TP53 germline variations influence the predisposition and prognosis of b-cell acute lymphoblastic leukemia in children

Maoxiang Qian, Xueyuan Cao, Meenakshi Devidas, Wenjian Yang, Cheng Cheng, Yunfeng Dai, Andrew Carroll, Nyla A. Heerema, Hui Zhang, Takaya Moriyama, Julie M. Gastier-Foster, Heng Xu, Elizabeth Raetz, Eric Larsen, Naomi Winick, W. Paul Bowman, Paul L. Martin, Elaine R. Mardis, Robert Fulton, Gerard Zambetti & 11 others Michael Borowitz, Brent Wood, Kim E. Nichols, William L. Carroll, Ching Hon Pui, Charles G. Mullighan, William E. Evans, Stephen P. Hunger, Mary V. Relling, Mignon L. Loh, Jun J. Yang

Research output: Contribution to journalArticle

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Abstract

Purpose Germline TP53 variation is the genetic basis of Li-Fraumeni syndrome, a highly penetrant cancer predisposition condition. Recent reports of germline TP53 variants in childhood hypodiploid acute lymphoblastic leukemia (ALL) suggest that this type of leukemia is another manifestation of Li- Fraumeni syndrome; however, the pattern, prevalence, and clinical relevance of TP53 variants in childhood ALL remain unknown. Patients and Methods Targeted sequencing of TP53 coding regions was performed in 3,801 children from the Children's Oncology Group frontline ALL clinical trials, AALL0232 and P9900. TP53 variant pathogenicity was evaluated according to experimentally determined transcriptional activity, in silico prediction of damaging effects, and prevalence in non-ALL control populations. TP53 variants were analyzed for their association with ALL presenting features and treatment outcomes. Results We identified 49 unique nonsilent rare TP53 coding variants in 77 (2.0%) of 3,801 patients sequenced, of which 22 variants were classified as pathogenic. TP53 pathogenic variants were significantly over-represented in ALL compared with non-ALL controls (odds ratio, 5.2; P , .001). Children with TP53 pathogenic variants were significantly older at ALL diagnosis (median age, 15.5 years v 7.3 years; P , .001) and were more likely to have hypodiploid ALL (65.4% v 1.2%; P , .001). Carrying germline TP53 pathogenic variants was associated with inferior event-free survival and overall survival (hazard ratio, 4.2 and 3.9; P , .001 and .001, respectively). In particular, children with TP53 pathogenic variants were at a dramatically higher risk of second cancers than those without pathogenic variants, with 5-year cumulative incidence of 25.1% and 0.7% (P , .001), respectively. Conclusion Loss-of-function germline TP53 variants predispose children to ALL and to adverse treatment outcomes with ALL therapy, particularly the risk of second malignant neoplasms.

Original languageEnglish (US)
Pages (from-to)591-599
Number of pages9
JournalJournal of Clinical Oncology
Volume36
Issue number6
DOIs
StatePublished - Feb 20 2018

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Precursor Cell Lymphoblastic Leukemia-Lymphoma
Li-Fraumeni Syndrome
Second Primary Neoplasms
Computer Simulation
Disease-Free Survival
Virulence
Leukemia
Odds Ratio
Clinical Trials
Survival
Incidence

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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TP53 germline variations influence the predisposition and prognosis of b-cell acute lymphoblastic leukemia in children. / Qian, Maoxiang; Cao, Xueyuan; Devidas, Meenakshi; Yang, Wenjian; Cheng, Cheng; Dai, Yunfeng; Carroll, Andrew; Heerema, Nyla A.; Zhang, Hui; Moriyama, Takaya; Gastier-Foster, Julie M.; Xu, Heng; Raetz, Elizabeth; Larsen, Eric; Winick, Naomi; Bowman, W. Paul; Martin, Paul L.; Mardis, Elaine R.; Fulton, Robert; Zambetti, Gerard; Borowitz, Michael; Wood, Brent; Nichols, Kim E.; Carroll, William L.; Pui, Ching Hon; Mullighan, Charles G.; Evans, William E.; Hunger, Stephen P.; Relling, Mary V.; Loh, Mignon L.; Yang, Jun J.

In: Journal of Clinical Oncology, Vol. 36, No. 6, 20.02.2018, p. 591-599.

