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Inherited coding variants at the CDKN2A locus influence susceptibility to acute lymphoblastic leukaemia in children.

Xu H, Zhang H, Yang W, Yadav R, Morrison AC, Qian M, Devidas M, Liu Y, Perez-Andreu V, Zhao X, Gastier-Foster JM, Lupo PJ, Neale G, Raetz E, Larsen E, Bowman WP, Carroll WL, Winick N, Williams R, Hansen T, Holm JC, Mardis E, Fulton R, Pui CH, Zhang J, Mullighan CG, Evans WE, Hunger SP, Gupta R, Schmiegelow K, Loh ML, Relling MV, Yang JJ - Nat Commun (2015)

Bottom Line: There is increasing evidence from genome-wide association studies for a strong inherited genetic basis of susceptibility to acute lymphoblastic leukaemia (ALL) in children, yet the effects of protein-coding variants on ALL risk have not been systematically evaluated.Here we show a missense variant in CDKN2A associated with the development of ALL at genome-wide significance (rs3731249, P=9.4 × 10(-23), odds ratio=2.23).Resequencing the CDKN2A-CDKN2B locus in 2,407 childhood ALL cases reveals 19 additional putative functional germline variants.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA [2] Department of Laboratory Medicine, National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.

ABSTRACT
There is increasing evidence from genome-wide association studies for a strong inherited genetic basis of susceptibility to acute lymphoblastic leukaemia (ALL) in children, yet the effects of protein-coding variants on ALL risk have not been systematically evaluated. Here we show a missense variant in CDKN2A associated with the development of ALL at genome-wide significance (rs3731249, P=9.4 × 10(-23), odds ratio=2.23). Functional studies indicate that this hypomorphic variant results in reduced tumour suppressor function of p16(INK4A), increases the susceptibility to leukaemic transformation of haematopoietic progenitor cells, and is preferentially retained in ALL tumour cells. Resequencing the CDKN2A-CDKN2B locus in 2,407 childhood ALL cases reveals 19 additional putative functional germline variants. These results provide direct functional evidence for the influence of inherited genetic variation on ALL risk, highlighting the important and complex roles of CDKN2A-CDKN2B tumour suppressors in leukaemogenesis.

No MeSH data available.


Related in: MedlinePlus

GWAS results of ALL susceptibility in European Americans.Association between genotype and ALL was evaluated for 35,802 SNPs in 1,773 ALL cases and 10,448 non-ALL controls. P-values (the logistic regression test, −log10P, y axis) were plotted against respective chromosomal position of each SNP (x axis). Gene, symbols were indicated for 3 loci achieving genome-wide significance threshold (P<5 × 10−8, dashed blue line): ARID5B (10q21.2), IKZF1 (7p12.2) and CDKN2A (9p21.3). Blue dots indicated SNPs within 2M bp of the top ALL susceptibility variants at the ARID5B (rs10821936) and IKZF1(rs4132601) loci, the red dots indicated SNPs in the 2M-bp region around the novel ALL risk variant rs3731249 in CDKN2A.
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f1: GWAS results of ALL susceptibility in European Americans.Association between genotype and ALL was evaluated for 35,802 SNPs in 1,773 ALL cases and 10,448 non-ALL controls. P-values (the logistic regression test, −log10P, y axis) were plotted against respective chromosomal position of each SNP (x axis). Gene, symbols were indicated for 3 loci achieving genome-wide significance threshold (P<5 × 10−8, dashed blue line): ARID5B (10q21.2), IKZF1 (7p12.2) and CDKN2A (9p21.3). Blue dots indicated SNPs within 2M bp of the top ALL susceptibility variants at the ARID5B (rs10821936) and IKZF1(rs4132601) loci, the red dots indicated SNPs in the 2M-bp region around the novel ALL risk variant rs3731249 in CDKN2A.

