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High-sensitivity BRAF mutation analysis: BRAF V600E is acquired early during tumor development but is heterogeneously distributed in a subset of papillary thyroid carcinomas.
J Clin Endocrinol Metab. 2014 Aug; 99(8):E1530-8.JC

Abstract

CONTEXT

The homogeneous distribution of BRAF V600E in papillary thyroid carcinoma (PTC) has been called into question by recent reports. These studies claim that BRAF V600E is heterogeneous and is limited to tumor cell subsets in the majority of PTCs.

OBJECTIVE

The objective of the study was to understand the allele distribution of BRAF V600E by evaluating the percentage of mutated neoplastic cells in a group of PTCs using two different highly sensitive analytical approaches: allele-specific locked nucleic acid PCR and 454 next-generation sequencing targeted to BRAF exon 15.

STUDY DESIGN

BRAF V600E was investigated using allele-specific locked nucleic acid PCR on 155 consecutive samples of PTC. Mutated cases were reanalyzed by 454 next-generation sequencing and immunohistochemistry. Because the evaluation of genetic heterogeneity in tumor samples can be profoundly biased by contamination with normal cells, all mutation frequency data were normalized to the real amount of neoplastic cells within each tumor.

RESULTS

Eighty-five of 155 PTCs (54.8%) were BRAF V600E mutated. The distribution of mutated neoplastic cells within the tumor was as follows: greater than 80% in 37 of 85 (43.5%), 30-80% in 39 of 85 (45.9%), and less than 30% in 9 of 85 (10.6%). In most of the PTCs with less than 80% BRAF V600E-positive neoplastic cells, the mutation was present in large neoplastic cell subpopulations. Tumors with less than 30% mutated neoplastic cells were smaller than tumors with a percentage of mutated cells greater than 80% or between 30% and 80% (P < .05).

CONCLUSIONS

BRAF V600E is heterogeneously distributed in some PTCs. The large BRAF V600E neoplastic cell subpopulations found in mutated cases is consistent with the view that the BRAF V600E is acquired early during PTC development.

Authors+Show Affiliations

Department of Medicine (D.d.B., V.C., G.T.), Anatomic Pathology Unit, Ospedale Bellaria, University of Bologna, 40139 Bologna, Italy; Department of Pharmacology and Biotechnology (V.C., M.V., A.P.), University of Bologna, 40100 Bologna, Italy; Anatomic Pathology Unit (G.P.C.) and Endocrinology Unit (N.C.), Ospedale Maggiore, 40133 Bologna, Italy; and Molecular Biology Laboratory (G.G., V.S., A.C.) and Anatomic Pathology Unit (M.R.), Istituto di Ricovero e Cura a Carattere Scientifico-Arcispedale Santa Maria Nuova, 42123 Reggio Emilia, Italy.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24780046

Citation

de Biase, Dario, et al. "High-sensitivity BRAF Mutation Analysis: BRAF V600E Is Acquired Early During Tumor Development but Is Heterogeneously Distributed in a Subset of Papillary Thyroid Carcinomas." The Journal of Clinical Endocrinology and Metabolism, vol. 99, no. 8, 2014, pp. E1530-8.
de Biase D, Cesari V, Visani M, et al. High-sensitivity BRAF mutation analysis: BRAF V600E is acquired early during tumor development but is heterogeneously distributed in a subset of papillary thyroid carcinomas. J Clin Endocrinol Metab. 2014;99(8):E1530-8.
de Biase, D., Cesari, V., Visani, M., Casadei, G. P., Cremonini, N., Gandolfi, G., Sancisi, V., Ragazzi, M., Pession, A., Ciarrocchi, A., & Tallini, G. (2014). High-sensitivity BRAF mutation analysis: BRAF V600E is acquired early during tumor development but is heterogeneously distributed in a subset of papillary thyroid carcinomas. The Journal of Clinical Endocrinology and Metabolism, 99(8), E1530-8. https://doi.org/10.1210/jc.2013-4389
de Biase D, et al. High-sensitivity BRAF Mutation Analysis: BRAF V600E Is Acquired Early During Tumor Development but Is Heterogeneously Distributed in a Subset of Papillary Thyroid Carcinomas. J Clin Endocrinol Metab. 2014;99(8):E1530-8. PubMed PMID: 24780046.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - High-sensitivity BRAF mutation analysis: BRAF V600E is acquired early during tumor development but is heterogeneously distributed in a subset of papillary thyroid carcinomas. AU - de Biase,Dario, AU - Cesari,Valentina, AU - Visani,Michela, AU - Casadei,Gian Piero, AU - Cremonini,Nadia, AU - Gandolfi,Greta, AU - Sancisi,Valentina, AU - Ragazzi,Moira, AU - Pession,Annalisa, AU - Ciarrocchi,Alessia, AU - Tallini,Giovanni, Y1 - 2014/04/29/ PY - 2014/5/1/entrez PY - 2014/5/2/pubmed PY - 2014/10/28/medline SP - E1530 EP - 8 JF - The Journal of clinical endocrinology and metabolism JO - J. Clin. Endocrinol. Metab. VL - 99 IS - 8 N2 - CONTEXT: The homogeneous distribution of BRAF V600E in papillary thyroid carcinoma (PTC) has been called into question by recent reports. These studies claim that BRAF V600E is heterogeneous and is limited to tumor cell subsets in the majority of PTCs. OBJECTIVE: The objective of the study was to understand the allele distribution of BRAF V600E by evaluating the percentage of mutated neoplastic cells in a group of PTCs using two different highly sensitive analytical approaches: allele-specific locked nucleic acid PCR and 454 next-generation sequencing targeted to BRAF exon 15. STUDY DESIGN: BRAF V600E was investigated using allele-specific locked nucleic acid PCR on 155 consecutive samples of PTC. Mutated cases were reanalyzed by 454 next-generation sequencing and immunohistochemistry. Because the evaluation of genetic heterogeneity in tumor samples can be profoundly biased by contamination with normal cells, all mutation frequency data were normalized to the real amount of neoplastic cells within each tumor. RESULTS: Eighty-five of 155 PTCs (54.8%) were BRAF V600E mutated. The distribution of mutated neoplastic cells within the tumor was as follows: greater than 80% in 37 of 85 (43.5%), 30-80% in 39 of 85 (45.9%), and less than 30% in 9 of 85 (10.6%). In most of the PTCs with less than 80% BRAF V600E-positive neoplastic cells, the mutation was present in large neoplastic cell subpopulations. Tumors with less than 30% mutated neoplastic cells were smaller than tumors with a percentage of mutated cells greater than 80% or between 30% and 80% (P < .05). CONCLUSIONS: BRAF V600E is heterogeneously distributed in some PTCs. The large BRAF V600E neoplastic cell subpopulations found in mutated cases is consistent with the view that the BRAF V600E is acquired early during PTC development. SN - 1945-7197 UR - https://www.unboundmedicine.com/medline/citation/24780046/High_sensitivity_BRAF_mutation_analysis:_BRAF_V600E_is_acquired_early_during_tumor_development_but_is_heterogeneously_distributed_in_a_subset_of_papillary_thyroid_carcinomas_ L2 - https://academic.oup.com/jcem/article-lookup/doi/10.1210/jc.2013-4389 DB - PRIME DP - Unbound Medicine ER -