Skip to main content
PMC home page
The American Journal of Pathology logoLink to The American Journal of Pathology
. 1997 Dec;151(6):1531–1539.

Molecular aberrations of the G1-S checkpoint in myxoid and round cell liposarcoma.

A P Dei Tos 1, S Piccinin 1, C Doglioni 1, T Vukosavljevic 1, T Mentzel 1, M Boiocchi 1, C D Fletcher 1
PMCID: PMC1858364  PMID: 9403703

Abstract

Myxoid and round cell liposarcoma represents a morphological spectrum in which tumor progression from low-grade myxoid to high-grade round cell areas is frequently observed. A distinctive t(12;16)(q13;p11) reciprocal translocation rearranges the CHOP gene localized to 12q13 in most cases. Data concerning the occurrence of cell cycle aberrations in this subset of mesenchymal malignancies are very limited. Therefore, we analyzed a histologically homogeneous series of 21 cases of myxoid and round cell liposarcoma. The p53 pathway was studied by investigating the TP53 gene and protein, mdm2 protein, and p21Waf1 protein. The Rb-cyclin D pathway was analyzed by studying the pRb protein, the p16MTS1 gene, cyclin D1, cyclin D3, p27Kip1, cdk4, and cdk6 proteins. In contrast with the rare involvement of the TP53 gene in well differentiated liposarcoma, aberrations of the TP53 gene were observed in approximately 30% of cases of myxoid and round cell liposarcoma. Notably, mdm2 overexpression was seen in 56% of cases and correlated with histological grade, therefore indicating a possible role in tumor progression. Abnormalities involving the Rb-cyclin D pathway were observed in more than 90% of cases. pRb loss was present in one-third of cases and, at variance with that observed in other subsets of sarcoma, overexpression of cyclin Ds represented a rare event. Interestingly, upregulation of either cdk4 or cdk6 was demonstrated in 85% of cases.

