Germline genetic variation in ETV6 and risk of childhood acute lymphoblastic leukaemia

A systematic genetic study

Takaya Moriyama, Monika L. Metzger, Gang Wu, Rina Nishii, Maoxiang Qian, Meenakshi Devidas, Wenjian Yang, Cheng Cheng, Xueyuan Cao, Emily Quinn, Susana Raimondi, Julie M. Gastier-Foster, Elizabeth Raetz, Eric Larsen, Paul L. Martin, W. Paul Bowman, Naomi Winick, Yoshihiro Komada, Shuoguo Wang, Michael Edmonson & 12 others Heng Xu, Elaine Mardis, Robert Fulton, Ching Hon Pui, Charles Mullighan, William E. Evans, Jinghui Zhang, Stephen P. Hunger, Mary V. Relling, Kim E. Nichols, Mignon L. Loh, Jun J. Yang

Research output: Contribution to journalArticle

61 Citations (Scopus)

Abstract

Background: Hereditary predisposition is rarely suspected for childhood acute lymphoblastic leukaemia (ALL). Recent reports of germline ETV6 variations associated with substantial familial clustering of haematological malignancies indicated that this gene is a potentially important genetic determinant for ALL susceptibility. Our aims in this study were to comprehensively identify ALL predisposition variants in ETV6 and to determine the extent to which they contributed to the overall risk of childhood ALL. Methods: Whole-exome sequencing of an index family with several cases of ALL was done to identify causal variants for ALL predisposition. Targeted sequencing of ETV6 was done in children from the Children's Oncology Group and St Jude Children's Research Hospital front-line ALL trials. Patients were included in this study on the basis of their enrolment in these clinical trials and the availability of germline DNA. ETV6 variant genotypes were compared with non-ALL controls to define ALL-related germline risk variants. ETV6 variant function was characterised bioinformatically and correlated with clinical and demographic features in children with ALL. Findings: We identified a novel non-sense ETV6 variant (p.Arg359X) with a high penetrance in an index family. Subsequent targeted sequencing of ETV6 in 4405 childhood ALL cases identified 31 exonic variants (four non-sense, 21 missense, one splice site, and five frameshift variants) that were potentially related to ALL risk in 35 cases (1%). 15 (48%) of 31 ALL-related ETV6 variants clustered in the erythroblast transformation specific domain and were predicted to be highly deleterious. Children with ALL-related ETV6 variants were significantly older at leukaemia diagnosis than those without (10·2 years [IQR 5·3-13·8] vs 4·7 years [3·0-8·7]; p=0·017). The hyperdiploid leukaemia karyotype was highly over-represented in ALL cases harbouring germline ETV6 risk variants compared with the wild-type group (nine [64%] of 14 cases vs 538 [27%] of 2007 cases; p=0·0050). Interpretation: Our findings indicated germline ETV6 variations as the basis of a novel genetic syndrome associated with predisposition to childhood ALL. The development of recommendations for clinical interventions and surveillance for individuals harbouring ALL-related ETV6 variants are needed. Funding: US National Institutes of Health and American Lebanese Syrian Associated Charities.

Original languageEnglish (US)
Pages (from-to)1659-1666
Number of pages8
JournalThe Lancet Oncology
Volume16
Issue number16
DOIs
StatePublished - Jan 1 2015

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Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia
Exome
Charities
Erythroblasts
Polyploidy
Penetrance
National Institutes of Health (U.S.)
Hematologic Neoplasms
Karyotype
Cluster Analysis

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

Moriyama, T., Metzger, M. L., Wu, G., Nishii, R., Qian, M., Devidas, M., ... Yang, J. J. (2015). Germline genetic variation in ETV6 and risk of childhood acute lymphoblastic leukaemia: A systematic genetic study. The Lancet Oncology, 16(16), 1659-1666. https://doi.org/10.1016/S1470-2045(15)00369-1

Germline genetic variation in ETV6 and risk of childhood acute lymphoblastic leukaemia : A systematic genetic study. / Moriyama, Takaya; Metzger, Monika L.; Wu, Gang; Nishii, Rina; Qian, Maoxiang; Devidas, Meenakshi; Yang, Wenjian; Cheng, Cheng; Cao, Xueyuan; Quinn, Emily; Raimondi, Susana; Gastier-Foster, Julie M.; Raetz, Elizabeth; Larsen, Eric; Martin, Paul L.; Bowman, W. Paul; Winick, Naomi; Komada, Yoshihiro; Wang, Shuoguo; Edmonson, Michael; Xu, Heng; Mardis, Elaine; Fulton, Robert; Pui, Ching Hon; Mullighan, Charles; Evans, William E.; Zhang, Jinghui; Hunger, Stephen P.; Relling, Mary V.; Nichols, Kim E.; Loh, Mignon L.; Yang, Jun J.

