Genetic variants in apoptosis and immunoregulation-related genes are associated with risk of chronic lymphocytic leukemia.

To identify low-penetrance susceptibility alleles for chronic lymphocytic leukemia (CLL), we performed a case-control study genotyping 768 single-nucleotide polymorphisms (SNP) in 692 cases of CLL and 738 controls. We investigated nonsynonymous SNPs, SNPs with potential functional effect, and tag SNPs in regulatory gene regions in a total of 172 genes involved in cancer biology. After adjustment for multiple testing, we found a strong association between CLL risk and six genetic variants: CCNH (rs2266690, V270A), APAF1 (rs17028658, 3'region), IL16 (rs4505265, first intron), CASP8 (rs1045485, D302H), NOS2A (rs2779251, promoter), and CCR7 (rs3136687, intron 1). We found association with CLL susceptibility and 22 haplotypes in APAF1, IL6, TNFRSF13B, IL16, CASP3, CCR7, LTA/TNF, BAX, BCL2, CXCL12, CASP10/CASP8, CASP1, CCL2, BAK1, and IL1A candidate genes. Finally, we evaluated using public data sets the potential functional effect on gene expression levels of the CLL associated genetic variants detected in regulatory regions. Minor alleles for APAF1 and IL16 were associated with lower mRNA levels; no expression differences were observed for CCR7, whereas NOS2A could not be assessed. This study suggests that common genetic variation in apoptosis- and immunoregulation-related genes is associated with the CLL risk.

[1]  E. Papaemmanuil,et al.  Analysis of a large multi‐generational family provides insight into the genetics of chronic lymphocytic leukemia , 2008, British journal of haematology.

[2]  R. Houlston,et al.  Scan of 977 nonsynonymous SNPs in CLL4 trial patients for the identification of genetic variants influencing prognosis. , 2008, Blood.

[3]  J. Cerhan,et al.  Susceptibility genes and B‐chronic lymphocytic leukaemia , 2007, British journal of haematology.

[4]  G. Marti,et al.  A high-density SNP genome-wide linkage search of 206 families identifies susceptibility loci for chronic lymphocytic leukemia. , 2007, Blood.

[5]  L. Almasy,et al.  Discovery of expression QTLs using large-scale transcriptional profiling in human lymphocytes , 2007, Nature Genetics.

[6]  L. Liang,et al.  A genome-wide association study of global gene expression , 2007, Nature Genetics.

[7]  Jaana M. Hartikainen,et al.  A common coding variant in CASP8 is associated with breast cancer risk , 2007, Nature Genetics.

[8]  R. Redon,et al.  Relative Impact of Nucleotide and Copy Number Variation on Gene Expression Phenotypes , 2007, Science.

[9]  G. Marti,et al.  Identification of a novel chromosome region, 13q21.33-q22.2, for susceptibility genes in familial chronic lymphocytic leukemia. , 2007, Blood.

[10]  D. Weisenburger,et al.  Family history of hematopoietic malignancies and risk of non-Hodgkin lymphoma (NHL): a pooled analysis of 10 211 cases and 11 905 controls from the International Lymphoma Epidemiology Consortium (InterLymph). , 2006, Blood.

[11]  M. Daly,et al.  Transferability of tag SNPs in genetic association studies in multiple populations , 2006, Nature Genetics.

[12]  X. Solé,et al.  SNPStats: a web tool for the analysis of association studies , 2006, Bioinform..

[13]  R. Houlston,et al.  Variants in the ATM-BRCA2-CHEK2 axis predispose to chronic lymphocytic leukemia. , 2006, Blood.

[14]  R. Jain,et al.  The role of nitric oxide in tumour progression , 2006, Nature Reviews Cancer.

[15]  K. Kuliczkowski,et al.  Lack of association between the TNF‐α promoter gene polymorphism and susceptibility to B‐cell chronic lymphocytic leukaemia , 2006, International journal of immunogenetics.

[16]  W. Au,et al.  Tumor necrosis factor alpha promoter polymorphism and the risk of chronic lymphocytic leukemia and myeloma in the Chinese population , 2006, Leukemia & lymphoma.

[17]  H. Adami,et al.  Family history of hematopoietic malignancy and risk of lymphoma. , 2005, Journal of the National Cancer Institute.

[18]  J. Olsen,et al.  Familial Aggregation and Heterogeneity of Non-Hodgkin Lymphoma in Population-Based Samples , 2005, Cancer Epidemiology Biomarkers & Prevention.

[19]  M. Dyer,et al.  A high-density SNP genomewide linkage scan for chronic lymphocytic leukemia-susceptibility loci. , 2005, American journal of human genetics.

[20]  K. Hemminki,et al.  Familial risk for non-Hodgkin lymphoma and other lymphoproliferative malignancies by histopathologic subtype: the Swedish Family-Cancer Database. , 2005, Blood.

[21]  Joaquín Dopazo,et al.  PupasView: a visual tool for selecting suitable SNPs, with putative pathological effect in genes, for genotyping purposes , 2005, Nucleic Acids Res..

