PMID- 12745272
OWN - NLM
STAT- MEDLINE
DCOM- 20030606
LR  - 20161124
IS  - 1592-8721 (Electronic)
IS  - 0390-6078 (Linking)
VI  - 88
IP  - 5
DP  - 2003 May
TI  - Gene abnormalities in multiple myeloma; the relevance of TP53, MDM2, and CDKN2A.
PG  - 529-37
AB  - BACKGROUND AND OBJECTIVES: 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. DESIGN AND 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. INTERPRETATIONS AND 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.
FAU - Elnenaei, Manal O
AU  - Elnenaei MO
AD  - Academic Department of Haematology and Cytogenetics, The Institute of Cancer 
      Research and Royal Marsden Hospital Trust, 203 Fulham Road, London SW3 6JJ, UK.
FAU - Gruszka-Westwood, Alicja M
AU  - Gruszka-Westwood AM
FAU - A'Hernt, Roger
AU  - A'Hernt R
FAU - Matutes, Estella
AU  - Matutes E
FAU - Sirohi, Bhawna
AU  - Sirohi B
FAU - Powles, Ray
AU  - Powles R
FAU - Catovsky, Daniel
AU  - Catovsky D
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - Italy
TA  - Haematologica
JT  - Haematologica
JID - 0417435
RN  - 0 (Cyclin-Dependent Kinase Inhibitor p16)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - EC 2.3.2.27 (MDM2 protein, human)
RN  - EC 2.3.2.27 (Proto-Oncogene Proteins c-mdm2)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Alleles
MH  - Cyclin-Dependent Kinase Inhibitor p16/*genetics
MH  - Female
MH  - Gene Amplification
MH  - Gene Deletion
MH  - Gene Dosage
MH  - Humans
MH  - In Situ Hybridization, Fluorescence
MH  - Male
MH  - Middle Aged
MH  - Multiple Myeloma/diagnosis/drug therapy/*genetics
MH  - *Mutation
MH  - *Nuclear Proteins
MH  - Prognosis
MH  - Proto-Oncogene Proteins/*genetics
MH  - Proto-Oncogene Proteins c-mdm2
MH  - Trisomy
MH  - Tumor Suppressor Protein p53/*genetics
EDAT- 2003/05/15 05:00
MHDA- 2003/06/07 05:00
CRDT- 2003/05/15 05:00
PHST- 2003/05/15 05:00 [pubmed]
PHST- 2003/06/07 05:00 [medline]
PHST- 2003/05/15 05:00 [entrez]
PST - ppublish
SO  - Haematologica. 2003 May;88(5):529-37.