Chordoma Foundation

MDM2

Mouse double minute 2 (MDM2) is an E3 ubiquitin ligase that acts as a negative regulator of the tumor suppressor TP53. MDM2 is an important controller of the G1-S checkpoint in the cell cycle.

Location: Chromosome 12q15

Activation of MDM2 disrupts cell cycle checkpoints and leads to nuclear pleomorphism and tumor cell proliferation.1

MDM2 in Chordoma

Overexpression of MDM2 has been identified in a subset of chordoma cases and abnormalities in the p53/MDM2 signaling pathway are well known to contribute to cell cycle deregulation and tumorigenesis in numerous cancers, including chordoma.1 Though drugs that inhibit MDM2 have not been studied in chordoma, inhibitors of the CDK4/6 kinases downstream of p53/MDM2 have had promising results in chordoma.

Molecular Evidence


Copy Number Variation

  • MDM2 amplification was identified in 15% of chordomas but not correlated with MDM2 overexpression.1
  • MDM2 amplification was not correlated with clinical outcome.1

Protein Expression and Activation

  • MDM2 overexpression was found in 4/46 (9%) skull base chordomas and 4/24 (17%) nonskull base chordomas in one study.1 Another study found MDM2 overexpression in 14/25 (56%) chordomas with 6/25 (24%) having strong immunoreactivity.4
  • In one study, 5/5 chordoma cases were positive for MDM2 with 4-45% of nuclei reacting against the MDM2 antibody using immunohistochemistry.2 A different study did not detect MDM2 in 1 case of chordoma.3
  • MDM2 overexpression was positively correlated with MIB-1 labeling index, which is a measure of cell proliferation.1 4
  • Overexpression of both MDM2 and p53 was significantly associated with nuclear pleomorphism.1
  • Aberration of MDM2 was not correlated with clinical outcome.1

References

1.
Naka T, Boltze C, Kuester D, et al. Alterations of G1-S checkpoint in chordoma: the prognostic impact of p53 overexpression. Cancer. 2005;104(6):1255-1263. [PubMed]
2.
Daugaard S, Christensen L, Høgdall E. Markers aiding the diagnosis of chondroid tumors: an immunohistochemical study including osteonectin, bcl-2, cox-2, actin, calponin, D2-40 (podoplanin), mdm-2, CD117 (c-kit), and YKL-40. APMIS. 2009;117(7):518-525. [PubMed]
3.
Stefanou D, Nonni A, Agnantis N, Athanassiadou S, Briassoulis E, Pavlidis N. p53/MDM-2 immunohistochemical expression correlated with proliferative activity in different subtypes of human sarcomas: a ten-year follow-up study. Anticancer Res. 1998;18(6B):4673-4681. [PubMed]
4.
Yakkioui Y, Temel Y, Creytens D, et al. A comparison of cell-cycle markers in skull base and sacral chordomas. World Neurosurg. 2014;82(1-2):e311-8. [PubMed]