Research output: Contribution to journalArticle

Qian, M, Cao, X, Devidas, M, Yang, W, Cheng, C, Dai, Y, Carroll, A, Heerema, NA, Zhang, H, Moriyama, T, Gastier-Foster, JM, Xu, H, Raetz, E, Larsen, E, Winick, N, Bowman, WP, Martin, PL, Mardis, ER, Fulton, R, Zambetti, G, Borowitz, M, Wood, B, Nichols, KE, Carroll, WL, Pui, CH, Mullighan, CG, Evans, WE, Hunger, SP, Relling, MV, Loh, ML & Yang, JJ 2018, 'TP53 germline variations influence the predisposition and prognosis of b-cell acute lymphoblastic leukemia in children', Journal of Clinical Oncology, vol. 36, no. 6, pp. 591-599. https://doi.org/10.1200/JCO.2017.75.5215
Qian, Maoxiang ; Cao, Xueyuan ; Devidas, Meenakshi ; Yang, Wenjian ; Cheng, Cheng ; Dai, Yunfeng ; Carroll, Andrew ; Heerema, Nyla A. ; Zhang, Hui ; Moriyama, Takaya ; Gastier-Foster, Julie M. ; Xu, Heng ; Raetz, Elizabeth ; Larsen, Eric ; Winick, Naomi ; Bowman, W. Paul ; Martin, Paul L. ; Mardis, Elaine R. ; Fulton, Robert ; Zambetti, Gerard ; Borowitz, Michael ; Wood, Brent ; Nichols, Kim E. ; Carroll, William L. ; Pui, Ching Hon ; Mullighan, Charles G. ; Evans, William E. ; Hunger, Stephen P. ; Relling, Mary V. ; Loh, Mignon L. ; Yang, Jun J. / TP53 germline variations influence the predisposition and prognosis of b-cell acute lymphoblastic leukemia in children. In: Journal of Clinical Oncology. 2018 ; Vol. 36, No. 6. pp. 591-599.
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title = "TP53 germline variations influence the predisposition and prognosis of b-cell acute lymphoblastic leukemia in children",
abstract = "Purpose Germline TP53 variation is the genetic basis of Li-Fraumeni syndrome, a highly penetrant cancer predisposition condition. Recent reports of germline TP53 variants in childhood hypodiploid acute lymphoblastic leukemia (ALL) suggest that this type of leukemia is another manifestation of Li- Fraumeni syndrome; however, the pattern, prevalence, and clinical relevance of TP53 variants in childhood ALL remain unknown. Patients and Methods Targeted sequencing of TP53 coding regions was performed in 3,801 children from the Children's Oncology Group frontline ALL clinical trials, AALL0232 and P9900. TP53 variant pathogenicity was evaluated according to experimentally determined transcriptional activity, in silico prediction of damaging effects, and prevalence in non-ALL control populations. TP53 variants were analyzed for their association with ALL presenting features and treatment outcomes. Results We identified 49 unique nonsilent rare TP53 coding variants in 77 (2.0{\%}) of 3,801 patients sequenced, of which 22 variants were classified as pathogenic. TP53 pathogenic variants were significantly over-represented in ALL compared with non-ALL controls (odds ratio, 5.2; P , .001). Children with TP53 pathogenic variants were significantly older at ALL diagnosis (median age, 15.5 years v 7.3 years; P , .001) and were more likely to have hypodiploid ALL (65.4{\%} v 1.2{\%}; P , .001). Carrying germline TP53 pathogenic variants was associated with inferior event-free survival and overall survival (hazard ratio, 4.2 and 3.9; P , .001 and .001, respectively). In particular, children with TP53 pathogenic variants were at a dramatically higher risk of second cancers than those without pathogenic variants, with 5-year cumulative incidence of 25.1{\%} and 0.7{\%} (P , .001), respectively. Conclusion Loss-of-function germline TP53 variants predispose children to ALL and to adverse treatment outcomes with ALL therapy, particularly the risk of second malignant neoplasms.",
author = "Maoxiang Qian and Xueyuan Cao and Meenakshi Devidas and Wenjian Yang and Cheng Cheng and Yunfeng Dai and Andrew Carroll and Heerema, {Nyla A.} and Hui Zhang and Takaya Moriyama and Gastier-Foster, {Julie M.} and Heng Xu and Elizabeth Raetz and Eric Larsen and Naomi Winick and Bowman, {W. Paul} and Martin, {Paul L.} and Mardis, {Elaine R.} and Robert Fulton and Gerard Zambetti and Michael Borowitz and Brent Wood and Nichols, {Kim E.} and Carroll, {William L.} and Pui, {Ching Hon} and Mullighan, {Charles G.} and Evans, {William E.} and Hunger, {Stephen P.} and Relling, {Mary V.} and Loh, {Mignon L.} and Yang, {Jun J.}",
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TY - JOUR

T1 - TP53 germline variations influence the predisposition and prognosis of b-cell acute lymphoblastic leukemia in children

AU - Qian, Maoxiang

AU - Cao, Xueyuan

AU - Devidas, Meenakshi

AU - Yang, Wenjian

AU - Cheng, Cheng

AU - Dai, Yunfeng

AU - Carroll, Andrew

AU - Heerema, Nyla A.

