Mapping and characterization of the amplicon near APOA2 in 1q23 in human sarcomas by FISH and array CGH.

Stine H Kresse,Simon G Gregory,Jeanne-Marie Berner,Joe W Gray,Wen-Lin Kuo,Ola Myklebost,Anne Forus,Leonardo A Meza-Zepeda

doi:10.1186/1476-4598-4-39

Abstract

BackgroundAmplification of the q21-q23 region on chromosome 1 is frequently found in sarcomas and a variety of other solid tumours. Previous analyses of sarcomas have indicated the presence of at least two separate amplicons within this region, one located in 1q21 and one located near the apolipoprotein A-II (APOA2) gene in 1q23. In this study we have mapped and characterized the amplicon in 1q23 in more detail.ResultsWe have used fluorescence in situ hybridisation (FISH) and microarray-based comparative genomic hybridisation (array CGH) to map and define the borders of the amplicon in 10 sarcomas. A subregion of approximately 800 kb was identified as the core of the amplicon. The amplification patterns of nine possible candidate target genes located to this subregion were determined by Southern blot analysis. The genes activating transcription factor 6 (ATF6) and dual specificity phosphatase 12 (DUSP12) showed the highest level of amplification, and they were also shown to be over-expressed by quantitative real-time reverse transcription PCR (RT-PCR). In general, the level of expression reflected the level of amplification in the different tumours. DUSP12 was expressed significantly higher than ATF6 in a subset of the tumours. In addition, two genes known to be transcriptionally activated by ATF6, glucose-regulated protein 78 kDa and -94 kDa (GRP78 and GRP94), were shown to be over-expressed in the tumours that showed over-expression of ATF6.ConclusionATF6 and DUSP12 seem to be the most likely candidate target genes for the 1q23 amplification in sarcomas. Both genes have possible roles in promoting cell growth, which makes them interesting candidate targets.

Highlights

Amplification of the q21-q23 region on chromosome 1 is frequently found in sarcomas and a variety of other solid tumours
Sarcomas are a heterogeneous group of malignant tumours of various supporting- and connective tissues, ranging from the almost benign well-differentiated liposarcomas (WDLS) to aggressive tumour forms, such as fibrosarcomas, osteosarcomas and malignant fibrous histiocytomas (MFH) [5]
Studies of renal clear cell, hepatocellular and colorectal carcinomas revealed a higher frequency of 1q21-q23 gains in metastatic tumours [10,11], and gains of 1q21-q25 showed a trend toward short overall survival in high-grade osteosarcomas and neuroblastomas [12,13]

Summary

Introduction

Amplification of the q21-q23 region on chromosome 1 is frequently found in sarcomas and a variety of other solid tumours. Sarcomas are a heterogeneous group of malignant tumours of various supporting- and connective tissues, ranging from the almost benign well-differentiated liposarcomas (WDLS) to aggressive tumour forms, such as fibrosarcomas, osteosarcomas and malignant fibrous histiocytomas (MFH) [5]. Infrequent, these tumours have been widely studied at the molecular level, and this has provided insight into mechanisms of importance for tumour development in general. Sarcomas of borderline malignancy, such as WDLS, show frequent amplification of 1q21-q23 [2,3,14], and 1q21 is recurrently gained in desmoid tumours [15]

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