant BRAF. These results suggest that BRAF mutation in PTC is a later subclonal event, its intratumoral heterogeneity may hamper the efficacy of targeted pharmacotherapy, and its association with a more aggressive disease should be reevaluated.
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U2 - 10.1210/jc.2011-0618
DO - 10.1210/jc.2011-0618
M3 - Article
C2 - 22170714
AN - SCOPUS:84856798619
VL - 97
SP - 517
EP - 524
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
SN - 0021-972X
IS - 2
ER -