title: Quantification of BRAF V600E alleles predicts papillary thyroid cancer progression.
abstract: The BRAF V600E mutation is the most common genetic alteration in thyroid cancer. However, its clinicopathological significance and clonal mutation frequency remain unclear. To clarify the inconsistent results, we investigated the association between the allelic frequency of BRAF V600E and the clinicopathological features of classic papillary thyroid carcinoma (PTC). Tumour tissues from two independent sets of patients with classic PTC were manually microdissected and analysed for the presence or absence of the BRAF mutation and the mutant allelic frequency using quantitative pyrosequencing. For external validation, the Cancer Genome Atlas (TCGA) data were analysed. The BRAF V600E mutation was found in 264 (82.2%) out of 321 classic PTCs in the training set. The presence of BRAF V600E was only associated with extrathyroidal extension and the absence of thyroiditis. In BRAF V600E-positive tumours, the mutant allelic frequency varied from 8 to 41% of the total BRAF alleles (median, 20%) and directly correlated with tumour size and the number of metastatic lymph nodes. Lymph node metastases were more frequent in PTCs with a high (≥20%) abundance of mutant alleles than in those with a low abundance of mutant alleles (P=0.010). These results were reinforced by validation dataset (n=348) analysis but were not reproduced in the TCGA dataset. In a population with prevalent BRAF mutations, quantitative analysis of the BRAF mutation could provide additional information regarding tumour behaviour, which is not reflected by qualitative analysis. Nonetheless, prospective studies are needed before the mutated allele percentage can be considered as a prognostic factor.
authors.affiliation: Division of Endocrinology and MetabolismDepartment of Internal MedicineDepartment of SurgeryDepartment of Hospital PathologyMedical Life SciencesCollege of Medicine, The Catholic University of Korea, 222 Banpodaero, Seocho-gu, Seoul 137-701, Republic of Korea.
authors.forename: Min-Hee
authors.initials: MH
authors.lastname: Kim
authors.affiliation: Division of Endocrinology and MetabolismDepartment of Internal MedicineDepartment of SurgeryDepartment of Hospital PathologyMedical Life SciencesCollege of Medicine, The Catholic University of Korea, 222 Banpodaero, Seocho-gu, Seoul 137-701, Republic of Korea.
authors.forename: Ja Seong
authors.initials: JS
authors.lastname: Bae
authors.affiliation: Division of Endocrinology and MetabolismDepartment of Internal MedicineDepartment of SurgeryDepartment of Hospital PathologyMedical Life SciencesCollege of Medicine, The Catholic University of Korea, 222 Banpodaero, Seocho-gu, Seoul 137-701, Republic of Korea.
authors.forename: Dong-Jun
authors.initials: DJ
authors.lastname: Lim
authors.affiliation: Division of Endocrinology and MetabolismDepartment of Internal MedicineDepartment of SurgeryDepartment of Hospital PathologyMedical Life SciencesCollege of Medicine, The Catholic University of Korea, 222 Banpodaero, Seocho-gu, Seoul 137-701, Republic of Korea.
authors.forename: Hyoungnam
authors.initials: H
authors.lastname: Lee
authors.affiliation: Division of Endocrinology and MetabolismDepartment of Internal MedicineDepartment of SurgeryDepartment of Hospital PathologyMedical Life SciencesCollege of Medicine, The Catholic University of Korea, 222 Banpodaero, Seocho-gu, Seoul 137-701, Republic of Korea Division of Endocrinology and MetabolismDepartment of Internal MedicineDepartment of SurgeryDepartment of Hospital PathologyMedical Life SciencesCollege of Medicine, The Catholic University of Korea, 222 Banpodaero, Seocho-gu, Seoul 137-701, Republic of Korea.
authors.forename: So Ra
authors.initials: SR
authors.lastname: Jeon
authors.affiliation: Division of Endocrinology and MetabolismDepartment of Internal MedicineDepartment of SurgeryDepartment of Hospital PathologyMedical Life SciencesCollege of Medicine, The Catholic University of Korea, 222 Banpodaero, Seocho-gu, Seoul 137-701, Republic of Korea.
authors.forename: Gyeong Sin
authors.initials: GS
authors.lastname: Park
authors.affiliation: Division of Endocrinology and MetabolismDepartment of Internal MedicineDepartment of SurgeryDepartment of Hospital PathologyMedical Life SciencesCollege of Medicine, The Catholic University of Korea, 222 Banpodaero, Seocho-gu, Seoul 137-701, Republic of Korea ckjung@catholic.ac.kr.
authors.forename: Chan Kwon
authors.initials: CK
authors.lastname: Jung
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D019943:Amino Acid Substitution; D002291:Carcinoma, Papillary / Q000235:genetics / Q000556:secondary*; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D011379:Prognosis; D000090063:Proto-Oncogene Mas; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D012189:Retrospective Studies; D013964:Thyroid Neoplasms / Q000235:genetics / Q000473:pathology*; D055815:Young Adult
chemical_list: C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: mutation; papillary thyroid carcinoma; proteins BRAF; proto-oncogene