Mentions: In the discovery GWAS, we genotyped 1,773 children with B-ALL and 10,448 non-ALL controls of European descent2021 for 247,505 variants using the Illumina Infinium HumanExome array. Three loci with genome-wide significant association signals were observed: ARID5B (10q21.2), IKZF1 (7q12.2) and CDKN2A (9p21.3) (Fig. 1). Non-coding variants rs10821936 in ARID5B and rs4132601 in IKZF1 showed the strongest association (P=9.9 × 10−46 and 4.3 × 10−37, the logistic regression test, respectively; Fig. 1 and Supplementary Table 1), confirming previous GWAS findings from our group and others56. No coding variants in ARID5B and IKZF1 were significantly associated with ALL susceptibility. The third genome-wide significant hit was a missense SNP at the CDKN2A locus (rs3731249, P=9.4 × 10−23, the logistic regression test, Fig. 1, Table 1). The T allele at rs3731249 was over-represented in ALL compared with controls (6.8% versus 3.0%, Table 1), with every copy of the allele conferring 2.23-fold increase in disease risk (95% confidence interval 1.90–2.61). The C-to-T nucleotide substitution at rs3731249 (c.C442T) resulted in an alanine-to-threonine change in amino-acid sequence (p.A148T) for tumour suppressor p16INK4A. This variant also locates in the 3′ untranslated region (3′-UTR) of the p14ARF transcript, an alternative open reading frame at this locus encoding a different tumour suppressor. Interestingly, previous GWAS had identified an intronic variant in CDKN2A (rs3731217) to be strongly associated with susceptibility to ALL in populations of European descent9. Genotype correlation between the coding variant rs3731249 and the intronic rs3731217 is exceedingly low (r2<0.01 in Europeans, Supplementary Fig. 1), and multivariate analyses including both SNPs indicated their independent contribution to ALL risk (Supplementary Table 2). In the replication cohort of 409 childhood ALL cases and 1,599 non-ALL controls of European descent in Denmark, the association signal at rs3731249 was validated (P=5.2 × 10−4, odds ratio=1.73 (1.27–2.36), the logistic regression test, Table 1) and this variant also remained significant after adjusting for rs3731217.


Inherited coding variants at the CDKN2A locus influence susceptibility to acute lymphoblastic leukaemia in children.

Xu H, Zhang H, Yang W, Yadav R, Morrison AC, Qian M, Devidas M, Liu Y, Perez-Andreu V, Zhao X, Gastier-Foster JM, Lupo PJ, Neale G, Raetz E, Larsen E, Bowman WP, Carroll WL, Winick N, Williams R, Hansen T, Holm JC, Mardis E, Fulton R, Pui CH, Zhang J, Mullighan CG, Evans WE, Hunger SP, Gupta R, Schmiegelow K, Loh ML, Relling MV, Yang JJ - Nat Commun (2015)

GWAS results of ALL susceptibility in European Americans.Association between genotype and ALL was evaluated for 35,802 SNPs in 1,773 ALL cases and 10,448 non-ALL controls. P-values (the logistic regression test, −log10P, y axis) were plotted against respective chromosomal position of each SNP (x axis). Gene, symbols were indicated for 3 loci achieving genome-wide significance threshold (P<5 × 10−8, dashed blue line): ARID5B (10q21.2), IKZF1 (7p12.2) and CDKN2A (9p21.3). Blue dots indicated SNPs within 2M bp of the top ALL susceptibility variants at the ARID5B (rs10821936) and IKZF1(rs4132601) loci, the red dots indicated SNPs in the 2M-bp region around the novel ALL risk variant rs3731249 in CDKN2A.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4544058&req=5