Full text

PDF
1531

Images in this article

1532Figure 1
on p.1532
1534Figure 2
on p.1534
1535Figure 3
on p.1535

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Andreassen A., Oyjord T., Hovig E., Holm R., Flørenes V. A., Nesland J. M., Myklebost O., Høie J., Bruland O. S., Børresen A. L. p53 abnormalities in different subtypes of human sarcomas. Cancer Res. 1993 Feb 1;53(3):468–471. [PubMed] [Google Scholar]
  2. Arnold A., Kim H. G., Gaz R. D., Eddy R. L., Fukushima Y., Byers M. G., Shows T. B., Kronenberg H. M. Molecular cloning and chromosomal mapping of DNA rearranged with the parathyroid hormone gene in a parathyroid adenoma. J Clin Invest. 1989 Jun;83(6):2034–2040. doi: 10.1172/JCI114114. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Ashar H. R., Fejzo M. S., Tkachenko A., Zhou X., Fletcher J. A., Weremowicz S., Morton C. C., Chada K. Disruption of the architectural factor HMGI-C: DNA-binding AT hook motifs fused in lipomas to distinct transcriptional regulatory domains. Cell. 1995 Jul 14;82(1):57–65. doi: 10.1016/0092-8674(95)90052-7. [DOI] [PubMed] [Google Scholar]
  4. Berner J. M., Forus A., Elkahloun A., Meltzer P. S., Fodstad O., Myklebost O. Separate amplified regions encompassing CDK4 and MDM2 in human sarcomas. Genes Chromosomes Cancer. 1996 Dec;17(4):254–259. doi: 10.1002/(SICI)1098-2264(199612)17:4<254::AID-GCC7>3.0.CO;2-2. [DOI] [PubMed] [Google Scholar]
  5. Cordon-Cardo C., Latres E., Drobnjak M., Oliva M. R., Pollack D., Woodruff J. M., Marechal V., Chen J., Brennan M. F., Levine A. J. Molecular abnormalities of mdm2 and p53 genes in adult soft tissue sarcomas. Cancer Res. 1994 Feb 1;54(3):794–799. [PubMed] [Google Scholar]
  6. Cordon-Cardo C. Mutations of cell cycle regulators. Biological and clinical implications for human neoplasia. Am J Pathol. 1995 Sep;147(3):545–560. [PMC free article] [PubMed] [Google Scholar]
  7. De Chiara A., T'Ang A., Triche T. J. Expression of the retinoblastoma susceptibility gene in childhood rhabdomyosarcomas. J Natl Cancer Inst. 1993 Jan 20;85(2):152–157. doi: 10.1093/jnci/85.2.152. [DOI] [PubMed] [Google Scholar]
  8. Dei Tos A. P., Doglioni C., Laurino L., Barbareschi M., Fletcher C. D. p53 protein expression in non-neoplastic lesions and benign and malignant neoplasms of soft tissue. Histopathology. 1993 Jan;22(1):45–50. doi: 10.1111/j.1365-2559.1993.tb00068.x. [DOI] [PubMed] [Google Scholar]
  9. Dei Tos A. P., Doglioni C., Piccinin S., Maestro R., Mentzel T., Barbareschi M., Boiocchi M., Fletcher C. D. Molecular abnormalities of the p53 pathway in dedifferentiated liposarcoma. J Pathol. 1997 Jan;181(1):8–13. doi: 10.1002/(SICI)1096-9896(199701)181:1<8::AID-PATH700>3.0.CO;2-#. [DOI] [PubMed] [Google Scholar]
  10. Dei Tos A. P., Maestro R., Doglioni C., Gasparotto D., Boiocchi M., Laurino L., Fletcher C. D. Ultraviolet-induced p53 mutations in atypical fibroxanthoma. Am J Pathol. 1994 Jul;145(1):11–17. [PMC free article] [PubMed] [Google Scholar]
  11. Dei Tos A. P., Maestro R., Doglioni C., Piccinin S., Libera D. D., Boiocchi M., Fletcher C. D. Tumor suppressor genes and related molecules in leiomyosarcoma. Am J Pathol. 1996 Apr;148(4):1037–1045. [PMC free article] [PubMed] [Google Scholar]
  12. Dei Tos A. P., Mentzel T., Newman P. L., Fletcher C. D. Spindle cell liposarcoma, a hitherto unrecognized variant of liposarcoma. Analysis of six cases. Am J Surg Pathol. 1994 Sep;18(9):913–921. doi: 10.1097/00000478-199409000-00006. [DOI] [PubMed] [Google Scholar]
  13. Doglioni C., Pelosio P., Laurino L., Macri E., Meggiolaro E., Favretti F., Barbareschi M. p21/WAF1/CIP1 expression in normal mucosa and in adenomas and adenocarcinomas of the colon: its relationship with differentiation. J Pathol. 1996 Jul;179(3):248–253. doi: 10.1002/(SICI)1096-9896(199607)179:3<248::AID-PATH571>3.0.CO;2-6. [DOI] [PubMed] [Google Scholar]
