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.

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We performed single-molecule telomere length and telomere fusion analysis in patients at different stages of chronic lymphocytic leukemia (CLL). Our work identified the shortest telomeres ever recorded in primary human tissue, reinforcing the concept that there is significant cell division in CLL. Furthermore, we provide direct evidence that critical telomere shortening, dysfunction, and fusion contribute to disease progression. The frequency of short telomeres and fusion events increased with advanced disease, but importantly these were also found in a subset of early-stage patient samples, indicating that these events can precede disease progression. Sequence analysis of fusion events isolated from persons with the shortest telomeres revealed limited numbers of repeats at the breakpoint, subtelomeric deletion, and microhomology. Array-comparative genome hybridization analysis of persons displaying evidence of telomere dysfunction revealed large-scale genomic rearrangements that were concentrated in the telomeric regions; this was not observed in samples with longer telomeres. The telomere dynamics observed in CLL B cells were indistinguishable from that observed in cells undergoing crisis in culture after abrogation of the p53 pathway. Taken together, our data support the concept that telomere erosion and subsequent telomere fusion are critical in the progression of CLL and that this paradigm may extend to other malignancies. (Blood. 2010;116(11): 1899-1907) IntroductionNonreciprocal translocations (NRTs) are considered to be key mutational events that can drive many types of malignancy. 1 The underlying mechanisms that result in these types of events can include, among others, deficiencies in double-strand break repair, 2 mitotic checkpoints, 3,4 and telomere dysfunction. 5 Telomeres play a key role in upholding genomic integrity; in the context of DNA damage checkpoint defects, cells in culture undergo crisis and have extensive telomere erosion, chromosomal fusion, and genomic rearrangements. 6,7 NRTs, as well as localized gene amplification, 8 can arise as a consequence of cycles of anaphase-bridging, breakage, and fusion initiated by the formation of dicentric chromosomes after telomere fusion. 9 This paradigm is exemplified in vivo by telomerase knockout mice, where short telomeres appear to drive the formation of tumors containing NRTs. 5 However, evidence for this phenomenon in humans is circumstantial. Numerous malignancies, including breast, prostate, colorectal, and chronic lymphocytic leukemia (CLL), [10][11][12][13][14][15] have been documented to exhibit shorter telomeres compared with normal tissues. These data are consistent with the expected levels of cell division during the progression to malignancy but do not indicate that telomeres become short enough to lose their end-capping function. Telomere fusion, as well as other chromosomal defects, can lead to the formation of anaphase bridges; in situ data show an increase in anaphase bridges, often interpreted as a surrogate marker for telomere f...

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.

Purpose: Patients with chronic lymphocytic leukemia (CLL) display immune deficiency that is most obvious in advanced stage disease. Here we investigated whether this immune dysfunction plays a pathologic role in the progression of early stage disease patients.Experimental Design: We carried out eight-color immunophenotyping analysis in a cohort of 110 untreated early stage CLL patients and 22 age-matched healthy donors and correlated our findings with clinical outcome data.Results: We found a significant reduction in naive CD4 þ and CD8 þ T cells in CLL patients. Only the CD4 þ subset showed significantly increased effector memory cells (T EM and T EMRA ) in the whole cohort (P ¼ 0.004 and P ¼ 0.04, respectively). However, patients with inverted CD4:CD8 ratios (52 of 110) showed preferential expansion of the CD8 compartment, with a skewing of CD8 þ T EMRA (P ¼ 0.03) coupled with increased percentage of CD57 þ CD28 À CD27 À T cells (P ¼ 0.008) and PD-1 positivity (P ¼ 0.027), consistent with a replicative senescence phenotype. Furthermore, inverted CD4:CD8 ratios were associated with shorter lymphocyte doubling time (P ¼ 0.03), shorter time to first treatment (P ¼ 0.03), and reduced progression-free survival (P ¼ 0.005). Conclusions: Our data show that the emergence of CD8 þ PD-1 þ replicative senescence phenotype in early stage CLL patients is associated with more aggressive clinical disease. Importantly, these findings were independent of tumor cell prognostic markers and could not be accounted for by patient age, changes in regulatory T-cell frequency, or cytomegalovirus serostatus. Clin Cancer Res; 18(3); 678-87. Ó2011 AACR.