[22]  G. Abecasis,et al.  A note on exact tests of Hardy-Weinberg equilibrium. , 2005, American journal of human genetics.

[23]  V. Misra,et al.  G125A single-nucleotide polymorphism in the human BAX promoter affects gene expression , 2005, Oncogene.

[24]  C. Fegan,et al.  Common polymorphism G(-248)A in the promoter region of the bax gene results in significantly shorter survival in patients with chronic lymphocytic Leukemia once treatment is initiated. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[25]  E. Montserrat,et al.  Geographic patterns and pathogenetic implications of IGHV gene usage in chronic lymphocytic leukemia: the lesson of the IGHV3-21 gene. , 2005, Blood.

[26]  D. Clayton,et al.  Genome-wide association studies: theoretical and practical concerns , 2005, Nature Reviews Genetics.

[27]  L. Johnson,et al.  CAK—Cyclin-Dependent Activating Kinase: A Key Kinase in Cell Cycle Control and a Target for Drugs? , 2005, Cell cycle.

[28]  M. Daly,et al.  Haploview: analysis and visualization of LD and haplotype maps , 2005, Bioinform..

[29]  J. Cerhan,et al.  Risk of non-Hodgkin's lymphoma and family history of lymphatic, hematologic, and other cancers. , 2004, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[30]  M. T. de la Fuente,et al.  Bcl-2 family gene modulation during spontaneous apoptosis of B-chronic lymphocytic leukemia cells. , 2004, Biochemical and biophysical research communications.

[31]  D. Fulcher,et al.  Chemokine Receptor Expression in B-cell Lymphoproliferative Disorders , 2004, Leukemia & lymphoma.

[32]  Toshihiro Tanaka.  The International HapMap Project , 2003, Nature.

[33]  D. Oscier,et al.  P2X7 polymorphism and chronic lymphocytic leukaemia: lack of correlation with incidence, survival and abnormalities of chromosome 12 , 2003, Leukemia.

[34]  A. Pettitt,et al.  High frequency of p53 dysfunction and low level of VH mutation in chronic lymphocytic leukemia patients using the VH3-21 gene segment. , 2003, Blood.

[35]  E. Jaffe.  Pathology and Genetics: Tumours of Haematopoietic and Lymphoid Tissues , 2003 .

[36]  D. Sheridan,et al.  Association of a novel single nucleotide polymorphism, G(-248)A, in the 5'-UTR of BAX gene in chronic lymphocytic leukemia with disease progression and treatment resistance. , 2002, Cancer letters.

[37]  P. Bork,et al.  Human non-synonymous SNPs: server and survey. , 2002, Nucleic acids research.

[38]  S. Gabriel,et al.  The Structure of Haplotype Blocks in the Human Genome , 2002, Science.

[39]  Göran Roos,et al.  Somatically mutated Ig V(H)3-21 genes characterize a new subset of chronic lymphocytic leukemia. , 2002, Blood.

[40]  D. Hossfeld.  E.S. Jaffe, N.L. Harris, H. Stein, J.W. Vardiman (eds). World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues , 2002 .

[41]  D. Schaid,et al.  Score tests for association between traits and haplotypes when linkage phase is ambiguous. , 2002, American journal of human genetics.

[42]  L. Sobin,et al.  World Health Organization classification of tumors , 2000, Cancer.

[43]  K. Roeder,et al.  Genomic Control for Association Studies , 1999, Biometrics.

[44]  F. Sigaux,et al.  B-cell chronic lymphocytic leukemia cells express a functional inducible nitric oxide synthase displaying anti-apoptotic activity. , 1998, Blood.

[45]  M. Schmid,et al.  Polymorphism of the tumour necrosis factor‐alpha and lymphotoxin‐alpha genes in chronic lymphocytic leukaemia , 1997, British journal of haematology.

[46]  K. Jöckel,et al.  Association of a novel regulatory polymorphism (-938C>A) in the BCL2 gene promoter with disease progression and survival in chronic lymphocytic leukemia. , 2007, Blood.

[47]  H. Döhner,et al.  The G(-248)A polymorphism in the promoter region of the Bax gene does not correlate with prognostic markers or overall survival in chronic lymphocytic leukemia , 2006, Leukemia.

[48]  Nathaniel Rothman,et al.  Assessing the probability that a positive report is false: an approach for molecular epidemiology studies. , 2004, Journal of the National Cancer Institute.

[49]  Cdm Fletcher,et al.  World Health Organization Classification of Tumours , 2002 .

[50]  L. Vilpo,et al.  Interleukin-1 β, interleukin-1 receptor antagonist and interleukin-6 plasma levels and cytokine gene polymorphisms in chronic lymphocytic leukemia: correlation with prognostic parameters , 2000 .

[51]  M. Hurme,et al.  Interleukin-1 beta, interleukin-1 receptor antagonist and interleukin-6 plasma levels and cytokine gene polymorphisms in chronic lymphocytic leukemia: correlation with prognostic parameters. , 2000, Haematologica.