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Copy number aberrations of genes regulating normal thymus development in thymic epithelial tumors.

ABSTRACT: PURPOSES:To determine whether the deregulation of genes relevant for normal thymus development can contribute to the biology of thymic epithelial tumors (TET). EXPERIMENTAL DESIGN:Using array comparative genomic hybridization, we evaluated the copy number aberrations of genes regulating thymus development. The expression of genes most commonly involved in copy number aberrations was evaluated by immunohistochemistry and correlated with patients' outcome. Correlation between FOXC1 copy number loss and gene expression was determined in a confirmation cohort. Cell lines were used to test the role of FOXC1 in tumors. RESULTS:Among 31 thymus development-related genes, PBX1 copy number gain and FOXC1 copy number loss were presented in 43.0% and 39.5% of the tumors, respectively. Immunohistochemistry on a series of 132 TETs, including those evaluated by comparative genomic hybridization, revealed a correlation between protein expression and copy number status only for FOXC1 but not for PBX1. Patients with FOXC1-negative tumors had a shorter time to progression and a trend for a shorter disease-related survival. The correlation between FOXC1 copy number loss and mRNA expression was confirmed in a separate cohort of 27 TETs. Ectopic FOXC1 expression attenuated anchorage-independent cell growth and cell migration in vitro. CONCLUSION:Our data support a tumor suppressor role of FOXC1 in TETs.

SUBMITTER: Petrini I

PROVIDER: S-EPMC3630263 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Copy number aberrations of genes regulating normal thymus development in thymic epithelial tumors.

Petrini Iacopo I Wang Yisong Y Zucali Paolo A PA Lee Hye Seung HS Pham Trung T Voeller Donna D Meltzer Paul S PS Giaccone Giuseppe G

Clinical cancer research : an official journal of the American Association for Cancer Research 20130226 8

<h4>Purposes</h4>To determine whether the deregulation of genes relevant for normal thymus development can contribute to the biology of thymic epithelial tumors (TET).<h4>Experimental design</h4>Using array comparative genomic hybridization, we evaluated the copy number aberrations of genes regulating thymus development. The expression of genes most commonly involved in copy number aberrations was evaluated by immunohistochemistry and correlated with patients' outcome. Correlation between FOXC1 ...[more]

PMID: 23444221

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Project description:Multistage tumorigenesis is a dynamic process characterized by the accumulation of mutations. Thus, a tumor mass is composed of genetically divergent cell subclones. With the advancement of next-generation sequencing (NGS), mathematical models have been recently developed to decompose tumor subclonal architecture from a collective genome sequencing data. Most of the methods focused on single-nucleotide variants (SNVs). However, somatic copy number aberrations (CNAs) also play critical roles in carcinogenesis. Therefore, further modeling subclonal CNAs composition would hold the promise to improve the analysis of tumor heterogeneity and cancer evolution. To address this issue, we developed a two-way mixture Poisson model, named CloneDeMix for the deconvolution of read-depth information. It can infer the subclonal copy number, mutational cellular prevalence (MCP), subclone composition, and the order in which mutations occurred in the evolutionary hierarchy. The performance of CloneDeMix was systematically assessed in simulations. As a result, the accuracy of CNA inference was nearly 93% and the MCP was also accurately restored. Furthermore, we also demonstrated its applicability using head and neck cancer samples from TCGA. Our results inform about the extent of subclonal CNA diversity, and a group of candidate genes that probably initiate lymph node metastasis during tumor evolution was also discovered. Most importantly, these driver genes are located at 11q13.3 which is highly susceptible to copy number change in head and neck cancer genomes. This study successfully estimates subclonal CNAs and exhibit the evolutionary relationships of mutation events. By doing so, we can track tumor heterogeneity and identify crucial mutations during evolution process. Hence, it facilitates not only understanding the cancer development but finding potential therapeutic targets. Briefly, this framework has implications for improved modeling of tumor evolution and the importance of inclusion of subclonal CNAs.

Dataset Information

Copy number aberrations of genes regulating normal thymus development in thymic epithelial tumors.

Publications

Copy number aberrations of genes regulating normal thymus development in thymic epithelial tumors.

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