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Richard Houlston and colleagues report results of a genome-wide association study of chronic lymphocytic leukemia. They validate several new susceptibility loci for this disease, including variants near POT1 , TERC and TERT . Genome-wide association studies (GWAS) of chronic lymphocytic leukemia (CLL) have shown that common genetic variation contributes to the heritable risk of CLL. To identify additional CLL susceptibility loci, we conducted a GWAS and performed a meta-analysis with a published GWAS totaling 1,739 individuals with CLL (cases) and 5,199 controls with validation in an additional 1,144 cases and 3,151 controls. A combined analysis identified new susceptibility loci mapping to 3q26.2 (rs10936599, P = 1.74 × 10 −9 ), 4q26 (rs6858698, P = 3.07 × 10 −9 ), 6q25.2 ( IPCEF1 , rs2236256, P = 1.50 × 10 −10 ) and 7q31.33 ( POT1 , rs17246404, P = 3.40 × 10 −8 ). Additionally, we identified a promising association at 5p15.33 ( CLPTM1L , rs31490, P = 1.72 × 10 −7 ) and validated recently reported putative associations at 5p15.33 ( TERT , rs10069690, P = 1.12 × 10 −10 ) and 8q22.3 (rs2511714, P = 2.90 × 10 −9 ). These findings provide further insights into the genetic and biological basis of inherited genetic susceptibility to CLL.

Richard Houlston and colleagues identify common variants at four loci associated with risk of chronic lymphocytic leukemia, including a coding variant in FARP2 on 2q37.3 and a noncoding variant in the region upstream of MYC on 8q24.21. To identify new 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 new risk loci for CLL at 2q37.3 (rs757978, FARP2 ; odds ratio (OR) = 1.39; P = 2.11 × 10 −9 ), 8q24.21 (rs2456449; OR = 1.26; P = 7.84 × 10 −10 ), 15q21.3 (rs7169431; OR = 1.36; P = 4.74 × 10 −7 ) and 16q24.1 (rs305061; OR = 1.22; P = 3.60 × 10 −7 ). We also found evidence for risk loci at 15q25.2 (rs783540, CPEB1 ; OR = 1.18; P = 3.67 × 10 −6 ) and 18q21.1 (rs1036935; OR = 1.22; P = 2.28 × 10 −6 ). These data provide further evidence for genetic susceptibility to this B-cell hematological malignancy.

[...]allogeneic stem-cell transplantation carries substantial risks, including opportunistic infections, graft-versus-host disease, and relapse, and up to 40% of patients succumb to transplant-related mortality.5 Furthermore, many patients with CLL present with co-morbidities or do not have a suitable donor, and therefore allogeneic transplantation is not an option anyway.

Richard Houlston and colleagues report a genome-wide association study of multiple myeloma and identify four loci associated with susceptibility to this malignancy. To identify variants for multiple myeloma risk, we conducted a genome-wide association study with validation in additional series totaling 4,692 individuals with multiple myeloma (cases) and 10,990 controls. We identified four risk loci at 3q26.2 (rs10936599, P = 8.70 × 10 −14 ), 6p21.33 (rs2285803, PSORS1C2 , P = 9.67 × 10 −11 ), 17p11.2 (rs4273077, TNFRSF13B , P = 7.67 × 10 −9 ) and 22q13.1 (rs877529, CBX7 , P = 7.63 × 10 −16 ). These data provide further evidence for genetic susceptibility to this B-cell hematological malignancy, as well as insight into the biological basis of predisposition.

Richard Houlston and colleagues identify variants at six loci associated with risk of chronic lymphocytic leukemia. These findings confirm that common, low-penetrance susceptibility alleles contribute to this hematological malignancy and provide new insights into disease etiology. 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 × 10 −10 ), 2q37.1 (rs13397985, SP140 ; P = 5.40 × 10 −10 ), 6p25.3 (rs872071, IRF4 ; P = 1.91 × 10 −20 ), 11q24.1 (rs735665; P = 3.78 × 10 −12 ), 15q23 (rs7176508; P = 4.54 × 10 −12 ) and 19q13.32 (rs11083846, PRKD2; P = 3.96 × 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.

