title: Subclonality for BRAF Mutation in Papillary Thyroid Carcinoma Is Associated With Earlier Disease Stage.
abstract: The presence of driver mutations only in a subset of tumor cells within a single lesion, defined as subclonality, is being appreciated as a clinically significant factor. BRAF mutation is the most common driver mutation in papillary thyroid carcinoma (PTC). There are conflicting data in the literature regarding the presence of BRAF mutation subclonality in PTC and its clinical significance.
  
  
  
  The purpose of the present study was to use a molecular and morphometric approach to determine BRAF clonality status and its clinical-pathological correlates.
  
  
  
  Fifty-nine cases of PTC were studied. DNA extracted from the tumors underwent deep sequencing to determine the percentage of BRAF mutant allele copies. Additionally, we used computerized morphometry to determine the fraction of tumor cells in each sample. Using both variables, we were able to determine the presence or absence of subclonality for BRAF mutation, which was further correlated with clinical, pathological, and prognostic data.
  
  
  
  BRAF mutation was found in 49 (83%) cases. The average percentage of tumor cells and of BRAF mutant alleles in the samples were 68.1 ± 9.8 and 26 ± 6.7, respectively. Based on the molecular and morphometric analysis, 11 (24%) cases were found to be subclonal for BRAF mutation. Tumors with subclonal BRAF mutations were significantly smaller compared to tumors with clonal mutation (0.82 ± 0.38 cm vs 1.37 ± 0.57 cm, P = .005) and were less likely to have lymph node metastasis (0% vs 32%, P = .03).
  
  
  
  In PTC, subclonality for BRAF mutation is associated with earlier stage. Molecular-morphometric analysis of PTC can provide clonality information with potential clinical significance.
authors.affiliation: B. Rappaport Faculty of Medicine (A.F., L.L., E.P., E.S.), Technion-Israel Institute of Technology, Haifa, Israel; Institute of Pathology (E.Si., T.B. E.Sa., O.B.-I., D.H.), Rambam Health Care Campus, Haifa, Israel; and TICC (O.B.-I., D.H.), Technion Integrative Cancer Center at the Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Alona
authors.initials: A
authors.lastname: Finkel
authors.affiliation: B. Rappaport Faculty of Medicine (A.F., L.L., E.P., E.S.), Technion-Israel Institute of Technology, Haifa, Israel; Institute of Pathology (E.Si., T.B. E.Sa., O.B.-I., D.H.), Rambam Health Care Campus, Haifa, Israel; and TICC (O.B.-I., D.H.), Technion Integrative Cancer Center at the Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Lior
authors.initials: L
authors.lastname: Liba
authors.affiliation: B. Rappaport Faculty of Medicine (A.F., L.L., E.P., E.S.), Technion-Israel Institute of Technology, Haifa, Israel; Institute of Pathology (E.Si., T.B. E.Sa., O.B.-I., D.H.), Rambam Health Care Campus, Haifa, Israel; and TICC (O.B.-I., D.H.), Technion Integrative Cancer Center at the Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Einav
authors.initials: E
authors.lastname: Simon
authors.affiliation: B. Rappaport Faculty of Medicine (A.F., L.L., E.P., E.S.), Technion-Israel Institute of Technology, Haifa, Israel; Institute of Pathology (E.Si., T.B. E.Sa., O.B.-I., D.H.), Rambam Health Care Campus, Haifa, Israel; and TICC (O.B.-I., D.H.), Technion Integrative Cancer Center at the Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Tova
authors.initials: T
authors.lastname: Bick
authors.affiliation: B. Rappaport Faculty of Medicine (A.F., L.L., E.P., E.S.), Technion-Israel Institute of Technology, Haifa, Israel; Institute of Pathology (E.Si., T.B. E.Sa., O.B.-I., D.H.), Rambam Health Care Campus, Haifa, Israel; and TICC (O.B.-I., D.H.), Technion Integrative Cancer Center at the Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Elad
authors.initials: E
authors.lastname: Prinz
authors.affiliation: B. Rappaport Faculty of Medicine (A.F., L.L., E.P., E.S.), Technion-Israel Institute of Technology, Haifa, Israel; Institute of Pathology (E.Si., T.B. E.Sa., O.B.-I., D.H.), Rambam Health Care Campus, Haifa, Israel; and TICC (O.B.-I., D.H.), Technion Integrative Cancer Center at the Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Edmond
authors.initials: E
authors.lastname: Sabo
authors.affiliation: B. Rappaport Faculty of Medicine (A.F., L.L., E.P., E.S.), Technion-Israel Institute of Technology, Haifa, Israel; Institute of Pathology (E.Si., T.B. E.Sa., O.B.-I., D.H.), Rambam Health Care Campus, Haifa, Israel; and TICC (O.B.-I., D.H.), Technion Integrative Cancer Center at the Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Ofer
authors.initials: O
authors.lastname: Ben-Izhak
authors.affiliation: B. Rappaport Faculty of Medicine (A.F., L.L., E.P., E.S.), Technion-Israel Institute of Technology, Haifa, Israel; Institute of Pathology (E.Si., T.B. E.Sa., O.B.-I., D.H.), Rambam Health Care Campus, Haifa, Israel; and TICC (O.B.-I., D.H.), Technion Integrative Cancer Center at the Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Dov
authors.initials: D
authors.lastname: Hershkovitz
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D002291:Carcinoma, Papillary / Q000235:genetics / Q000556:secondary* / Q000601:surgery; D005260:Female; D005500:Follow-Up Studies; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000235:genetics / Q000473:pathology* / Q000601:surgery
chemical_list: D014408:Biomarkers, Tumor; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf