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

Journal of Pathology - Tập 215 Số 2 - Trang 145-154 - 2008
Ivan Jovanović1, Brett Delahunt1, Bryan McIver2, Norman L. Eberhardt3,2, Stefan K. Grebe4,2
1Department of Pathology and Molecular Medicine, University of Otago, School of Medicine and Health Sciences, Wellington, New Zealand
2Department of Medicine, Mayo Clinic, Rochester, MN, USA,
3Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA;
4Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA

Tóm tắt

AbstractPapillary 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 BRAFV600E 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. BRAFV600E 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 BRAFV600E 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 intra‐glandular spread. In monoclonal BRAFV600E‐positive mPTCs, BRAFV600E 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. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Từ khóa


Tài liệu tham khảo

10.1002/1097-0142(19920915)70:6<1585::AID-CNCR2820700623>3.0.CO;2-Z

10.1056/NEJM199801293380506

10.1210/jc.2003-031982

10.1002/ijc.22290

Thomas GA, 1989, The clonal origin of thyroid nodules and adenomas, Am J Pathol, 134, 141

Hicks DG, 1990, Clonal analysis of solitary follicular nodules in the thyroid, Am J Pathol, 137, 553

10.1172/JCI114673

10.1046/j.1365-2168.1998.00783.x

Chung DH, 1999, Clonal analysis of a solitary follicular nodule of the thyroid with the polymerase chain reaction method, Mod Pathol, 12, 265

10.1530/eje.0.1460027

10.1210/jc.83.11.4116

10.1056/NEJMoa044190

10.1002/cncr.22218

10.1158/1078-0432.CCR-05-2818

10.1210/jc.2007-0594

10.1016/S0002-9440(10)65254-6

10.1016/S1525-1578(10)60696-4

FelsensteinJ. PHYLIP (Phylogeny Interference Package) Version 3.5c:http://evolution.genetics.washington.edu/phylip/software.pars.html#PHYLIP[accessed 15 January 2008].

10.1210/jc.83.2.525

10.1080/0031302021000062370

10.1210/jc.2002-021552

Jang SJ, 2000, Methylation patterns in human androgen receptor gene and clonality analysis, Cancer Res, 60, 864

Sakurazawa N, 2000, Instability of X chromosome methylation in aberrant crypt foci of the human colon, Cancer Res, 60, 3165

10.1210/jc.2004-2353

10.1089/105072501316973118

10.1016/S0002-9440(10)61164-9

10.1210/jc.2003-031870

10.1038/sj.bjc.6603109

Thông tin
Thông tin xuất bản

Journal of Pathology

Tập 215 Số 2

145-154

Thông tin tác giả