Correlation of TP53 and MDM2 genotypes with response to therapy in sarcoma. Issue 5 (16th November 2012)

• Record Type: Journal Article
• Authors: Ohnstad, Hege O.; Castro, Russell; Sun, Jinchang; Heintz, Karen‐Marie; Vassilev, Lyubomir T.; Bjerkehagen, Bodil; Kresse, Stine H.; Meza‐Zepeda, Leonardo A.; Myklebost, Ola
• Is Part Of: Cancer. Volume 119:Issue 5(2013)
• Page Start: 1013
• Page End: 1022
• Publication Date: 2012-11-16
• Subjects: Cancer -- Periodicals; Cancer -- Cytopathology -- Periodicals; 616.99405
• DOI: 10.1002/cncr.27837
• Languages: English
• ISSNs: 0008-543X

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <sec id="abs1-1" sec-type="section"> <title>BACKGROUND:</title> <p>Relatively few sarcomas harbor <italic>TP53</italic> (tumor protein p53) mutations, but in many cases, amplification of <italic>MDM2</italic> (murine double minute 2) effectively inactivate p53. The p53 pathway activity can also be affected by normal genetic variation.</p> </sec> <sec id="abs1-2" sec-type="section"> <title>METHODS:</title> <p>The mutation status of <italic>TP53</italic> and expression of <italic>MDM2</italic>, <italic>TP53</italic>, and their genetic variants <italic>SNP309</italic> and R72P (Arg72Pro) were investigated in 125 sarcoma patient samples and 18 sarcoma cell lines. Association of the different genotypes and gene aberrations with chemotherapy response and survival, as well as response to MDM2 antagonists <italic>in vitro</italic> was evaluated.</p> </sec> <sec id="abs1-3" sec-type="section"> <title>RESULTS:</title> <p>Twenty‐two percent of the tumors had mutant <italic>TP53</italic> and 20% <italic>MDM2</italic> gene amplification. Patients with wild‐type <italic>TP53</italic> (<italic>TP53</italic><sup><italic>Wt</italic></sup>) tumors had improved survival (<italic>P</italic> < .001) and <italic>TP53</italic><sup><italic>Wt</italic></sup> was an independent prognostic factor (hazard ratio = 0.41; 95% confidence interval = 0.23‐0.74; <italic>P</italic> = .03). Interestingly, there was a trend toward longer time to progression after chemotherapy for tumors with the apoptosis‐prone p53 variant R72 (<italic>P</italic> = .07), which was strongest with doxorubicin/ifosfamide‐based regimens (<italic>P</italic> = .01). Liposarcomas had low R72 frequency (33% versus 56%), but increased levels of <italic>MDM2</italic> and <italic>MDM4</italic> (51% and 11%, <italic>P</italic> < .001). <italic>MDM2</italic> overexpression on a <italic>TP53</italic><sup><italic>Wt</italic></sup> background predicted better response to MDM2 antagonist Nutlin‐3a, irrespective of R72P or <italic>SNP309</italic> status.</p> </sec> <sec id="abs1-4" sec-type="section"> <title>CONCLUSIONS:</title> <p>Improved survival after chemotherapy was found in patients with <italic>TP53</italic><sup><italic>Wt</italic></sup> tumors harboring the R72 variant. <italic>MDM2</italic> overexpression in <italic>TP53</italic><sup><italic>Wt</italic></sup> tumors predicted good response to MDM2 antagonists, irrespective of R72P or <italic>SNP309</italic> status. Thus, detailed <italic>TP53</italic> and <italic>MDM2</italic> genotype analyses prior to systemic therapy are recommended. Cancer 2013. © 2012 American Cancer Society.</p> </sec> </abstract>