f1: GWAS results of ALL susceptibility in European Americans.Association between genotype and ALL was evaluated for 35,802 SNPs in 1,773 ALL cases and 10,448 non-ALL controls. P-values (the logistic regression test, −log10P, y axis) were plotted against respective chromosomal position of each SNP (x axis). Gene, symbols were indicated for 3 loci achieving genome-wide significance threshold (P<5 × 10−8, dashed blue line): ARID5B (10q21.2), IKZF1 (7p12.2) and CDKN2A (9p21.3). Blue dots indicated SNPs within 2M bp of the top ALL susceptibility variants at the ARID5B (rs10821936) and IKZF1(rs4132601) loci, the red dots indicated SNPs in the 2M-bp region around the novel ALL risk variant rs3731249 in CDKN2A.
Mentions: In the discovery GWAS, we genotyped 1,773 children with B-ALL and 10,448 non-ALL controls of European descent2021 for 247,505 variants using the Illumina Infinium HumanExome array. Three loci with genome-wide significant association signals were observed: ARID5B (10q21.2), IKZF1 (7q12.2) and CDKN2A (9p21.3) (Fig. 1). Non-coding variants rs10821936 in ARID5B and rs4132601 in IKZF1 showed the strongest association (P=9.9 × 10−46 and 4.3 × 10−37, the logistic regression test, respectively; Fig. 1 and Supplementary Table 1), confirming previous GWAS findings from our group and others56. No coding variants in ARID5B and IKZF1 were significantly associated with ALL susceptibility. The third genome-wide significant hit was a missense SNP at the CDKN2A locus (rs3731249, P=9.4 × 10−23, the logistic regression test, Fig. 1, Table 1). The T allele at rs3731249 was over-represented in ALL compared with controls (6.8% versus 3.0%, Table 1), with every copy of the allele conferring 2.23-fold increase in disease risk (95% confidence interval 1.90–2.61). The C-to-T nucleotide substitution at rs3731249 (c.C442T) resulted in an alanine-to-threonine change in amino-acid sequence (p.A148T) for tumour suppressor p16INK4A. This variant also locates in the 3′ untranslated region (3′-UTR) of the p14ARF transcript, an alternative open reading frame at this locus encoding a different tumour suppressor. Interestingly, previous GWAS had identified an intronic variant in CDKN2A (rs3731217) to be strongly associated with susceptibility to ALL in populations of European descent9. Genotype correlation between the coding variant rs3731249 and the intronic rs3731217 is exceedingly low (r2<0.01 in Europeans, Supplementary Fig. 1), and multivariate analyses including both SNPs indicated their independent contribution to ALL risk (Supplementary Table 2). In the replication cohort of 409 childhood ALL cases and 1,599 non-ALL controls of European descent in Denmark, the association signal at rs3731249 was validated (P=5.2 × 10−4, odds ratio=1.73 (1.27–2.36), the logistic regression test, Table 1) and this variant also remained significant after adjusting for rs3731217.

Bottom Line: There is increasing evidence from genome-wide association studies for a strong inherited genetic basis of susceptibility to acute lymphoblastic leukaemia (ALL) in children, yet the effects of protein-coding variants on ALL risk have not been systematically evaluated.Here we show a missense variant in CDKN2A associated with the development of ALL at genome-wide significance (rs3731249, P=9.4 × 10(-23), odds ratio=2.23).Resequencing the CDKN2A-CDKN2B locus in 2,407 childhood ALL cases reveals 19 additional putative functional germline variants.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA [2] Department of Laboratory Medicine, National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.

ABSTRACT
There is increasing evidence from genome-wide association studies for a strong inherited genetic basis of susceptibility to acute lymphoblastic leukaemia (ALL) in children, yet the effects of protein-coding variants on ALL risk have not been systematically evaluated. Here we show a missense variant in CDKN2A associated with the development of ALL at genome-wide significance (rs3731249, P=9.4 × 10(-23), odds ratio=2.23). Functional studies indicate that this hypomorphic variant results in reduced tumour suppressor function of p16(INK4A), increases the susceptibility to leukaemic transformation of haematopoietic progenitor cells, and is preferentially retained in ALL tumour cells. Resequencing the CDKN2A-CDKN2B locus in 2,407 childhood ALL cases reveals 19 additional putative functional germline variants. These results provide direct functional evidence for the influence of inherited genetic variation on ALL risk, highlighting the important and complex roles of CDKN2A-CDKN2B tumour suppressors in leukaemogenesis.

No MeSH data available.


Related in: MedlinePlus