We conducted a genome-wide association study of 299,983 tagging SNPs for chronic lymphocytic leukemia (CLL) and performed validation in two additional series totaling 1,529 cases and 3,115 controls. We identified six previously unreported CLL risk loci at 2q13 (rs17483466; P = 2.36 x 10(-10)), 2q37.1 (rs13397985, SP140; P = 5.40 x 10(-10)), 6p25.3 (rs872071, IRF4; P = 1.91 x 10(-20)), 11q24.1 (rs735665; P = 3.78 x 10(-12)), 15q23 (rs7176508; P = 4.54 x 10(-12)) and 19q13.32 (rs11083846, PRKD2; P = 3.96 x 10(-9)). These data provide the first evidence for the existence of common, low-penetrance susceptibility to a hematological malignancy and new insights into disease causation in CLL.

To identify novel risk variants for chronic lymphocytic leukemia (CLL) we conducted a genome-wide association study of 299,983 tagging SNPs, with validation in four additional series totaling 2,503 cases and 5,789 controls. We identified four risk loci for CLL at 2q37.3 (rs757978, FARP2; odds ratio [OR] = 1.39; P = 2.11 x 10-9), 8q24.21 (rs2456449; OR = 1.26; P = 7.84 x 10-10), 15q21.3 (rs7169431; OR = 1.36; P = 4.74 x 10-7) and 16q24.1 (rs305061; OR = 1.22; P = 3.60 x 10-7). There was also evidence for risk loci at 15q25.2 (rs783540, CPEB1; OR = 1.18; P = 3.67 x 10-6) and 18q21.1 (rs1036935; OR = 1.22; P = 2.28 x 10-6). These data provide further evidence for genetic susceptibility to this B-cell hematological malignancy.

) and 8q22.3 (rs2511714, P=2.90x10 -9 ). These findings provide further insights into the genetic and biological basis of inherited genetic susceptibility to CLL. Speedy et al 3Chronic lymphocytic leukemia (CLL) is the most common hematological malignancy in Western countries 1 and is characterized by a 8-fold increased risk in first-degree relatives 2 . Genome-wide association studies (GWASs) have so far identified common variants at 24 loci that contribute to the heritable risk of CLL [3][4][5][6] . Current projections for the number of independent regions harboring common variants associated with CLL suggest that additional risk loci conferring modest effects should be identified by expansion of discovery GWAS datasets.To identify additional novel susceptibility loci for CLL, we conducted an independent primary scan of CLL and performed a genome-wide meta-analysis with a previously published GWAS followed by analysis of the top single nucleotide polymorphisms (SNPs) in two separate case-control series.In the primary scan (UK-CLL-2), 1,271 CLL cases were genotyped using the Illumina Omni Express Figure 1). To harmonize the two GWAS datasets, we imputed UK-CLL-1 to recover untyped SNPs directly genotyped in UK-CLL-2, using data from the 1000 Genomes Project as reference. Using data on all cases and controls from each GWAS, we derived joint odds ratios (ORs) and confidence intervals (CIs) under a fixed effects model for each SNP and associated P-values, restricting analysis to SNPs with MAF >1%. After filtering on the basis of pre-specified quality-control measures Table 2). We also identified promising association signals (i.e. P<1.0×10−5 ) at 11 additional loci (Supplementary Table 2). We applied 1000 Genomes imputation to UK-CLL-1 and UK-CLL-2 at these loci to investigate if a statistically significant stronger SNP association could be identified, recovering an additional SNP which was significant at the genome-wide threshold (rs6858698; Supplementary Table 2). We performed replication genotyping of six SNPs selected on the basis of statistical significance (rs2236256, rs6062501, rs6858698) and gene centricity coupled with Table 4). While we found no evidence for a relationship between rs10936599, and telomere length in 246 CLL patients (Supplementary Table 5), carrier status for the rs10936599-C risk allele is previously been associated with significantly longer telomeres in leukocytes 10,11 .The third significant association was at rs6858698 on 4q26 (OR=1.31, 95% C.I. 1.20-1.44; P=3.07x10 linked to cis-platinum resistance by enhancing apoptosis. A recent GWAS of CLL has reported promising associations at 5p15.33 defined by rs10069690 and at 8q22.33 defined by rs2511714 6 . Combining the Pvalues for rs10069690 and rs2511714 obtained in our meta-analysis (P=1.0x10 -4 and 1.0x10respectively) with published data 6 provides robust evidence for both associations (combined P-values 1.10x10 -10 and 2.90x10 -9 respectively; Supplementary Figure 4). rs10069690 maps to intron 4 of TERT (telomerase reverse trans...

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SummaryDefining the prognosis of individual cancer sufferers remains a significant clinical challenge. Here we assessed the ability of high-resolution single telomere length analysis (STELA), combined with an experimentally derived definition of telomere dysfunction, to predict the clinical outcome of patients with chronic lymphocytic leukaemia (CLL). We defined the upper telomere length threshold at which telomere fusions occur and then used the mean of the telomere 'fusogenic' range as a prognostic tool. Patients with telomeres within the fusogenic range had a significantly shorter overall survival (P < 0Á0001; Hazard ratio [HR] = 13Á2, 95% confidence interval [CI] = 11Á6-106Á4) and this was preserved in early-stage disease patients (P < 0Á0001, HR=19Á3, 95% CI = 17Á8-802Á5). Indeed, our assay allowed the accurate stratification of Binet stage A patients into those with indolent disease (91% survival at 10 years) and those with poor prognosis (13% survival at 10 years). Furthermore, patients with telomeres above the fusogenic mean showed superior prognosis regardless of their IGHV mutation status or cytogenetic risk group. In keeping with this finding, telomere dysfunction was the dominant variable in multivariate analysis. Taken together, this study provides compelling evidence for the use of high-resolution telomere length analysis coupled with a definition of telomere dysfunction in the prognostic assessment of CLL.