Copy number alteration and uniparental disomy analysis categorizes Japanese papillary thyroid carcinomas into distinct groups.

Michiko Matsuse,Shigeki Minami,Koh-Ichiro Yoshiura,Shunichi Yamashita,Hisayoshi Kondo,Vladimir Saenko,Keiji Suzuki,Chisa Hayashida,Eijun Nishihara,Kensaku Sasaki,Norisato Mitsutake

doi:10.1371/journal.pone.0036063

Michiko Matsuse, Shigeki Minami + Show 9 more

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https://doi.org/10.1371/journal.pone.0036063

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Journal: PloS one	Publication Date: Apr 30, 2012
Citations: 52	License type: CC BY 4.0

Affiliation: Nagasaki University, Kuma Hospital

Abstract

The aim of the present study was to investigate chromosomal aberrations in sporadic Japanese papillary thyroid carcinomas (PTCs), concomitant with the analysis of oncogene mutational status. Twenty-five PTCs (11 with BRAFV600E, 4 with RET/PTC1, and 10 without mutation in HRAS, KRAS, NRAS, BRAF, RET/PTC1, or RET/PTC3) were analyzed using Genome-Wide Human SNP Array 6.0 which allows us to detect copy number alteration (CNA) and uniparental disomy (UPD), also referred to as copy neutral loss of heterozygosity, in a single experiment. The Japanese PTCs showed relatively stable karyotypes. Seven cases (28%) showed CNA(s), and 6 (24%) showed UPD(s). Interestingly, CNA and UPD were rarely overlapped in the same tumor; the only one advanced case showed both CNA and UPD with a highly complex karyotype. Thirteen (52%) showed neither CNA nor UPD. Regarding CNA, deletions tended to be more frequent than amplifications. The most frequent and recurrent region was the deletion in chromosome 22; however, it was found in only 4 cases (16%). The degree of genomic instability did not depend on the oncogene status. However, in oncogene-positive cases (BRAFV600E and RET/PTC1), tumors with CNA/UPD were less frequent (5/15, 33%), whereas tumors with CNA/UPD were more frequent in oncogene-negative cases (7/10, 70%), suggesting that chromosomal aberrations may play a role in the development of PTC, especially in oncogene-negative tumors. These data suggest that Japanese PTCs may be classified into three distinct groups: CNA+, UPD+, and no chromosomal aberrations. BRAFV600E mutational status did not correlate with any parameters of chromosomal defects.

Highlights

Papillary thyroid carcinoma (PTC) is the most common malignant tumor in endocrine organs, and its incidence has increased over the past decades [1]
mega bases (Mb) and,24.6 Mb were included for reference we cannot exclude the possibility that these uniparental disomy (UPD) are germline
In oncogene-positive cases (BRAFV600E and RET/ PTC1), tumors with copy number alteration (CNA)/UPD were less frequent (5/15, 33%), whereas tumors with CNA/UPD were more frequent in oncogene-negative cases (7/10, 70%)

Summary

Introduction

Papillary thyroid carcinoma (PTC) is the most common malignant tumor in endocrine organs, and its incidence has increased over the past decades [1]. PTCs have characteristic genetic alterations leading to the activation of mitogen-activated protein kinase (MAPK) signaling pathway. Those include RET/ PTC rearrangements and point mutations in BRAF and RAS family genes [2]. They are found in approximately 60–70% of all PTCs and rarely overlap in the same tumor [3,4,5]. The lack of coexistence provides strong genetic evidence for the requirement of constitutively active MAPK signaling for development of PTC. The remaining 30–40% of PTC cases do not have genetic changes in these genes, suggesting that other factors may exist as a trigger to activate the MAPK pathway

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