B-cell malignancies (BCM) originate from the same cell of origin, but at different maturation stages and have distinct clinical phenotypes. Although genetic risk variants for individual BCMs have been identified, an agnostic, genome-wide search for shared genetic susceptibility has not been performed. We explored genome-wide association studies of chronic lymphocytic leukaemia (CLL, N = 1,842), Hodgkin lymphoma (HL, N = 1,465) and multiple myeloma (MM, N = 3,790). We identified a novel pleiotropic risk locus at 3q22.2 ( NCK1 , rs11715604, P  = 1.60 × 10 −9 ) with opposing effects between CLL ( P  = 1.97 × 10 −8 ) and HL ( P  = 3.31 × 10 −3 ). Eight established non-HLA risk loci showed pleiotropic associations. Within the HLA region, Ser37 + Phe37 in HLA-DRB1 ( P  = 1.84 × 10 −12 ) was associated with increased CLL and HL risk ( P  = 4.68 × 10 −12 ), and reduced MM risk ( P  = 1.12 × 10 −2 ), and Gly70 in HLA-DQB1 ( P  = 3.15 × 10 −10 ) showed opposing effects between CLL ( P  = 3.52 × 10 −3 ) and HL ( P  = 3.41 × 10 −9 ). By integrating eQTL, Hi-C and ChIP-seq data, we show that the pleiotropic risk loci are enriched for B-cell regulatory elements, as well as an over-representation of binding of key B-cell transcription factors. These data identify shared biological pathways influencing the development of CLL, HL and MM. The identification of these risk loci furthers our understanding of the aetiological basis of BCMs.

Chronic lymphocytic leukemia is the most common adult leukemia and is currently incurable with conventional chemotherapeutic agents. Over the last few years, significant discoveries have been made regarding the biology that underpins this disease. These new insights have allowed us to develop more rational prognostic tools and identify promising novel therapeutic targets. In this review, we highlight the importance of both constitutive and inducible DNA binding of the transcription factor NF- κB in chronic lymphocytic leukemia. We describe the current knowledge regarding the activity and function of specific NF- κB subunits in this disease, and discuss the complex mechanisms that regulate NF- κB activation . In addition, we provide compelling evidence for the utility of the NF- κB subunit, Rel A, as a prognostic marker and as a therapeutic target in this disease, and we also describe how this protein may contribute to the drug resistance commonly encountered with this condition.

The clustering of different types of B-cell malignancies in families raises the possibility of shared aetiology. To examine this, we performed cross-trait linkage disequilibrium (LD)-score regression of multiple myeloma (MM) and chronic lymphocytic leukaemia (CLL) genome-wide association study (GWAS) data sets, totalling 11,734 cases and 29,468 controls. A significant genetic correlation between these two B-cell malignancies was shown (Rg = 0.4, P = 0.0046). Furthermore, four of the 45 known CLL risk loci were shown to associate with MM risk and five of the 23 known MM risk loci associate with CLL risk. By integrating eQTL, Hi-C and ChIP-seq data, we show that these pleiotropic risk loci are enriched for B-cell regulatory elements and implicate B-cell developmental genes. These data identify shared biological pathways influencing the development of CLL and, MM and further our understanding of the aetiological basis of these B-cell malignancies.

Chronic lymphocytic leukemia is the most common adult leukemia and is currently incurable with conventional chemotherapeutic agents. Over the last few years, significant discoveries have been made regarding the biology that underpins this disease. These new insights have allowed us to develop more rational prognostic tools and identify promising novel therapeutic targets. In this review, we highlight the importance of both constitutive and inducible DNA binding of the transcription factor NF-kB in chronic lymphocytic leukemia. We describe the current knowledge regarding the activity and function of specific NF-kB subunits in this disease, and discuss the complex mechanisms that regulate NF-kB activation in vivo. In addition, we provide compelling evidence for the utility of the NF-kB subunit, Rel A, as a prognostic marker and as a therapeutic target in this disease, and we also describe how this protein may contribute to the drug resistance commonly encountered with this condition.