Most multifocal papillary thyroid carcinomas acquire genetic and morphotype diversity through subclonal evolution following the intra-glandular spread of the initial neoplastic clone

L. Jovanovic, B. Delahunt, B. McIver, N. L. Eberhardt, S. K.G. Grebe

Research output: Contribution to journalArticle

46 Scopus citations

Abstract

Papillary thyroid carcinoma (PTC) is frequently multifocal (mPTC), with synchronous tumour foci often showing varied morphology. The genetic mechanisms underlying the development of multiple and histologically diverse tumour foci remain uncertain. Different tumour foci might develop either through intrathyroidal dissemination of a single malignant clone, with morphotype differentiation occurring as a result of subclonal progression, or they may stem from independent transformational events involving multiple progenitor clones. To determine the clonal derivation of multiple tumour foci and to map their clonal relationships and genetic progression in mPTC, we evaluated genome-wide allelic imbalances (AI) and BRAFV 600E mutation status in 55 synchronous tumour foci from 18 mPTC patients. For apparently monoclonal tumours, we calculated the probabilities of monoclonal derivation and used phylogenetic analysis to model clonal evolution. Genome-wide allelotyping and BRAF mutation analysis showed genetic alterations consistent with monoclonal origin in 83% of cases, mostly with evidence of subclonal evolution. BRAF V 600E mutations were early events during clonal evolution of most, but not all cases. MPTC with morphologically diverse tumour foci also arose through monoclonal derivation in 75% of cases, demonstrating that morphotype-determining genetic changes can be acquired during clonal diversification, subsequent to the spread of the original malignant progenitor clone. In 17% of patients, discordant AI or BRAFV 600E profiles implied that mPTCs can occasionally develop from distinct transformation events. This study suggests that mPTC originates usually from neoplastic transformation and subsequent intrathyroidal spread of a single malignant progenitor clone. Clonal progression and morphotype differentiation occur through progressive acquisition of genetic alterations subsequent to the initial intraglandular spread. In monoclonal BRAFV 600E-positive mPTCs, BRAF V 600E is not always present in all tumour foci, indicating that other tumour-genetic factors in the primary progenitor clone can also trigger PTC neoplastic transformation.

Original languageEnglish (US)
Pages (from-to)145-154
Number of pages10
JournalJournal of Pathology
Volume215
Issue number2
DOIs
StatePublished - Jun 1 2008

Keywords

  • Allelic imbalance
  • BRAF
  • Clonal evolution
  • Clonality
  • Loss of heterozygosity
  • Multifocal
  • Mutation
  • Papillary thyroid carcinoma
  • Phylogenetic analysis

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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