Susceptibility loci associated with specific and shared subtypes of lymphoid malignancies.
The genetics of lymphoma susceptibility reflect the marked heterogeneity of diseases that comprise this broad phenotype. However, multiple subtypes of lymphoma are observed in some families, suggesting shared pathways of genetic predisposition to these pathologically distinct entities. Using a two-stage GWAS, we tested 530,583 SNPs in 944 cases of lymphoma, including 282 familial cases, and 4,044 public shared controls, followed by genotyping of 50 SNPs in 1,245 cases and 2,596 controls. A novel region on 11q12.1 showed association with combined lymphoma (LYM) subtypes. SNPs in this region included rs12289961 near LPXN, (P(LYM) = 3.89×10(-8), OR = 1.29) and rs948562 (P(LYM) = 5.85×10(-7), OR = 1.29). A SNP in a novel non-HLA region on 6p23 (rs707824, P(NHL) = 5.72×10(-7)) was suggestive of an association conferring susceptibility to lymphoma. Four SNPs, all in a previously reported HLA region, 6p21.32, showed genome-wide significant associations with follicular lymphoma. The most significant association with follicular lymphoma was for rs4530903 (P(FL) = 2.69×10(-12), OR = 1.93). Three novel SNPs near the HLA locus, rs9268853, rs2647046, and rs2621416, demonstrated additional variation contributing toward genetic susceptibility to FL associated with this region. Genes implicated by GWAS were also found to be cis-eQTLs in lymphoblastoid cell lines; candidate genes in these regions have been implicated in hematopoiesis and immune function. These results, showing novel susceptibility regions and allelic heterogeneity, point to the existence of pathways of susceptibility to both shared as well as specific subtypes of lymphoid malignancy.
Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Joseph
J
Vijai
Tomas
T
Kirchhoff
Kasmintan A
KA
Schrader
Jennifer
J
Brown
Ana Virginia
AV
Dutra-Clarke
Christopher
C
Manschreck
Nichole
N
Hansen
Rohini
R
Rau-Murthy
Kara
K
Sarrel
Jennifer
J
Przybylo
Sohela
S
Shah
Srujana
S
Cheguri
Zsofia
Z
Stadler
Liying
L
Zhang
Ora
O
Paltiel
Dina
D
Ben-Yehuda
Agnes
A
Viale
Carol
C
Portlock
David
D
Straus
Steven M
SM
Lipkin
Mortimer
M
Lacher
Mark
M
Robson
Robert J
RJ
Klein
Andrew
A
Zelenetz
Kenneth
K
Offit
D000483:Alleles; D045744:Cell Line, Tumor; D002880:Chromosomes, Human, Pair 11; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D007945:Leukemia, Lymphoid / Q000235:genetics* / Q000473:pathology; D008224:Lymphoma, Follicular; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci