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Blood, 1 February 2008, Vol. 111, No. 3, pp. 1625-1633.
Prepublished online as a Blood First Edition Paper on November 15, 2007; DOI 10.1182/blood-2007-08-110130.
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Submitted August 30, 2007
Accepted November 5, 2007
Scan of 977 non-synonymous SNPs in CLL4 trial patients for the identification of genetic variants influencing prognosis
Gabrielle S Sellick, Rachel Wade, Susan Richards, David G. Oscier, Daniel Catovsky, and Richard S Houlston*
Section of Cancer Genetics, Institute of Cancer Research, Sutton, United Kingdom
Clinical Trial Service Unit, University of Oxford, Oxford, United Kingdom
Department of Haematology, Royal Bournemouth Hospital, Bournemouth, United Kingdom
Section of Haemato-Oncology, Institute of Cancer Research, Sutton, United Kingdom
* Corresponding author; email: richard.houlston{at}icr.ac.uk.
To identify genetic variants associated with outcome from chronic lymphocytic leukemia (CLL) we genotyped 977 non-synonymous SNPs (nsSNPs) in 755 genes with relevance to cancer biology in 425 patients participating in a phase III trial comparing the efficacy of fludarabine, chlorambucil, and fludarabine with cyclophosphamide as first-line treatment. Selection of nsSNPs was biased towards 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-pathological variables. 78 SNPs (51 dominantly acting and a further 27 recessively acting) were associated with PFS (9 also impacting on OS) at the 5% level. These included SNPs mapping to the immune regulation genes IL16 P434S (P=0.03), IL19 S213F (P=0.001), LILRA4 P27L (P=0.004), KLRC4 S29I (P=0.007) and CD5 V471A (P=0.002) and DNA response genes POLB P242R (P=0.04), and TOPBP1 S730L (P=0.02) which were all independently prognostic of IgVH mutational status. The variants identified warrant further evaluation as promising prognostic markers of patient outcome. To facilitate the identification of prognostic markers through pooled analyses we have made all data from our analysis publicly available.
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