Characterization of centromere alterations in liposarcomas

Sirvent, Nicolas; Forus, Anne; Lescaut, W; Burel, F.; Benzaken, Sylvia; Chazal, M; Bourgeon, A; Vermeesch, Joris Robert; Myklebost, Ola; Turc‐Carel, Claude; Ayraud, N; Coindre, Jean Michél; Pédeutour, Florence

doi:10.1002/1098-2264(2000)9999:9999<::aid-gcc1014>3.0.co;2-q

Cited by 71 publications

(58 citation statements)

References 32 publications

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“…15 They represent satellite DNA sequence of centromere 12, whereas other genes such as MDM2 and CDK4 derive from chromosome 12q13-15 in the ring/giant chromosome. 28 To our knowledge, this abnormality has not been demonstrated unequivocally by FISH in atypical lipomatous tumors on formalin-fixed paraffin-embedded material previously.…”

Section: Discussionmentioning

confidence: 99%

“…Of note was that in the two cases of dedifferentiated liposarcoma, the gain of multiple alphoid 12 signals was B twofold greater in the dedifferentiated component compared with the respective well-differentiated areas, a finding mirrored in the greater number of MDM2/ CDK4 copies in the high-grade component of dedifferentiated liposarcoma compared with their respective low-grade component. Although multiple faint alphoid 12 signals was found to be associated with aggressive behavior in other tumors, 14,15,26 analysis of a larger cohort of patients is required to determine whether the presence of multiple faint alphoid 12 signals is associated with a significant risk of the tumor dedifferentiation.…”

Section: Discussionmentioning

confidence: 99%

“…These multiple faint alphoid 12 signals, which were shown to represent multiple copies of D12Z3 sequences, could be distinguished from centromere 12 signals by the signal intensity of the latter (Figures 1f, g and 3). 15 In an attempt to explain the presence of the multiple faint alphoid signals, FISH and immunohistochemistry for CDK4 were performed on those cases with this finding. CDK4 amplification was identified in six of the eight tumors from six individuals: FISH in the remaining two cases were uninformative (Table 3, case 1 and 2).…”

Section: Atypical Lipomatous Tumor and Dedifferentiated Liposarcoma Wmentioning

confidence: 99%

“…8,13,14 It is also reported that the supernumerary ring or giant marker chromosomes present in atypical lipomatous tumors rarely contain alpha 12 satellite sequences (alphoid 12), which represent the repeated DNA sequences that compose part of the centromere 12. [14][15][16] The recent availability of the commercial MDM2 fluorescent probe made us consider the value of using the presence of MDM2 amplification as an ancillary diagnostic tool for distinguishing lipomas from ALT in our clinical service. Furthermore, the presence of MDM2 amplification may be valuable for stratifying patients for treatment in the future as targeted therapy against MDM2 is already being developed.…”

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confidence: 99%

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Sensitivity of MDM2 amplification and unexpected multiple faint alphoid 12 (alpha 12 satellite sequences) signals in atypical lipomatous tumor

Kashima

Halai

et al. 2012

Modern Pathology

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This study assessed whether analysis of MDM2 copy number by fluorescence in situ hybridization (FISH) would help distinguish lipomas from atypical lipomatous tumors, otherwise referred to as well-differentiated liposarcomas, using a commercially available MDM2 FISH kit. 227 lipomatous and 201 non-lipomatous tumors were analyzed to assess its sensitivity and specificity. Of 178 mature lipomatous tumors, 86 were classified histologically as lipoma and 92 as atypical lipomatous tumor. Two of the lipomas harboring MDM2 amplification were reclassified as atypical lipomatous tumors. Overall, 13 atypical lipomatous tumors did not reveal MDM2 or CDK4 amplification, although this was reduced to 12 following analysis of multiple slides. Three of these cases revealed very occasional tumor cells harboring high-level MDM2 amplification, two had a dedifferentiated component, and MDM2 amplification was detected when one tumor recurred. The remaining six cases exhibited reactive/inflammatory features and were reclassified as lipomas. The findings indicate that MDM2 amplification is 93.5% sensitive for diagnosing atypical lipomatous tumor. A total of 2 of the 20 dedifferentiated liposarcomas failed to reveal MDM2 amplification. All atypical lipomatous tumors measured 410 cm, two dedifferentiated liposarcoma presented de novo at o10 cm, and B50% of lipomas measured 410 cm. Spindle cell lipomas, lipoblastomas, hibernomas and pleomorphic liposarcomas did not reveal MDM2 amplification. Of 201 nonlipomatous tumors, eight revealed MDM2 amplification or multiple faint alphoid 12 signals and were reclassified as dedifferentiated liposarcoma. Multiple faint alphoid 12 signals were observed in nine tumors from seven patients, an observation not previously reported on paraffin sections: these included four atypical lipomatous tumors, and three dedifferentiated liposarcomas, one previously diagnosed as a myxofibrosarcoma, all of which also revealed amplification of CDK4, although two lacked MDM2 amplification. MDM2 FISH test is a useful adjunct to histology for distinguishing lipoma from atypical lipomatous tumor. The limitations of molecular genetic tests must be known before introducing them into a clinical service.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Atypical Lipomatous Tumor and Dedifferentiated Liposarcoma Wmentioning

confidence: 99%

mentioning

confidence: 99%

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Sensitivity of MDM2 amplification and unexpected multiple faint alphoid 12 (alpha 12 satellite sequences) signals in atypical lipomatous tumor

