TY - JOUR
T1 - Genomic variation by whole-genome SNP mapping arrays predicts time-to-event outcome in patients with chronic lymphocytic Leukemia
T2 - A comparison of CLL and HapMap genotypes
AU - Schweighofer, Carmen D.
AU - Coombes, Kevin R.
AU - Majewski, Tadeusz
AU - Barron, Lynn L.
AU - Lerner, Susan
AU - Sargent, Rachel L.
AU - O'Brien, Susan
AU - Ferrajoli, Alessandra
AU - Wierda, William G.
AU - Czerniak, Bogdan A.
AU - Medeiros, L. Jeffrey
AU - Keating, Michael J.
AU - Abruzzo, Lynne V.
N1 - Funding Information:
Supported by a European Hematology Association and American Society of Hematology grant (C.D.S.), CLL Global Research Foundation grant (C.D.S. and L.V.A.), Commonwealth Foundation for Cancer Research and Mr. and Mrs. William H. Goodwin, Jr. , grants (L.V.A.), and National Cancer Institute grant R01CA123252 (L.V.A.).
PY - 2013/3
Y1 - 2013/3
N2 - Genomic abnormalities, such as deletions in 11q22 or 17p13, are associated with poorer prognosis in patients with chronic lymphocytic leukemia (CLL). We hypothesized that unknown regions of copy number variation (CNV) affect clinical outcome and can be detected by array-based single-nucleotide polymorphism (SNP) genotyping. We compared SNP genotypes from 168 untreated patients with CLL with genotypes from 73 white HapMap controls. We identified 322 regions of recurrent CNV, 82 of which occurred significantly more often in CLL than in HapMap (CLL-specific CNV), including regions typically aberrant in CLL: deletions in 6q21, 11q22, 13q14, and 17p13 and trisomy 12. In univariate analyses, 35 of total and 11 of CLL-specific CNVs were associated with unfavorable time-to-event outcomes, including gains or losses in chromosomes 2p, 4p, 4q, 6p, 6q, 7q, 11p, 11q, and 17p. In multivariate analyses, six CNVs (ie, CLL-specific variations in 11p15.1-15.4 or 6q27) predicted time-to-treatment or overall survival independently of established markers of prognosis. Moreover, genotypic complexity (ie, the number of independent CNVs per patient) significantly predicted prognosis, with a median time-to-treatment of 64 months versus 23 months in patients with zero to one versus two or more CNVs, respectively (P = 3.3 × 10-8). In summary, a comparison of SNP genotypes from patients with CLL with HapMap controls allowed us to identify known and unknown recurrent CNVs and to determine regions and rates of CNV that predict poorer prognosis in patients with CLL.
AB - Genomic abnormalities, such as deletions in 11q22 or 17p13, are associated with poorer prognosis in patients with chronic lymphocytic leukemia (CLL). We hypothesized that unknown regions of copy number variation (CNV) affect clinical outcome and can be detected by array-based single-nucleotide polymorphism (SNP) genotyping. We compared SNP genotypes from 168 untreated patients with CLL with genotypes from 73 white HapMap controls. We identified 322 regions of recurrent CNV, 82 of which occurred significantly more often in CLL than in HapMap (CLL-specific CNV), including regions typically aberrant in CLL: deletions in 6q21, 11q22, 13q14, and 17p13 and trisomy 12. In univariate analyses, 35 of total and 11 of CLL-specific CNVs were associated with unfavorable time-to-event outcomes, including gains or losses in chromosomes 2p, 4p, 4q, 6p, 6q, 7q, 11p, 11q, and 17p. In multivariate analyses, six CNVs (ie, CLL-specific variations in 11p15.1-15.4 or 6q27) predicted time-to-treatment or overall survival independently of established markers of prognosis. Moreover, genotypic complexity (ie, the number of independent CNVs per patient) significantly predicted prognosis, with a median time-to-treatment of 64 months versus 23 months in patients with zero to one versus two or more CNVs, respectively (P = 3.3 × 10-8). In summary, a comparison of SNP genotypes from patients with CLL with HapMap controls allowed us to identify known and unknown recurrent CNVs and to determine regions and rates of CNV that predict poorer prognosis in patients with CLL.
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U2 - 10.1016/j.jmoldx.2012.09.006
DO - 10.1016/j.jmoldx.2012.09.006
M3 - Article
C2 - 23273604
AN - SCOPUS:84874548075
SN - 1525-1578
VL - 15
SP - 196
EP - 209
JO - Journal of Molecular Diagnostics
JF - Journal of Molecular Diagnostics
IS - 2
ER -