Genetic variation in H2AFX contributes to risk of non-Hodgkin lymphoma.
Non-Hodgkin lymphoma (NHL) comprises a group of lymphoid tumors that have in common somatic translocations. H2AFX encodes a key histone involved in the detection of the DNA double-stranded breaks that can lead to translocations. H2afx is a dosage-dependent gene that protects against B-cell lymphomas in mice, making its human orthologue an ideal candidate gene for susceptibility to lymphoma. We did a population-based genetic association study of H2AFX variants in 487 NHL cases and 531 controls. Complete resequencing of the human H2AFX gene in 95 NHL cases was done to establish the spectrum of variation in affected individuals; this was followed by both direct and indirect tests for association at the level of individual single nucleotide polymorphisms (SNP) and as haplotypes. Homozygosity for the AA genotype of a SNP 417 bp upstream of the translational start of H2AFX is strongly associated [odds ratio (OR), 0.54; P = 0.001] with protection from NHL. We find a strong association of this SNP with the follicular lymphoma subtype of NHL (AA genotype: OR, 0.40; P = 0.004) and with mantle cell lymphoma (AA genotype: OR, 0.20; P = 0.01) that remains significant after adjustment for the false discovery rate, but not with diffuse large B-cell lymphoma. These data support the hypothesis that genetic variation in the H2AFX gene influences genetic susceptibility or resistance to some subtypes of NHL by contributing to the maintenance of genome stability.
Novik
Karen L
KL
Genome Sciences Centre, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada V5Z 1L3.
Spinelli
John J
JJ
Macarthur
Amy C
AC
Shumansky
Karey
K
Sipahimalani
Payal
P
Leach
Stephen
S
Lai
Agnes
A
Connors
Joseph M
JM
Gascoyne
Randy D
RD
Gallagher
Richard P
RP
Brooks-Wilson
Angela R
AR
D000328:Adult; D000368:Aged; D000818:Animals; D001483:Base Sequence; D005075:Biological Evolution; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006657:Histones / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D008228:Lymphoma, Non-Hodgkin / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012689:Sequence Homology, Nucleic Acid
C468783:H2AX protein, human; D006657:Histones