  14. Gonzalez-Zulueta M., Bender C. M., Yang A. S., Nguyen T., Beart R. W., Van Tornout J. M., Jones P. A. Methylation of the 5' CpG island of the p16/CDKN2 tumor suppressor gene in normal and transformed human tissues correlates with gene silencing. Cancer Res. 1995 Oct 15;55(20):4531–4535. [PubMed] [Google Scholar]
  15. Greenblatt M. S., Bennett W. P., Hollstein M., Harris C. C. Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res. 1994 Sep 15;54(18):4855–4878. [PubMed] [Google Scholar]
  16. Harper J. W., Adami G. R., Wei N., Keyomarsi K., Elledge S. J. The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell. 1993 Nov 19;75(4):805–816. doi: 10.1016/0092-8674(93)90499-g. [DOI] [PubMed] [Google Scholar]
  17. Kamb A., Gruis N. A., Weaver-Feldhaus J., Liu Q., Harshman K., Tavtigian S. V., Stockert E., Day R. S., 3rd, Johnson B. E., Skolnick M. H. A cell cycle regulator potentially involved in genesis of many tumor types. Science. 1994 Apr 15;264(5157):436–440. doi: 10.1126/science.8153634. [DOI] [PubMed] [Google Scholar]
  18. Karpeh M. S., Brennan M. F., Cance W. G., Woodruff J. M., Pollack D., Casper E. S., Dudas M. E., Latres E., Drobnjak M., Cordon-Cardo C. Altered patterns of retinoblastoma gene product expression in adult soft-tissue sarcomas. Br J Cancer. 1995 Oct;72(4):986–991. doi: 10.1038/bjc.1995.447. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Kilpatrick S. E., Doyon J., Choong P. F., Sim F. H., Nascimento A. G. The clinicopathologic spectrum of myxoid and round cell liposarcoma. A study of 95 cases. Cancer. 1996 Apr 15;77(8):1450–1458. doi: 10.1002/(SICI)1097-0142(19960415)77:8<1450::AID-CNCR5>3.0.CO;2-G. [DOI] [PubMed] [Google Scholar]
  20. Knight J. C., Renwick P. J., Dal Cin P., Van den Berghe H., Fletcher C. D. Translocation t(12;16)(q13;p11) in myxoid liposarcoma and round cell liposarcoma: molecular and cytogenetic analysis. Cancer Res. 1995 Jan 1;55(1):24–27. [PubMed] [Google Scholar]
  21. Knudson A. G., Jr Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A. 1971 Apr;68(4):820–823. doi: 10.1073/pnas.68.4.820. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Latres E., Drobnjak M., Pollack D., Oliva M. R., Ramos M., Karpeh M., Woodruff J. M., Cordon-Cardo C. Chromosome 17 abnormalities and TP53 mutations in adult soft tissue sarcomas. Am J Pathol. 1994 Aug;145(2):345–355. [PMC free article] [PubMed] [Google Scholar]
  23. Leach F. S., Tokino T., Meltzer P., Burrell M., Oliner J. D., Smith S., Hill D. E., Sidransky D., Kinzler K. W., Vogelstein B. p53 Mutation and MDM2 amplification in human soft tissue sarcomas. Cancer Res. 1993 May 15;53(10 Suppl):2231–2234. [PubMed] [Google Scholar]
  24. Maelandsmo G. M., Berner J. M., Flørenes V. A., Forus A., Hovig E., Fodstad O., Myklebost O. Homozygous deletion frequency and expression levels of the CDKN2 gene in human sarcomas--relationship to amplification and mRNA levels of CDK4 and CCND1. Br J Cancer. 1995 Aug;72(2):393–398. doi: 10.1038/bjc.1995.344. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Maestro R., Dolcetti R., Gasparotto D., Doglioni C., Pelucchi S., Barzan L., Grandi E., Boiocchi M. High frequency of p53 gene alterations associated with protein overexpression in human squamous cell carcinoma of the larynx. Oncogene. 1992 Jun;7(6):1159–1166. [PubMed] [Google Scholar]
  26. Marchetti A., Buttitta F., Girlando S., Dalla Palma P., Pellegrini S., Fina P., Doglioni C., Bevilacqua G., Barbareschi M. mdm2 gene alterations and mdm2 protein expression in breast carcinomas. J Pathol. 1995 Jan;175(1):31–38. doi: 10.1002/path.1711750106. [DOI] [PubMed] [Google Scholar]
  27. Martin K., Trouche D., Hagemeier C., Sørensen T. S., La Thangue N. B., Kouzarides T. Stimulation of E2F1/DP1 transcriptional activity by MDM2 oncoprotein. Nature. 1995 Jun 22;375(6533):691–694. doi: 10.1038/375691a0. [DOI] [PubMed] [Google Scholar]
