Homozygous deletion mapping in myeloma samples identifies genes and an expression signature relevant to pathogenesis and outcome.
OBJECTIVE
Myeloma is a clonal malignancy of plasma cells. Poor-prognosis risk is currently identified by clinical and cytogenetic features. However, these indicators do not capture all prognostic information. Gene expression analysis can be used to identify poor-prognosis patients and this can be improved by combination with information about DNA-level changes.


METHODS
Using single nucleotide polymorphism-based gene mapping in combination with global gene expression analysis, we have identified homozygous deletions in genes and networks that are relevant to myeloma pathogenesis and outcome.


RESULTS
We identified 170 genes with homozygous deletions and corresponding loss of expression. Deletion within the "cell death" network was overrepresented and cases with these deletions had impaired overall survival. From further analysis of these events, we have generated an expression-based signature associated with shorter survival in 258 patients and confirmed this signature in data from two independent groups totaling 800 patients. We defined a gene expression signature of 97 cell death genes that reflects prognosis and confirmed this in two independent data sets.


CONCLUSIONS
We developed a simple 6-gene expression signature from the 97-gene signature that can be used to identify poor-prognosis myeloma in the clinical environment. This signature could form the basis of future trials aimed at improving the outcome of poor-prognosis myeloma.
Dickens
Nicholas J
NJ
Section of Haemato-Oncology, The Institute of Cancer Research, London, United Kingdom.
Walker
Brian A
BA
Leone
Paola E
PE
Johnson
David C
DC
Brito
José L
JL
Zeisig
Athanasia
A
Jenner
Matthew W
MW
Boyd
Kevin D
KD
Gonzalez
David
D
Gregory
Walter M
WM
Ross
Fiona M
FM
Davies
Faith E
FE
Morgan
Gareth J
GJ
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006720:Homozygote; D006801:Humans; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017384:Sequence Deletion; D015996:Survival Rate; D016896:Treatment Outcome
D014408:Biomarkers, Tumor