Homologous recombination of a flanking repeat gene cluster is a mechanism for a common contiguous gene deletion syndrome

Chen, K.-S.; Manian, Prasad; Koeuth, Thearith; Potocki, Lorraine; Zhao, Qi; Chinault, A. Craig; Lee, Cheng‐Chi; Lupski, James R.

doi:10.1038/ng1097-154

Cited by 356 publications

(369 citation statements)

References 72 publications

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“…Two possible candidate genes have so far been detected in this region: The TRE-2 oncogene whose product is expressed in Ewing sarcomas at 17p11. 2,33 and the PMP22 (peripheral myelin protein 22) gene that is related to the cell cycle progression and that was shown to be amplified in cell lines from osteogenic sarcoma and glioblastoma at 17p11.2-p22. 34 In contrast, high level amplifications within chromosomal subregion 12q13-q21 were consistently found in the high-grade areas of dedifferentiated LS but not in any of the pleomorphic LS analyzed, thus representing a genetic marker helpful in the discrimination between these two LS subtypes.…”

Section: Discussionmentioning

confidence: 99%

Distinct chromosomal imbalances in pleomorphic and in high‐grade dedifferentiated liposarcomas

Rieker

Joos

Bärtsch

et al. 2002

Intl Journal of Cancer

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Using comparative genomic hybridization, DNA copy number changes were studied in 14 pleomorphic liposarcomas and compared to those detected in high-grade areas of 9 dedifferentiated liposarcomas. A total of 251 gains and 84 losses were detected. The most frequent gains involved subregions of chromosomal arms 12q and 20q (70% each), 5p (57%), 6q and 9q (52% each), 1q, 7p and 17p (48% each), 1p (43%), 6p and 17q (39% each), 20p and 22q (35% each) as well as 7q and 12p (30% each). The same subregions were also affected by 30 high level amplifications. The most frequent losses were found in subregions of chromosomal arms 13q (35%) as well as 11q and 12p (30% each). Overall, gains of chromosomal material were more frequent than losses (p < 0.001). There were significant differences in the frequency and distribution of recurrent chromosomal imbalances between pleomorphic liposarcomas and the dedifferentiated areas of dedifferentiated liposarcomas. Gains of chromosomal material detected predominantly in pleomorphic liposarcomas involved subbands 5p13-p15 (p < 0.010), 1p21 (p < 0.019), 1q21-q22 (p < 0.040) and 7q22 (p < 0.049). Conversely, high level amplifications within chromosomal subregion 12q13-q21 were only found in the dedifferentiated components of dedifferentiated liposarcomas (p < 0.001). Overall, both gains and the less pronounced losses of chromosomal material were more frequent in pleomorphic than in dedifferentiated liposarcomas (p < 0.001 and p < 0.025, respectively). These results show that pleomorphic liposarcomas display a considerable number of recurrent chromosomal imbalances that are essentially different from those present in high-grade areas of dedifferentiated liposarcomas. Therefore, genetic data are considered as a helpful diagnostic adjunct for the discrimination between these 2 types of liposarcoma. The overall higher frequency of chromosomal imbalances in pleomorphic as compared to dedifferentiated liposarcomas could account for the more aggressive biological behavior of pleomorphic relative to dedifferentiated liposarcoma types. © 2002 Wiley-Liss, Inc. Key words: pleomorphic liposarcoma; dedifferentiated liposarcoma; molecular cytogeneticsLiposarcomas (LS) are the most common soft tissue sarcomas in adults. The World Health Organization classification distinguishes 5 subtypes: well-differentiated LS with its variants, myxoid LS, round cell LS, pleomorphic LS and dedifferentiated LS. 1 The morphological diversity of LS reflects their great variation in biological behavior ranging from non-metastasizing neoplasms like well-differentiated LS to lipogenic sarcomas with overt metastatic potential like round cell and pleomorphic LS. 2 Since the first description of a recurrent reciprocal translocation in myxoid LS, the t(12;16)(q13.3;p11.2), our knowledge of the cytogenetic profile of LS has significantly increased. Meanwhile it is established that the t(12;16)(q13.3;p11.2), which results in the chimeric fusion gene FUS/CHOP, is a recurrent and characteristic finding not only in myxoid but also i...

