Association of the independent polymorphisms in CDKN2A with susceptibility of acute lymphoblastic leukemia

Abstract

Acute lymphoblastic leukemia (ALL) is the most common cancer in children, and alterations in CDKN2A were considered to play an important role on leukemogenesis. Two single nucleotide polymorphisms (SNPs) at CDKN2A locus were identified to impact on ALL susceptibility via genome wide association studies, and followed by multiple subsequent replication studies at the specific hits. Here, we conducted a systematic review and meta-analysis to re-evaluate the association of both SNPs (rs3731217 and rs3731249) with ALL susceptibility by gathering the data from 24 independent studies, totally containing 7922 cases/21503 controls for rs3731217 and 6295 cases/24191 controls for rs3731249. Both SNPs were significantly associated with ALL risk (odds ratio [OR] = 0.72 and 2.26 respectively), however, exhibit race-specific pattern. In summary, our meta-analysis indicated that two SNPs at CDKN2A locus are associated with ALL susceptibility independently mainly in Caucasians. Future large-scale studies are required to validate the associations in other ethnicities.

Keywords: ALL; CDKN2A; rs3731217; rs3731249; susceptibility.

Figure 1. Flow chart of included studies for analyzing the association between rs3731217 and rs3731249 polymorphisms with ALL susceptibility

Abbreviation: ALL, acute lymphoblastic leukemia.

Figure 2. Forest plots of ALL predisposition associated with rs3731217 polymorphism under genetic models

(A) Allelic model analysis (C vs. T) of rs3731217 and ALL risk. (B) Dominant (TC + CC vs. TT) and recessive (CC vs. TC + TT) model analysis of rs3731217 and ALL risk. Studies were plotted refer to the first author followed by publication year. For each research, the estimates of OR and its 95% CI are exhibited with square and a horizontal line. The area of the squares reflects the weight. The diamond represents the summary OR and 95% CI. Abbreviations: ALL, acute lymphoblastic leukemia; CI, confidence interval; OR, odds ratio.

Figure 3. Forest plots of ALL suceptibility associated with rs3731217 polymorphism across ethnicity, age, and immunophenotype subtypes under the allelic model

Forest plots of ALL susceptibility associated with rs3731217 polymorphism across ethnicity (A), age (B), and immunophenotype (C) subtypes under the allelic model (C vs. T). For each study, the estimates of OR and its 95% CI are plotted with square and a horizontal line. The area of the squares reflects the weight. The diamond represents the summary OR and 95% CI; Abbreviations: ALL, acute lymphoblastic leukemia; CI, confidence interval; OR, odds ratio.

Figure 4. Forest plots of ALL predisposition associated with rs3731249 polymorphism under genetic models

(A) Allelic model analysis (T vs. C) of rs3731249 and ALL risk. (B) Dominant (TC + TT vs. CC) and recessive (TT vs. TC + CC) model analysis of rs3731249 and ALL risk. Studies were plotted refer to the first author followed by publication year. For each research, the estimates of OR and its 95% CI are exhibited with square and a horizontal line. The area of the squares reflects the weight. The diamond represents the summary OR and 95% CI. Abbreviations: ALL, acute lymphoblastic leukemia; CI, confidence interval; OR, odds ratio.

Figure 5. Epigenomic regulation signals at CDKN2A locus

(A) Dnase-sequencing and Chiq-seq signals in the overlapped LD block (described in Supplementary Table S7) at Chr9:21956078-22039426 in Caucasians, the yellow line indicates the location of rs2811711 and information acquired from the WashU Epigenome Browser (http://epigenomegateway.wustl.edu/). (B) DNA- binding proteins around the rs2811711 locus obtained from the UCSC Genome Browser (http://genome.ucsc.edu/) and the yellow line indicates the location of rs2811711. Chromosomal locations are based on hg19; LD, linkage disequilibrium.