The FRA2C common fragile site maps to the borders of MYCN amplicons in neuroblastoma and is associated with gross chromosomal rearrangements in different cancers

Blumrich, Anne; Zapatka, Marc; Brueckner, Lena M.; Zheglo, Diana; Schwab, Manfred; Savelyeva, Larissa

doi:10.1093/hmg/ddr027

Cited by 42 publications

(27 citation statements)

References 61 publications

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“…A fragile site (FRA2Ctel) located near the MYCN amplicon breakpoints has recently been identified. This fragile site was reported to be AT-rich and with significantly higher flexibility peaks than non-fragile regions of the genome, suggesting that secondary structures could form in this region (17). Although it remains unclear how far into the surrounding DNA this effect will reach, it is an intriguing feature that might help to explain the non-recurrent but clustered appearance of the breakpoint distribution.…”

Section: Discussionmentioning

confidence: 96%

MYCN amplicon junctions as tumor-specific targets for minimal residual disease detection in neuroblastoma

Kryh

Abrahamsson²,

Jegerås³

et al. 2011

Int J Oncol

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Abstract.The MYCN gene is frequently amplified in unfavorable neuroblastoma tumors. Therefore, this study aimed at characterizing the novel junctions connecting the amplified DNA segments (amplicons) and obtaining tumor-specific PCR fragments for use in detecting minimal residual disease (MRD). High-density SNP arrays were used to map the end-points of the MYCN amplicons in a subset of neuroblastoma tumors. Primers were designed to give rise to a tumor-specific PCR product and were examined for MRD in the blood and bone marrow using quantitative PCR. Tumor-specific junction fragments were detected in all cases, confirming a head-to-tail tandem orientation of the amplicons and revealing microhomology at the amplicon junctions, thus suggesting a rolling circle caused by microhomology-mediated break-induced replication (MMBIR) as a possible mechanism initiating the MYCN amplification. We also evaluated the use of these junctions as tumor-specific targets for detecting MRD and observed that tumor DNA could be readily detected and quantified in either blood or bone marrow at a sensitivity of 1/10 6 tumor/control DNA. This study provides new information on the mechanisms of oncogene amplification and envisages means of rapidly obtaining highly sensitive PCR-based tools for tumor/ patient-specific monitoring of treatment response and the early detection of relapse in patients with neuroblastoma.

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Section: Discussionmentioning

confidence: 96%

MYCN amplicon junctions as tumor-specific targets for minimal residual disease detection in neuroblastoma

Kryh

Abrahamsson²,

Jegerås³

et al. 2011

Int J Oncol

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“…MET amplification induced by FRA7G instability was later found in primary esophageal adenocarcinoma tumor cells [24]. Similarly, additional fragile sites (FRA11F, FRA2H, FRA2S, FRA2C and FRA7I) are involved in BFB-type oncogene amplifications in different cancer types [84][85][86][87].…”

Section: Genome Instability Of Cfss During Cancer Developmentmentioning

confidence: 95%

“…In different cancer models amplification of the oncogene MET, which involves breakpoints in FRA7G, as well as oncogene amplifications in FRA11F, FRA2H, FRA2S, FRA2G, FRA2C and FRA7I [84][85][86][87], were shown. CFSs are also involved in the formation of translocations.…”

Section: Genome Instability Of Cfss During Cancer Developmentmentioning

confidence: 99%

Interplay between genetic and epigenetic factors governs common fragile site instability in cancer

Ozeri-Galai

Tur-Sinai

Bester

et al. 2014

Cell. Mol. Life Sci.

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Common fragile sites (CFSs) are regions within the normal chromosomal structure that were characterized as hotspots for genomic instability in cancer almost 30 years ago. In recent years, many efforts have been made to understand the basis of CFS fragility and their involvement in the genomic signature of instability found in malignant tumors. CFSs are among the first regions to undergo genomic instability during cancer development because of their intrinsic sensitivity to replication stress conditions, which result from oncogene expression. The preferred sensitivity of CFSs to replication stress stems from various mechanisms including: replication fork arrest at AT-rich repeats, origin paucity along large genomic regions, failure in activation of dormant origins, late replication timing, collision between replication and transcription along large genes, all leading to incomplete replication of the CFS region and resulting in chromosomal instability. Here we review shared and unique characteristics of CFSs, their underlying causes and implications, particularly for the development of cancer.

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“…Despite growing evidence of their importance in disease development, most cFSs have not yet been investigated at the molecular level. Up to now, only nine of them have been characterised at kilobase resolution: FRA1E (Hormozian et al 2007), FRA2C (Blumrich et al 2011), FRA2G (Limongi et al 2003), FRA3B (Wilke et al 1994;Zimonjic et al 1997), FRA7K (Helmrich et al 2007), FRA9G (Sawinska et al 2007), FRA13A (Savelyeva et al 2006), FRA16D (Mangelsdorf et al 2000) and FRAXB . All of these cFSs span AT-rich genomic regions, ranging between 300 kb and 1 Mb, that appear to be enriched in peaks of enhanced DNA flexibility (Schwartz et al 2006).…”

Section: Introductionmentioning

confidence: 99%

“…CFS activation may also trigger gene amplification (e.g. MET, MYC, MYCN) (Blumrich et al 2011;Hellman et al 2002;Cicek et al 2009) and serve as preferred integration sites for several oncogenic viruses, such as hepatitis B and human papilloma viruses (Ferber et al 2003).…”

Section: Introductionmentioning

confidence: 99%

Genomic rearrangements at the FRA2H common fragile site frequently involve non-homologous recombination events across LTR and L1(LINE) repeats

et al. 2012

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Common fragile sites (cFSs) are non-random chromosomal regions that are prone to breakage under conditions of replication stress. DNA damage and chromosomal alterations at cFSs appear to be critical events in the development of various human diseases, especially carcinogenesis. Despite the growing interest in understanding the nature of cFS instability, only a few cFSs have been molecularly characterised. In this study, we fine-mapped the location of FRA2H using six-colour fluorescence in situ hybridisation and showed that it is one of the most active cFSs in the human genome. FRA2H encompasses approximately 530 kb of a gene-poor region containing a novel large intergenic non-coding RNA gene (AC097500.2). Using custom-designed array comparative genomic hybridisation, we detected gross and submicroscopic chromosomal rearrangements involving FRA2H in a panel of 54 neuroblastoma, colon and breast cancer cell lines. The genomic alterations frequently involved different classes of long terminal repeats and long interspersed nuclear elements. An analysis of breakpoint junction sequence motifs predominantly revealed signatures of microhomology-mediated non-homologous recombination events. Our data provide insight into the molecular structure of cFSs and sequence motifs affected by their activation in cancer. Identifying cFS sequences will accelerate the search for DNA biomarkers and targets for individualised therapies.

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The FRA2C common fragile site maps to the borders of MYCN amplicons in neuroblastoma and is associated with gross chromosomal rearrangements in different cancers

Cited by 42 publications

References 61 publications

MYCN amplicon junctions as tumor-specific targets for minimal residual disease detection in neuroblastoma

MYCN amplicon junctions as tumor-specific targets for minimal residual disease detection in neuroblastoma

Interplay between genetic and epigenetic factors governs common fragile site instability in cancer

Genomic rearrangements at the FRA2H common fragile site frequently involve non-homologous recombination events across LTR and L1(LINE) repeats

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