  28. Michieli P., Chedid M., Lin D., Pierce J. H., Mercer W. E., Givol D. Induction of WAF1/CIP1 by a p53-independent pathway. Cancer Res. 1994 Jul 1;54(13):3391–3395. [PubMed] [Google Scholar]
  29. Müller H., Lukas J., Schneider A., Warthoe P., Bartek J., Eilers M., Strauss M. Cyclin D1 expression is regulated by the retinoblastoma protein. Proc Natl Acad Sci U S A. 1994 Apr 12;91(8):2945–2949. doi: 10.1073/pnas.91.8.2945. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Nakayama T., Toguchida J., Wadayama B., Kanoe H., Kotoura Y., Sasaki M. S. MDM2 gene amplification in bone and soft-tissue tumors: association with tumor progression in differentiated adipose-tissue tumors. Int J Cancer. 1995 Oct 20;64(5):342–346. doi: 10.1002/ijc.2910640511. [DOI] [PubMed] [Google Scholar]
  31. Oliner J. D., Kinzler K. W., Meltzer P. S., George D. L., Vogelstein B. Amplification of a gene encoding a p53-associated protein in human sarcomas. Nature. 1992 Jul 2;358(6381):80–83. doi: 10.1038/358080a0. [DOI] [PubMed] [Google Scholar]
  32. Panagopoulos I., Höglund M., Mertens F., Mandahl N., Mitelman F., Aman P. Fusion of the EWS and CHOP genes in myxoid liposarcoma. Oncogene. 1996 Feb 1;12(3):489–494. [PubMed] [Google Scholar]
  33. Patterson H., Gill S., Fisher C., Law M. G., Jayatilake H., Fletcher C. D., Thomas M., Grimer R., Gusterson B. A., Cooper C. S. Abnormalities of the p53 MDM2 and DCC genes in human leiomyosarcomas. Br J Cancer. 1994 Jun;69(6):1052–1058. doi: 10.1038/bjc.1994.207. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Pilotti S., Della Torre G., Lavarino C., Di Palma S., Sozzi G., Minoletti F., Rao S., Pasquini G., Azzarelli A., Rilke F. Distinct mdm2/p53 expression patterns in liposarcoma subgroups: implications for different pathogenetic mechanisms. J Pathol. 1997 Jan;181(1):14–24. doi: 10.1002/(SICI)1096-9896(199701)181:1<14::AID-PATH730>3.0.CO;2-O. [DOI] [PubMed] [Google Scholar]
  35. Rosenberg C. L., Wong E., Petty E. M., Bale A. E., Tsujimoto Y., Harris N. L., Arnold A. PRAD1, a candidate BCL1 oncogene: mapping and expression in centrocytic lymphoma. Proc Natl Acad Sci U S A. 1991 Nov 1;88(21):9638–9642. doi: 10.1073/pnas.88.21.9638. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Schauer I. E., Siriwardana S., Langan T. A., Sclafani R. A. Cyclin D1 overexpression vs. retinoblastoma inactivation: implications for growth control evasion in non-small cell and small cell lung cancer. Proc Natl Acad Sci U S A. 1994 Aug 2;91(16):7827–7831. doi: 10.1073/pnas.91.16.7827. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Sherr C. J. Cancer cell cycles. Science. 1996 Dec 6;274(5293):1672–1677. doi: 10.1126/science.274.5293.1672. [DOI] [PubMed] [Google Scholar]
  38. Smith T. A., Easley K. A., Goldblum J. R. Myxoid/round cell liposarcoma of the extremities. A clinicopathologic study of 29 cases with particular attention to extent of round cell liposarcoma. Am J Surg Pathol. 1996 Feb;20(2):171–180. doi: 10.1097/00000478-199602000-00005. [DOI] [PubMed] [Google Scholar]
  39. Stratton M. R., Moss S., Warren W., Patterson H., Clark J., Fisher C., Fletcher C. D., Ball A., Thomas M., Gusterson B. A. Mutation of the p53 gene in human soft tissue sarcomas: association with abnormalities of the RB1 gene. Oncogene. 1990 Sep;5(9):1297–1301. [PubMed] [Google Scholar]
  40. Toguchida J., Yamaguchi T., Ritchie B., Beauchamp R. L., Dayton S. H., Herrera G. E., Yamamuro T., Kotoura Y., Sasaki M. S., Little J. B. Mutation spectrum of the p53 gene in bone and soft tissue sarcomas. Cancer Res. 1992 Nov 15;52(22):6194–6199. [PubMed] [Google Scholar]
  41. Xiao Z. X., Chen J., Levine A. J., Modjtahedi N., Xing J., Sellers W. R., Livingston D. M. Interaction between the retinoblastoma protein and the oncoprotein MDM2. Nature. 1995 Jun 22;375(6533):694–698. doi: 10.1038/375694a0. [DOI] [PubMed] [Google Scholar]

Articles from The American Journal of Pathology are provided here courtesy of American Society for Investigative Pathology

RESOURCES