MDM2 (12q15) Gene Amplification by FISH Test Cost & Procedure

Concise Description

This test identifies MDM2 gene amplification to classify specific adipocytic tumours. Well differentiated liposarcoma, which includes atypical lipomatous tumour (WDL/ALT), and dedifferentiated liposarcoma usually exhibit MDM2 amplifications. (DDLS). It can be challenging to tell these tumours from morphologically from other high grade sarcomas and benign tumours. Other soft tissue sarcomas rarely exhibit amplifications, and benign lipomas do not exhibit amplifications.

To destroy p53, MDM2 acts as an E3 ubiquitin ligase. MDM2 binds ARF, another tumour suppressor. This interaction locks MDM2 away from p53 in the nucleolus, activating p53. There are numerous other proteins that interact with MDM2. There are also known MDM2 uses that are not dependent on p53.

Crucial Elements

Many tumours' MDM2 amplification on extra ring or marker chromosomes resulted in p53 inhibition.

Frequently used to identify well-differentiated liposarcoma from dedifferentiated liposarcoma and to characterise atypical lipomatous tumour from imitators.

Separate benign fibrous and fibro-osseous lesions from low grade osteosarcomas and parosteal osteosarcomas (positive). (negative)

FISH is frequently used for testing, along with IHC and dual colour chromogenic in situ hybridization (DISH / CISH); FISH is commonly regarded as the gold standard.

P53 Is The Ubiquitination Target

The p53 tumour suppressor is Mdm2's main target. Mdm2, a p53-interacting protein that inhibits p53 transcriptional activity, has been discovered. Mdm2 inhibits p53's N-terminal trans-activation domain by attaching to it and inhibiting it. Mdm2 is a p53 sensitive gene, which means that p53 can activate its transcription. Therefore, Mdm2 transcription is likewise enhanced when p53 is stabilized, leading to larger Mdm2 protein levels.

Mdm2's P53-unrelated Role

The inhibition of DNA double-strand break repair by Mdm2 overexpression was demonstrated to be independent of p53 and mediated by a novel, direct interaction between Mdm2 and Nbs1. Whatever the p53 status, elevated amounts of Mdm2, but not Mdm2 lacking its Nbs1-binding domain, resulted in chromosomal abnormalities, chromosomal delays, and genomic instability. These findings showed that Mdm2-induced genomic instability can be mediated by Mdm2:Nbs1 interactions without the involvement of p53.

Clinical Traits

• MDM2 immunostaining corresponds with gene amplification when detected by comparative genomic hybridization, qualitative PCR, FISH, or DISH. (Virchows Arch 2010;456:167, Appl Immunohistochem Mol Morphol 2019;27:758, Cold Spring Harb Perspect Med 2016;6:a026336)
• Resistance to radiation, chemotherapy, tyrosine kinase inhibitors, and immune checkpoint inhibitors is linked to MDM2 amplification and overexpression in tumours. (Cancer Cell Int 2019;19:216)
• Particularly in tumours linked to ER signalling pathways, the MDM2 SNP309 (rs2279744) GG genotype (minor allele) is associated with increased MDM2 expression levels and may be somewhat more risky for cancer. (Cold Spring Harb Perspect Med 2016;6:a026336)Breast tumours with mutant TP53 are more likely to have the TT or TG genotype of MDM2 SNP309 than the GG genotype. (Int J Mol Sci 2019;20:509)
• Among Asians but not Caucasians, MDM2 SNP309 may be a risk factor for leukaemia (Leuk Lymphoma 2012;53:2245)
• SNP285 of MDM2 (rs117049649) SNP309 G is only found in a small percentage of Caucasians, and the C genotype is linked to it. Its effects may be modified or countered by the C genotype. (Cold Spring Harb Perspect Med 2016;6:a026336)
• The Cancer Genome Atlas data analysis revealed the overall impact of MDM2 single nucleotide polymorphisms on MDM2 expression levels.