Deletions of CDKN2C in multiple myeloma: biological and clinical implications.
OBJECTIVE
Deletions of chromosome 1 have been described in 7% to 40% of cases of myeloma with inconsistent clinical consequences. CDKN2C at 1p32.3 has been identified in myeloma cell lines as the potential target of the deletion. We tested the clinical impact of 1p deletion and used high-resolution techniques to define the role of CDKN2C in primary patient material.


METHODS
We analyzed 515 cases of monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), and newly diagnosed multiple myeloma using fluorescence in situ hybridization (FISH) for deletions of CDKN2C. In 78 myeloma cases, we carried out Affymetrix single nucleotide polymorphism mapping and U133 Plus 2.0 expression arrays. In addition, we did mutation, methylation, and Western blotting analysis.


RESULTS
By FISH we identified deletion of 1p32.3 (CDKN2C) in 3 of 66 MGUS (4.5%), 4 of 39 SMM (10.3%), and 55 of 369 multiple myeloma cases (15%). We examined the impact of copy number change at CDKN2C on overall survival (OS), and found that the cases with either hemizygous or homozygous deletion of CDKN2C had a worse OS compared with cases that were intact at this region (22 months versus 38 months; P = 0.003). Using gene mapping we identified three homozygous deletions at 1p32.3, containing CDKN2C, all of which lacked expression of CDKN2C. Cases with homozygous deletions of CDKN2C were the most proliferative myelomas, defined by an expression-based proliferation index, consistent with its biological function as a cyclin-dependent kinase inhibitor.


CONCLUSIONS
Our results suggest that deletions of CDKN2C are important in the progression and clinical outcome of myeloma.
Leone
Paola E
PE
Section of Haemato-Oncology, The Institute of Cancer Research, 15 Cotswold Road, London, United Kingdom.
Walker
Brian A
BA
Jenner
Matthew W
MW
Chiecchio
Laura
L
Dagrada
Gianpaolo
G
Protheroe
Rebecca K M
RK
Johnson
David C
DC
Dickens
Nicholas J
NJ
Brito
Jose Luis
JL
Else
Monica
M
Gonzalez
David
D
Ross
Fiona M
FM
Chen-Kiang
Selina
S
Davies
Faith E
FE
Morgan
Gareth J
GJ
D000368:Aged; D045744:Cell Line, Tumor; D002874:Chromosome Mapping / Q000379:methods; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000235:genetics*; D018450:Disease Progression; D017353:Gene Deletion; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008875:Middle Aged; D008957:Models, Genetic; D009101:Multiple Myeloma / Q000175:diagnosis / Q000235:genetics*; D013997:Time Factors; D016896:Treatment Outcome
C493971:CDKN2C protein, human; D050763:Cyclin-Dependent Kinase Inhibitor p18