AU - Zhang, Hui

AU - Moriyama, Takaya

AU - Gastier-Foster, Julie M.

AU - Xu, Heng

AU - Raetz, Elizabeth

AU - Larsen, Eric

AU - Winick, Naomi

AU - Bowman, W. Paul

AU - Martin, Paul L.

AU - Mardis, Elaine R.

AU - Fulton, Robert

AU - Zambetti, Gerard

AU - Borowitz, Michael

AU - Wood, Brent

AU - Nichols, Kim E.

AU - Carroll, William L.

AU - Pui, Ching Hon

AU - Mullighan, Charles G.

AU - Evans, William E.

AU - Hunger, Stephen P.

AU - Relling, Mary V.

AU - Loh, Mignon L.

AU - Yang, Jun J.

PY - 2018/2/20

Y1 - 2018/2/20

N2 - Purpose Germline TP53 variation is the genetic basis of Li-Fraumeni syndrome, a highly penetrant cancer predisposition condition. Recent reports of germline TP53 variants in childhood hypodiploid acute lymphoblastic leukemia (ALL) suggest that this type of leukemia is another manifestation of Li- Fraumeni syndrome; however, the pattern, prevalence, and clinical relevance of TP53 variants in childhood ALL remain unknown. Patients and Methods Targeted sequencing of TP53 coding regions was performed in 3,801 children from the Children's Oncology Group frontline ALL clinical trials, AALL0232 and P9900. TP53 variant pathogenicity was evaluated according to experimentally determined transcriptional activity, in silico prediction of damaging effects, and prevalence in non-ALL control populations. TP53 variants were analyzed for their association with ALL presenting features and treatment outcomes. Results We identified 49 unique nonsilent rare TP53 coding variants in 77 (2.0%) of 3,801 patients sequenced, of which 22 variants were classified as pathogenic. TP53 pathogenic variants were significantly over-represented in ALL compared with non-ALL controls (odds ratio, 5.2; P , .001). Children with TP53 pathogenic variants were significantly older at ALL diagnosis (median age, 15.5 years v 7.3 years; P , .001) and were more likely to have hypodiploid ALL (65.4% v 1.2%; P , .001). Carrying germline TP53 pathogenic variants was associated with inferior event-free survival and overall survival (hazard ratio, 4.2 and 3.9; P , .001 and .001, respectively). In particular, children with TP53 pathogenic variants were at a dramatically higher risk of second cancers than those without pathogenic variants, with 5-year cumulative incidence of 25.1% and 0.7% (P , .001), respectively. Conclusion Loss-of-function germline TP53 variants predispose children to ALL and to adverse treatment outcomes with ALL therapy, particularly the risk of second malignant neoplasms.

AB - Purpose Germline TP53 variation is the genetic basis of Li-Fraumeni syndrome, a highly penetrant cancer predisposition condition. Recent reports of germline TP53 variants in childhood hypodiploid acute lymphoblastic leukemia (ALL) suggest that this type of leukemia is another manifestation of Li- Fraumeni syndrome; however, the pattern, prevalence, and clinical relevance of TP53 variants in childhood ALL remain unknown. Patients and Methods Targeted sequencing of TP53 coding regions was performed in 3,801 children from the Children's Oncology Group frontline ALL clinical trials, AALL0232 and P9900. TP53 variant pathogenicity was evaluated according to experimentally determined transcriptional activity, in silico prediction of damaging effects, and prevalence in non-ALL control populations. TP53 variants were analyzed for their association with ALL presenting features and treatment outcomes. Results We identified 49 unique nonsilent rare TP53 coding variants in 77 (2.0%) of 3,801 patients sequenced, of which 22 variants were classified as pathogenic. TP53 pathogenic variants were significantly over-represented in ALL compared with non-ALL controls (odds ratio, 5.2; P , .001). Children with TP53 pathogenic variants were significantly older at ALL diagnosis (median age, 15.5 years v 7.3 years; P , .001) and were more likely to have hypodiploid ALL (65.4% v 1.2%; P , .001). Carrying germline TP53 pathogenic variants was associated with inferior event-free survival and overall survival (hazard ratio, 4.2 and 3.9; P , .001 and .001, respectively). In particular, children with TP53 pathogenic variants were at a dramatically higher risk of second cancers than those without pathogenic variants, with 5-year cumulative incidence of 25.1% and 0.7% (P , .001), respectively. Conclusion Loss-of-function germline TP53 variants predispose children to ALL and to adverse treatment outcomes with ALL therapy, particularly the risk of second malignant neoplasms.

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U2 - 10.1200/JCO.2017.75.5215

DO - 10.1200/JCO.2017.75.5215

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EP - 599

JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

SN - 0732-183X

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