In: The Lancet Oncology, Vol. 16, No. 16, 01.01.2015, p. 1659-1666.

Research output: Contribution to journalArticle

Moriyama, T, Metzger, ML, Wu, G, Nishii, R, Qian, M, Devidas, M, Yang, W, Cheng, C, Cao, X, Quinn, E, Raimondi, S, Gastier-Foster, JM, Raetz, E, Larsen, E, Martin, PL, Bowman, WP, Winick, N, Komada, Y, Wang, S, Edmonson, M, Xu, H, Mardis, E, Fulton, R, Pui, CH, Mullighan, C, Evans, WE, Zhang, J, Hunger, SP, Relling, MV, Nichols, KE, Loh, ML & Yang, JJ 2015, 'Germline genetic variation in ETV6 and risk of childhood acute lymphoblastic leukaemia: A systematic genetic study', The Lancet Oncology, vol. 16, no. 16, pp. 1659-1666. https://doi.org/10.1016/S1470-2045(15)00369-1
Moriyama, Takaya ; Metzger, Monika L. ; Wu, Gang ; Nishii, Rina ; Qian, Maoxiang ; Devidas, Meenakshi ; Yang, Wenjian ; Cheng, Cheng ; Cao, Xueyuan ; Quinn, Emily ; Raimondi, Susana ; Gastier-Foster, Julie M. ; Raetz, Elizabeth ; Larsen, Eric ; Martin, Paul L. ; Bowman, W. Paul ; Winick, Naomi ; Komada, Yoshihiro ; Wang, Shuoguo ; Edmonson, Michael ; Xu, Heng ; Mardis, Elaine ; Fulton, Robert ; Pui, Ching Hon ; Mullighan, Charles ; Evans, William E. ; Zhang, Jinghui ; Hunger, Stephen P. ; Relling, Mary V. ; Nichols, Kim E. ; Loh, Mignon L. ; Yang, Jun J. / Germline genetic variation in ETV6 and risk of childhood acute lymphoblastic leukaemia : A systematic genetic study. In: The Lancet Oncology. 2015 ; Vol. 16, No. 16. pp. 1659-1666.
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abstract = "Background: Hereditary predisposition is rarely suspected for childhood acute lymphoblastic leukaemia (ALL). Recent reports of germline ETV6 variations associated with substantial familial clustering of haematological malignancies indicated that this gene is a potentially important genetic determinant for ALL susceptibility. Our aims in this study were to comprehensively identify ALL predisposition variants in ETV6 and to determine the extent to which they contributed to the overall risk of childhood ALL. Methods: Whole-exome sequencing of an index family with several cases of ALL was done to identify causal variants for ALL predisposition. Targeted sequencing of ETV6 was done in children from the Children's Oncology Group and St Jude Children's Research Hospital front-line ALL trials. Patients were included in this study on the basis of their enrolment in these clinical trials and the availability of germline DNA. ETV6 variant genotypes were compared with non-ALL controls to define ALL-related germline risk variants. ETV6 variant function was characterised bioinformatically and correlated with clinical and demographic features in children with ALL. Findings: We identified a novel non-sense ETV6 variant (p.Arg359X) with a high penetrance in an index family. Subsequent targeted sequencing of ETV6 in 4405 childhood ALL cases identified 31 exonic variants (four non-sense, 21 missense, one splice site, and five frameshift variants) that were potentially related to ALL risk in 35 cases (1{\%}). 15 (48{\%}) of 31 ALL-related ETV6 variants clustered in the erythroblast transformation specific domain and were predicted to be highly deleterious. Children with ALL-related ETV6 variants were significantly older at leukaemia diagnosis than those without (10·2 years [IQR 5·3-13·8] vs 4·7 years [3·0-8·7]; p=0·017). The hyperdiploid leukaemia karyotype was highly over-represented in ALL cases harbouring germline ETV6 risk variants compared with the wild-type group (nine [64{\%}] of 14 cases vs 538 [27{\%}] of 2007 cases; p=0·0050). Interpretation: Our findings indicated germline ETV6 variations as the basis of a novel genetic syndrome associated with predisposition to childhood ALL. The development of recommendations for clinical interventions and surveillance for individuals harbouring ALL-related ETV6 variants are needed. Funding: US National Institutes of Health and American Lebanese Syrian Associated Charities.",
author = "Takaya Moriyama and Metzger, {Monika L.} and Gang Wu and Rina Nishii and Maoxiang Qian and Meenakshi Devidas and Wenjian Yang and Cheng Cheng and Xueyuan Cao and Emily Quinn and Susana Raimondi and Gastier-Foster, {Julie M.} and Elizabeth Raetz and Eric Larsen and Martin, {Paul L.} and Bowman, {W. Paul} and Naomi Winick and Yoshihiro Komada and Shuoguo Wang and Michael Edmonson and Heng Xu and Elaine Mardis and Robert Fulton and Pui, {Ching Hon} and Charles Mullighan and Evans, {William E.} and Jinghui Zhang and Hunger, {Stephen P.} and Relling, {Mary V.} and Nichols, {Kim E.} and Loh, {Mignon L.} and Yang, {Jun J.}",
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TY - JOUR

