Scan of 977 nonsynonymous SNPs in CLL4 trial patients for the identification of genetic variants influencing prognosis

Abstract

To identify genetic variants associated with outcome from chronic lymphocytic leukemia (CLL), we genotyped 977 nonsynonymous single nucleotide polymorphisms (nsSNPs) in 755 genes with relevance to cancer biology in 425 patients participating in a phase 3 trial comparing the efficacy of fludarabine, chlorambucil, and fludarabine with cyclophosphamide as first-line treatment. Selection of nsSNPs was biased toward those likely to be functionally deleterious. SNP genotypes were linked to individual patient outcome data and response to chemotherapy. The effect of genotype on progression-free survival (PFS) and overall survival (OS) was assessed by Cox regression analysis adjusting for treatment and clinico-pathologic variables. A total of 78 SNPs (51 dominantly acting and a further 27 recessively acting) were associated with PFS (9 also affecting OS) at the 5% level. These included SNPs mapping to the immune-regulation genes IL16 P434S (P ‫؍‬ .03), IL19 S213F (P ‫؍‬ .001), LILRA4 P27L (P ‫؍‬ .004), KLRC4 S29I (P ‫؍‬ .007), and CD5 V471A (P ‫؍‬ .002); and DNA response genes POLB P242R (P ‫؍‬ .04) and TOPBP1 S730L (P ‫؍‬ .02), which were all independently prognostic of immunoglobulin heavy-chain variable region (

Genetic Variants in Apoptosis and Immunoregulation-Related Genes Are Associated with Risk of Chronic Lymphocytic Leukemia

“…The in silico analysis suggests that these genetic variants and others in the same linkage disequilibrium block influence the germ-line IL16 expression differences in lymphocytes. Although the frequency of this variant in the population examined is relatively low, it is interesting that a nonsynonymous SNP (rs4072111; P434S) of this gene that is not in linkage disequilibrium with the rs4505265 variant has been recently associated with a favorable prognosis in CLL patients, suggesting that variants of this gene may play a role in the pathogenesis of the disease (44).…”

DNA Repair Deficiency Associated with Hematological Neoplasms

“…However, contradictory results were produced in another study, where XPD Lys751Gln was associated with a decreased risk of developing CLL; there was no distribution among different cytogenetic risk subgroups though (Enjuanes et al 2008). Similarly, XRCC1 Arg399Gln has not been correlated with CLL in previous studies, although there was again no distinction between different subgroups (Enjuanes et al 2008, Sellick et al 2008 . These data suggest that individual genetic polymorphisms may predict the clinical outcome of CLL; however, future studies should focus on confirming the results in a larger group of patients, with the view for clinical application.…”

Current Knowledge of Microarray Analysis for Gene Expression Profiling in Chronic Lymphocytic Leukemia

“…Table 6. Relationship between SNPs and drug response (Sellic et al, 2008) www.intechopen.com Gunnarsson et al, (2008) compared platform dynamics, an in-depth analysis of copynumber alterations (CNAs) using four high-resolution microarray platforms: BAC arrays (32K), oligonucleotide arrays (185K, Agilent) and two SNP arrays (250K, Affymetrix and 317K, Illumina). Ten CLL samples were analysed.…”