Genomic variation in myeloma: design, content, and initial application of the Bank On A Cure SNP Panel to detect associations with progression-free survival.
BACKGROUND
We have engaged in an international program designated the Bank On A Cure, which has established DNA banks from multiple cooperative and institutional clinical trials, and a platform for examining the association of genetic variations with disease risk and outcomes in multiple myeloma. We describe the development and content of a novel custom SNP panel that contains 3404 SNPs in 983 genes, representing cellular functions and pathways that may influence disease severity at diagnosis, toxicity, progression or other treatment outcomes. A systematic search of national databases was used to identify non-synonymous coding SNPs and SNPs within transcriptional regulatory regions. To explore SNP associations with PFS we compared SNP profiles of short term (less than 1 year, n = 70) versus long term progression-free survivors (greater than 3 years, n = 73) in two phase III clinical trials.


RESULTS
Quality controls were established, demonstrating an accurate and robust screening panel for genetic variations, and some initial racial comparisons of allelic variation were done. A variety of analytical approaches, including machine learning tools for data mining and recursive partitioning analyses, demonstrated predictive value of the SNP panel in survival. While the entire SNP panel showed genotype predictive association with PFS, some SNP subsets were identified within drug response, cellular signaling and cell cycle genes.


CONCLUSIONS
A targeted gene approach was undertaken to develop an SNP panel that can test for associations with clinical outcomes in myeloma. The initial analysis provided some predictive power, demonstrating that genetic variations in the myeloma patient population may influence PFS.
Van Ness
Brian
B
Cancer Center, University of Minnesota, Minneapolis, MN, USA. vanne001@umn.edu
Ramos
Christine
C
Haznadar
Majda
M
Hoering
Antje
A
Haessler
Jeff
J
Crowley
John
J
Jacobus
Susanna
S
Oken
Martin
M
Rajkumar
Vincent
V
Greipp
Philip
P
Barlogie
Bart
B
Durie
Brian
B
Katz
Michael
M
Atluri
Gowtham
G
Fang
Gang
G
Gupta
Rohit
R
Steinbach
Michael
M
Kumar
Vipin
V
Mushlin
Richard
R
Johnson
David
D
Morgan
Gareth
G
D030541:Databases, Genetic; D018572:Disease-Free Survival; D020022:Genetic Predisposition to Disease; D023281:Genomics; D006801:Humans; D009101:Multiple Myeloma / Q000175:diagnosis* / Q000235:genetics*; D016366:Open Reading Frames; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D011401:Promoter Regions, Genetic
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