Loss, mutation and deregulation of L3MBTL4 in breast cancers

Molecular Cancer

Research

Soraya Moulessehoul¹  Patrice Viens²  Christos Sotiriou³  José Adélaïde⁴  Anthony Ferrari⁴  Fabrice Sircoulomb⁴  Daniel Birnbaum⁴  Max Chaffanet⁴  Ismahane Bekhouche⁴  Pascal Finetti⁴  Nathalie Cervera⁴  Lynda Addou-Klouche⁴  François Bertucci⁵ 

[1] Biotoxicology laboratory, Djillali Liabes University, Sidi-Bel-Abbès, Algeria;Department of Medical Oncology, Institut Paoli-Calmettes, Marseille, France;Université de la Méditerranée, Marseille, France;Functional genomics and translational research unit, Institut Jules Bordet, Brussels, Belgium;Marseille Cancer Research Center; Department of Molecular Oncology, UMR891 Inserm; Institut Paoli-Calmettes;, Marseille, France;Marseille Cancer Research Center; Department of Molecular Oncology, UMR891 Inserm; Institut Paoli-Calmettes;, Marseille, France;Department of Medical Oncology, Institut Paoli-Calmettes, Marseille, France;Université de la Méditerranée, Marseille, France;

关键词: Tumor Suppressor Gene;    Molecular Subtype;    Malignant Brain Tumor;    Copy Number Aberration;    Copy Number Loss;   

DOI  :  10.1186/1476-4598-9-213

 received in 2010-03-18, accepted in 2010-08-10,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundMany alterations are involved in mammary oncogenesis, including amplifications of oncogenes and losses of tumor suppressor genes (TSG). Losses may affect almost all chromosome arms and many TSGs remain to be identified.ResultsWe studied 307 primary breast tumors and 47 breast cancer cell lines by high resolution array comparative genomic hybridization (aCGH). We identified a region on 18p11.31 lost in about 20% of the tumors and 40% of the cell lines. The minimal common region of loss (Chr18:6,366,938-6,375,929 bp) targeted the L3MBTL4 gene. This gene was also targeted by breakage in one tumor and in two cell lines. We studied the exon sequence of L3MBTL4 in 180 primary tumor samples and 47 cell lines and found six missense and one nonsense heterozygous mutations. Compared with normal breast tissue, L3MBTL4 mRNA expression was downregulated in 73% of the tumors notably in luminal, ERBB2 and normal-like subtypes. Losses of the 18p11 region were associated with low L3MBTL4 expression level. Integrated analysis combining genome and gene expression profiles of the same tumors pointed to 14 other potential 18p TSG candidates. Downregulated expression of ZFP161, PPP4R1 and YES1 was correlated with luminal B molecular subtype. Low ZFP161 gene expression was associated with adverse clinical outcome.ConclusionWe have identified L3MBTL4 as a potential TSG of chromosome arm 18p. The gene is targeted by deletion, breakage and mutations and its mRNA is downregulated in breast tumors. Additional 18p TSG candidates might explain the aggressive phenotype associated with the loss of 18p in breast tumors.

【 授权许可】

Unknown   
© Addou-Klouche et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.