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Multicenter Study
. 2011 Sep;9(9):e1001156.
doi: 10.1371/journal.pbio.1001156. Epub 2011 Sep 20.

ESRRA-C11orf20 is a recurrent gene fusion in serous ovarian carcinoma (V体育官网入口)

Julia Salzman  1 , Robert J Marinelli, Peter L Wang, Ann E Green, Julie S Nielsen, Brad H Nelson, Charles W Drescher, Patrick O Brown
Affiliations
Multicenter Study

ESRRA-C11orf20 is a recurrent gene fusion in serous ovarian carcinoma

V体育ios版 - Julia Salzman et al. PLoS Biol. 2011 Sep.

Abstract

Every year, ovarian cancer kills approximately 14,000 women in the United States and more than 140,000 women worldwide VSports手机版. Most of these deaths are caused by tumors of the serous histological type, which is rarely diagnosed before it has disseminated. By deep paired-end sequencing of mRNA from serous ovarian cancers, followed by deep sequencing of the corresponding genomic region, we identified a recurrent fusion transcript. The fusion transcript joins the 5' exons of ESRRA, encoding a ligand-independent member of the nuclear-hormone receptor superfamily, to the 3' exons of C11orf20, a conserved but uncharacterized gene located immediately upstream of ESRRA in the reference genome. To estimate the prevalence of the fusion, we tested 67 cases of serous ovarian cancer by RT-PCR and sequencing and confirmed its presence in 10 of these. Targeted resequencing of the corresponding genomic region from two fusion-positive tumor samples identified a nearly clonal chromosomal rearrangement positioning ESRRA upstream of C11orf20 in one tumor, and evidence of local copy number variation in the ESRRA locus in the second tumor. We hypothesize that the recurrent novel fusion transcript may play a role in pathogenesis of a substantial fraction of serous ovarian cancers and could provide a molecular marker for detection of the cancer. Gene fusions involving adjacent or nearby genes can readily escape detection but may play important roles in the development and progression of cancer. .

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Conflict of interest statement (VSports注册入口)

The authors have declared that no competing interests exist.

V体育平台登录 - Figures

Figure 1
Figure 1. Fusion transcripts identified in serous ovarian cancers.
(A) C11orf20 is an ORF transcribed from a region whose 5′ end is less than 1 kb upstream of ESRRA's transcriptional start in the wild-type genomic organization of 11q13.1. (B) Three isoforms of a fusion transcript, ESRRA-C11orf20, inconsistent with a wild-type genomic organization and canonical transcription have been detected by our sequence analysis of RNA from serous ovarian cancer cases. Each fusion isoform joins ESRRA exon 2 to a distinct exon of C11orf20. E2-C3 and E2-C5 are in frame events; E2-C4 is out of frame and has been detected in combination with E2-C3. (C) Representative RT-PCR reactions demonstrating the presence of the fusion in 5 individual cases. Patient 1–4 were from FHCRC and Patient 5 was from BCCA. Fusions were confirmed by Sanger sequencing; the specific fusion variants seen are detailed in Table S1. (D) All fusions are predicted to contain the N-terminal 108 amino acids of ESRRA, including the DNA-binding zinc finger and P-Box, and conserved phosphorylation and sumoylation sites (Ser 19, Lys 14, respectively); in-frame fusions all contain the C-terminal portion of C11orf20 with a basic putative nuclear-localization signal.
Figure 2
Figure 2. Genomic rearrangements in patient samples.
Data for genomic structures of tumors analyzed with respect to the reference human genome, build hg19. C11orf20 and ESRRA regions are color-coded and exons numbered. KCNK4 is the gene immediately upstream of C11orf20 and PRDX5 is the gene immediately downstream of ESRRA. (A) Model for Tumor 1 DNA rearrangement. Brackets indicate a genomic interval (coordinates ch11∶64,070,517-64,079,032) from upstream of C11orf20 exon 3 to downstream of ESRRA exon 2, tandemly duplicated in the tumor (model shown above the reference). The transcripts (E2-C3 and E2-C4) expressed by the tumor are pictured above the rearrangement model, as are the extents of three PCR products spanning the breakpoint (PCR1, PCR2, PCR3). (B) Copy number plots for two tumors. The point estimate for copy number (as a dot) and 95% confidence interval (as error bars) are shown for each sequence interval (bin) with reliable counts. These were computed by grouping single aligned reads into 100 bp bins after removing potential PCR duplicates and comparing to the corresponding bin from the normal PBMC sample. For Tumor 1, copy number estimate interior to breakpoints is approximately 1.5× the copy number exterior to breakpoints, consistent with the model in (A), where one of two diploid chromosomes has a tandem duplication. For Tumor 2, inspection of the 95% error bars indicates that Tumor 2 exhibits statistically significant copy number variation within ESRRA intron 2, as well as at additional points.
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V体育ios版 - References

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