Gene abnormalities in multiple myeloma; the relevance of TP53, MDM2, and CDKN2A.
OBJECTIVE
Disruption of either the p14ARF- mdm2- p53 or p16INK4A- Rb1 pathways produces a breakdown of regulatory mechanisms and creates a gateway for tumorigenesis. Since the incidence and clinical implications of abnormalities of TP53, CDKN2A (encoding for p16 and p14) and MDM2 genes (chromosome 12) in multiple myeloma (MM) is not clear, we investigated allelic loss at the former two loci and gain at the latter locus in a series of 82 MM patients.


METHODS
Dual color fluorescence in situ hybridization (FISH) was applied to bone marrow samples to establish the incidence of changes at the above mentioned loci. The CDKN2A locus was tested using a probe which hybridizes to 9p21 and also targets the p15INK4B gene.


RESULTS
FISH analysis revealed the presence of monoallelic TP53 deletions in 12% of patients. Ten percent of patients had hemizygous deletion at 9p21, while a further 8% had loss of 1 of 3 loci in the presence of trisomy 9. MDM2 amplification in the face of chromosome 12 diploidy was seen in 8%, while another 8% had trisomy 12 with an equivalent increase in signals for MDM2. Clinical correlations revealed that allelic loss of TP53 was the only factor associated with resistance to chemotherapy. The presence of 9p21 deletion was associated with an IgA isotype but none of the abnormalities had a significant influence on overall or event-free survival.


CONCLUSIONS
P53 and CDKN2A (9p21) allelic loss and amplifications of the MDM2 gene are infrequent events in myeloma. The incidence of the latter two events was, however, higher than previously reported. Deletion of the TP53 gene predicted resistance to chemotherapy, highlighting its importance in this disease process.
Elnenaei
Manal O
MO
Academic Department of Haematology and Cytogenetics, The Institute of Cancer Research and Royal Marsden Hospital Trust, 203 Fulham Road, London SW3 6JJ, UK.
Gruszka-Westwood
Alicja M
AM
A'Hernt
Roger
R
Matutes
Estella
E
Sirohi
Bhawna
B
Powles
Ray
R
Catovsky
Daniel
D
D000328:Adult; D000368:Aged; D000483:Alleles; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D005260:Female; D005784:Gene Amplification; D017353:Gene Deletion; D018628:Gene Dosage; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D009154:Mutation; D009687:Nuclear Proteins; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051736:Proto-Oncogene Proteins c-mdm2; D014314:Trisomy; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D019941:Cyclin-Dependent Kinase Inhibitor p16; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2