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Section: Discussionmentioning

confidence: 99%

Distinct chromosomal imbalances in pleomorphic and in high‐grade dedifferentiated liposarcomas

Rieker

Joos

Bärtsch

et al. 2002

Intl Journal of Cancer

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“…We estimated the size of the 17p11 duplication to 4 Mb by a locus-specific QMPSF indicating that this rearrangement, like previously reported cases, 12,37 can be considered as the reciprocal event of the common 4 Mb SMS deletion. (Figure 3b and c).…”

Section: Discussionmentioning

confidence: 99%

Simple detection of genomic microdeletions and microduplications using QMPSF in patients with idiopathic mental retardation

et al. 2006

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In contrast to the numerous well-known microdeletion syndromes, only a few microduplications have been described, and this discrepancy may be due in part to methodological bias. In order to facilitate the detection of genomic microdeletions and microduplications, we developed a new assay based on QMPSF (Quantitative Multiplex PCR of Short fluorescent Fragments) able to explore simultaneously 12 candidate loci involved in mental retardation (MR) and known to be the target of genomic rearrangements. We first screened 153 patients with MR and facial dysmorphism associated with malformations, or growth anomalies, or familial history, with cytogenetically normal chromosomes, and the absence of FRAXA mutation and subtelomeric rearrangements. In this series, we found a 5q35 deletion removing the NSD1 gene in a patient with severe epilepsy, profound MR and, retrospectively, craniofacial features of Sotos syndrome. In a second series, we screened 140 patients with MR and behaviour disturbance who did not fulfil the de Vries criteria for subtelomeric rearrangements and who had a normal karyotype and no detectable FRAXA mutation. We detected a 22q11 deletion in a patient with moderate MR, obesity, and facial dysmorphism and a 4 Mb 17p11 duplication in a patient with moderate MR, behaviour disturbance, strabismus, and aspecific facial features. This new QMPSF assay can be gradually upgraded to include additional loci involved in newly recognised microduplication/microdeletion syndromes, and should facilitate wide screenings of patients with idiopathic MR and provide better estimates of the microduplication frequency in the MR population.

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“…The 5 Mb deleted region in 17p11.2, associated with Smith-Magenis syndrome (SMS), is flanked by a repeat gene cluster that is likely to mediate the reciprocal duplication. 12 The deletions at 15q11-q13, 7q11.23 and 22q11.2, associated with Prader-Willi, Williams and diGeorge syndrome, respectively, are likely to be mediated by repeated sequences flanking each deletion region and the same holds true for the common 8p deletion duplication. 13 Here we describe two types of rearrangement involving the X chromosome at male meiosis and leading to deletion/ duplication for opposite regions, which appear to be the reciprocal products of abnormal misalignment between repeated and inverted sequences located in Xp and Xq.…”

Section: Introductionmentioning

confidence: 95%

Opposite deletions/duplications of the X chromosome: two novel reciprocal rearrangements

et al. 2000

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Paralogous sequences on the same chromosome allow refolding of the chromosome into itself and homologous recombination. Recombinant chromosomes have microscopic or submicroscopic rearrangements according to the distance between repeats. Examples are the submicroscopic inversions of factor VIII, of the IDS gene and of the FLN1/emerin region, all resulting from misalignment of inverted repeats, and double recombination. Most of these inversions are of paternal origin possibly because the X chromosome at male meiosis is free to refold into itself for most of its length. We report on two de novo rearrangements of the X chromosome found in four hypogonadic females. Two of them had an X chromosome deleted for most of Xp and duplicated for a portion of Xq and two had the opposite rearrangement (class I and class II rearrangements, respectively). The breakpoints were defined at the level of contiguous YACs. The same Xp11.23 breakpoint was found in the four cases. That of the long arm coincided in three cases (Xq21.3) and was more proximal in case 4 (Xq21.1). Thus class I rearrangements (cases 1 and 2) are reciprocal to that of case 3, whilst that of case 4 shares only the Xp breakpoint. The abnormal X was paternal in the three cases investigated. Repeated inverted sequences located at the breakpoints of rearrangements are likely to favour the refolding of the paternal X chromosome and the recombination of the repeats. The repeat at the Xp11 may synapse with either that at Xq21.3 or that at Xq21.1. These rearrangements seem to originate as the Xq28 submicroscopic inversions but they are identifiable at the microscopic level and result from a single recombination event.

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Homologous recombination of a flanking repeat gene cluster is a mechanism for a common contiguous gene deletion syndrome

Cited by 356 publications

References 72 publications

Distinct chromosomal imbalances in pleomorphic and in high‐grade dedifferentiated liposarcomas

Distinct chromosomal imbalances in pleomorphic and in high‐grade dedifferentiated liposarcomas

Simple detection of genomic microdeletions and microduplications using QMPSF in patients with idiopathic mental retardation

Opposite deletions/duplications of the X chromosome: two novel reciprocal rearrangements

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