Genetic Variants in Apoptosis and Immunoregulation-Related Genes Are Associated with Risk of Chronic Lymphocytic Leukemia

December 16, 2008

Cancer Research 68, 10178-10186, December 15, 2008. doi:

10.1158/0008-5472.CAN-08-2221

Genetic Variants in Apoptosis and Immunoregulation-Related Genes Are Associated

with Risk of Chronic Lymphocytic Leukemia

Enjuanes1, Yolanda Benavente3, Francesc Bosch2, Idoia Martín-Guerrero5,

Dolors Colomer1, a Pérez-Álvarez3, Reina3, T. Ardanaz6, Pedro

Jares1, Africa García-Orad5, A. Pujana4, Emili Montserrat2, Silvia de

Sanjosé3 and Elias Campo1

1 Hematopathology Section, Department of Anatomic Pathology, and 2 Department of

Hematology, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i

Sunyer, University of Barcelona; 3 Unit of Infections and Cancer, Cancer

Epidemiology Research Programme, Catalan Institut of Oncology, Institut

d'Investigació Biomèdica de Bellvitge, CIBER en Epidemiología y Salud Pública,

L'Hospitalet; 4 Biostatistics and Bioinformatics Unit, and Translational

Research Laboratory, Catalan Institut of Oncology, L'Hospitalet, Barcelona,

Spain; 5 Department of Genetics, Physical Anthropology, and Animal Physiology,

University of the Basque Country, Leioa, Bizkaia, Spain; and 6 Hospital

Txagorritxu, Vitoria, Alava, Spain

Requests for reprints: Elias Campo, Hematopathology Section, Hospital Clínic,

Villarroel 170, 08036-Barcelona, Spain. Phone: 34-93-227-5450; Fax:

34-93-227-5717; E-mail: ecampo@... .

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. [Cancer Res 2008;68(24):10178-86]

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