Kashima

Halai

et al. 2012

Modern Pathology

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“…These molecular events are consistently identified in these tumors and represent the main driver event. [6][7][8] To date, the role of these molecular abnormalities as predictive biomarkers for tumor behavior and prognosis has been explored in only a limited number of dedifferentiated liposarcoma cases. 9 The purpose of our study was to determine whether there are biomarkers that can be combined with morphological parameters to begin developing a risk stratification system or molecular grading system for dedifferentiated liposarcoma.…”

mentioning

confidence: 99%

Prognostic relevance of Fédération Nationale des Centres de Lutte Contre le Cancer grade and MDM2 amplification levels in dedifferentiated liposarcoma: a study of 50 cases

et al. 2015

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Dedifferentiated liposarcoma represents a form of liposarcoma composed of a non-lipogenic sarcoma associated with well-differentiated liposarcoma. The prognostic significance of histological grading of the dedifferentiated component remains to be elucidated due to vague grading criteria employed in previous studies. Molecular markers of tumor behavior, including amplification levels of murine double minute-2 (MDM2) and cyclindependent kinase-4 (CDK4) genes, have been explored in a limited number of cases. Here we investigate whether 'Fédération Nationale des Centres de Lutte Contre le Cancer' (FNCLCC) grade and MDM2 gene amplification levels have prognostic value in dedifferentiated liposarcoma in terms of local recurrence and disease-specific survival. Fifty cases were retrieved, reviewed and FNCLCC grade was scored for the dedifferentiated component. Testing for MDM2 gene amplification was performed by fluorescence in situ hybridization. Amplification was categorized as high level (Z20 copies) and as low level (o20 copies). Follow-up data was obtained through chart review. Log-rank test and Cox proportional hazard models were used to determine the effect of grade and level of MDM2 amplification on outcomes. Our series includes 50 patients (male n ¼ 28, female n ¼ 22) with an average age of 63 years (range, 28-88) and a median follow-up of 28 months (range, 2-120). Tumors were graded as grade 1 (6%), grade 2 (58%), and grade 3 (36%). When adjusted for age, sex, site, tumor size, and margin status, grade 3 patients had a higher recurrence rate than grades 1 and 2 (HR ¼ 2.07, 95% CI: 1.24, 7.62; P ¼ 0.015). Patients with high-level MDM2 amplification had higher recurrence rate on univariate analysis (P ¼ 0.028), but not on multivariate analysis (HR ¼ 1.69, 95% CI: 0.73, 3.94; P ¼ 0.221). FNCLCC grade 3 dedifferentiation confers a worse prognosis in dedifferentiated liposarcoma in terms of local recurrence. MDM2 amplification level remains a useful diagnostic tool in dedifferentiated liposarcoma, but has no prognostic value in terms of local recurrence.

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Cancer‐associated neochromosomes: a novel mechanism of oncogenesis

2009

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Malignant tumours are often characterised by significant rearrangement of the genome. This may be visible in the form of a deranged karyotype with both loss and gain of DNA sequences extending from chromosomal regions to whole chromosomes. In several tumour types, however, gross genomic derangements are minimal, and tumour cells contain one or more additional (supernumerary) chromosomes that may be unrecognisable in terms of a single origin. In this review we term such chromosomes cancer-associated neochromosomes (CaNCs). In the absence of other identified genomic abnormalities, and because the CaNC is a common feature of the cancer type, it is hypothesised that the genetic alterations required for cell transformation are contained within its structure. In this review, we discuss the potential impact of modern genomic technologies on our understanding of the nature and causes of CaNC formation, which is central to several cancer types, exemplified here by well-differentiated liposarcoma.

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Characterization of centromere alterations in liposarcomas

Cited by 71 publications

References 32 publications

Sensitivity of MDM2 amplification and unexpected multiple faint alphoid 12 (alpha 12 satellite sequences) signals in atypical lipomatous tumor

Sensitivity of MDM2 amplification and unexpected multiple faint alphoid 12 (alpha 12 satellite sequences) signals in atypical lipomatous tumor

Prognostic relevance of Fédération Nationale des Centres de Lutte Contre le Cancer grade and MDM2 amplification levels in dedifferentiated liposarcoma: a study of 50 cases

Cancer‐associated neochromosomes: a novel mechanism of oncogenesis

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