Limits...
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

Targeted resequencing of CDKN2A–CDKN2B locus identified additional germline coding variants in children with ALL.CDKN2A and CDKN2B genes were sequenced using Illumina HiSeq platform following capture-based enrichment of this genomic region in 2,407 ALL cases of European descent. Variants in non-ALL controls were based on publicly available data from the individuals of European descent within the NHLBI Exome Sequencing Project (N=4,300). Exonic variants are classified as silent or missense (grey or purple solid circles) and are mapped to three distinct open reading frames at this locus: p16INK4A, p14ARF and p15INK4B, for ALL cases (red vertical lines) and non-ALL controls (blue vertical lines), and functional domains are indicated by colour based on Pfam annotation. Each circle represents a unique individual carrying the indicated variant (heterozygous or homozygous), except for variants recurring in more than 10 individuals for which the number in the circle indicates the exact frequency of the observed variant.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4544058&req=5

f3: Targeted resequencing of CDKN2A–CDKN2B locus identified additional germline coding variants in children with ALL.CDKN2A and CDKN2B genes were sequenced using Illumina HiSeq platform following capture-based enrichment of this genomic region in 2,407 ALL cases of European descent. Variants in non-ALL controls were based on publicly available data from the individuals of European descent within the NHLBI Exome Sequencing Project (N=4,300). Exonic variants are classified as silent or missense (grey or purple solid circles) and are mapped to three distinct open reading frames at this locus: p16INK4A, p14ARF and p15INK4B, for ALL cases (red vertical lines) and non-ALL controls (blue vertical lines), and functional domains are indicated by colour based on Pfam annotation. Each circle represents a unique individual carrying the indicated variant (heterozygous or homozygous), except for variants recurring in more than 10 individuals for which the number in the circle indicates the exact frequency of the observed variant.

Mentions: To comprehensively identify putative functional ALL susceptibility variants at this locus, we resequenced the coding region of the CDKN2A and CDKN2B genes in germline DNA from 2,407 childhood ALL cases (1,450 of which were also included in the discovery GWAS). In addition to rs3731249, we observed another 13 germline exonic variants in tumour suppressors p16INK4A and p14ARF encoded by the CDKN2A gene, 12 of which result in amino-acid sequence changes (Fig. 3, Supplementary Table 3). These missense variants were all singletons, except for the p.D125H variant in p16INK4A and the p.A121T variant in p14ARF observed in two and five cases, respectively. Five variants were predicted to be damaging based on combined annotation dependent depletion23 (CADD score>13, Supplementary Table 3), and we did not observe germline insertions or deletions in CDKN2A in our ALL cohort. Comparing with 4,300 European American individuals from the NHLBI GO Exome Sequencing Project (ESP), there was a trend for a higher burden of rare missense variants in relative to controls the CDKN2A gene (p16INK4A and p14ARF) in children with ALL (0.71% versus 0.23%, P=0.0045, Fisher's exact test, Fig. 3). In addition, we identified six germline-coding variants in the adjacent CDKN2B gene in this cohort of children with ALL, although there was no significant over-representation compared with European controls in the ESP cohort (0.83% versus 0.79%, Fig. 3).


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)

Targeted resequencing of CDKN2A–CDKN2B locus identified additional germline coding variants in children with ALL.CDKN2A and CDKN2B genes were sequenced using Illumina HiSeq platform following capture-based enrichment of this genomic region in 2,407 ALL cases of European descent. Variants in non-ALL controls were based on publicly available data from the individuals of European descent within the NHLBI Exome Sequencing Project (N=4,300). Exonic variants are classified as silent or missense (grey or purple solid circles) and are mapped to three distinct open reading frames at this locus: p16INK4A, p14ARF and p15INK4B, for ALL cases (red vertical lines) and non-ALL controls (blue vertical lines), and functional domains are indicated by colour based on Pfam annotation. Each circle represents a unique individual carrying the indicated variant (heterozygous or homozygous), except for variants recurring in more than 10 individuals for which the number in the circle indicates the exact frequency of the observed variant.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f3: Targeted resequencing of CDKN2A–CDKN2B locus identified additional germline coding variants in children with ALL.CDKN2A and CDKN2B genes were sequenced using Illumina HiSeq platform following capture-based enrichment of this genomic region in 2,407 ALL cases of European descent. Variants in non-ALL controls were based on publicly available data from the individuals of European descent within the NHLBI Exome Sequencing Project (N=4,300). Exonic variants are classified as silent or missense (grey or purple solid circles) and are mapped to three distinct open reading frames at this locus: p16INK4A, p14ARF and p15INK4B, for ALL cases (red vertical lines) and non-ALL controls (blue vertical lines), and functional domains are indicated by colour based on Pfam annotation. Each circle represents a unique individual carrying the indicated variant (heterozygous or homozygous), except for variants recurring in more than 10 individuals for which the number in the circle indicates the exact frequency of the observed variant.
Mentions: To comprehensively identify putative functional ALL susceptibility variants at this locus, we resequenced the coding region of the CDKN2A and CDKN2B genes in germline DNA from 2,407 childhood ALL cases (1,450 of which were also included in the discovery GWAS). In addition to rs3731249, we observed another 13 germline exonic variants in tumour suppressors p16INK4A and p14ARF encoded by the CDKN2A gene, 12 of which result in amino-acid sequence changes (Fig. 3, Supplementary Table 3). These missense variants were all singletons, except for the p.D125H variant in p16INK4A and the p.A121T variant in p14ARF observed in two and five cases, respectively. Five variants were predicted to be damaging based on combined annotation dependent depletion23 (CADD score>13, Supplementary Table 3), and we did not observe germline insertions or deletions in CDKN2A in our ALL cohort. Comparing with 4,300 European American individuals from the NHLBI GO Exome Sequencing Project (ESP), there was a trend for a higher burden of rare missense variants in relative to controls the CDKN2A gene (p16INK4A and p14ARF) in children with ALL (0.71% versus 0.23%, P=0.0045, Fisher's exact test, Fig. 3). In addition, we identified six germline-coding variants in the adjacent CDKN2B gene in this cohort of children with ALL, although there was no significant over-representation compared with European controls in the ESP cohort (0.83% versus 0.79%, Fig. 3).

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