T1 - Germline genetic variation in ETV6 and risk of childhood acute lymphoblastic leukaemia

T2 - A systematic genetic study

AU - Moriyama, Takaya

AU - Metzger, Monika L.

AU - Wu, Gang

AU - Nishii, Rina

AU - Qian, Maoxiang

AU - Devidas, Meenakshi

AU - Yang, Wenjian

AU - Cheng, Cheng

AU - Cao, Xueyuan

AU - Quinn, Emily

AU - Raimondi, Susana

AU - Gastier-Foster, Julie M.

AU - Raetz, Elizabeth

AU - Larsen, Eric

AU - Martin, Paul L.

AU - Bowman, W. Paul

AU - Winick, Naomi

AU - Komada, Yoshihiro

AU - Wang, Shuoguo

AU - Edmonson, Michael

AU - Xu, Heng

AU - Mardis, Elaine

AU - Fulton, Robert

AU - Pui, Ching Hon

AU - Mullighan, Charles

AU - Evans, William E.

AU - Zhang, Jinghui

AU - Hunger, Stephen P.

AU - Relling, Mary V.

AU - Nichols, Kim E.

AU - Loh, Mignon L.

AU - Yang, Jun J.

PY - 2015/1/1

Y1 - 2015/1/1

N2 - Background: Hereditary predisposition is rarely suspected for childhood acute lymphoblastic leukaemia (ALL). Recent reports of germline ETV6 variations associated with substantial familial clustering of haematological malignancies indicated that this gene is a potentially important genetic determinant for ALL susceptibility. Our aims in this study were to comprehensively identify ALL predisposition variants in ETV6 and to determine the extent to which they contributed to the overall risk of childhood ALL. Methods: Whole-exome sequencing of an index family with several cases of ALL was done to identify causal variants for ALL predisposition. Targeted sequencing of ETV6 was done in children from the Children's Oncology Group and St Jude Children's Research Hospital front-line ALL trials. Patients were included in this study on the basis of their enrolment in these clinical trials and the availability of germline DNA. ETV6 variant genotypes were compared with non-ALL controls to define ALL-related germline risk variants. ETV6 variant function was characterised bioinformatically and correlated with clinical and demographic features in children with ALL. Findings: We identified a novel non-sense ETV6 variant (p.Arg359X) with a high penetrance in an index family. Subsequent targeted sequencing of ETV6 in 4405 childhood ALL cases identified 31 exonic variants (four non-sense, 21 missense, one splice site, and five frameshift variants) that were potentially related to ALL risk in 35 cases (1%). 15 (48%) of 31 ALL-related ETV6 variants clustered in the erythroblast transformation specific domain and were predicted to be highly deleterious. Children with ALL-related ETV6 variants were significantly older at leukaemia diagnosis than those without (10·2 years [IQR 5·3-13·8] vs 4·7 years [3·0-8·7]; p=0·017). The hyperdiploid leukaemia karyotype was highly over-represented in ALL cases harbouring germline ETV6 risk variants compared with the wild-type group (nine [64%] of 14 cases vs 538 [27%] of 2007 cases; p=0·0050). Interpretation: Our findings indicated germline ETV6 variations as the basis of a novel genetic syndrome associated with predisposition to childhood ALL. The development of recommendations for clinical interventions and surveillance for individuals harbouring ALL-related ETV6 variants are needed. Funding: US National Institutes of Health and American Lebanese Syrian Associated Charities.

AB - Background: Hereditary predisposition is rarely suspected for childhood acute lymphoblastic leukaemia (ALL). Recent reports of germline ETV6 variations associated with substantial familial clustering of haematological malignancies indicated that this gene is a potentially important genetic determinant for ALL susceptibility. Our aims in this study were to comprehensively identify ALL predisposition variants in ETV6 and to determine the extent to which they contributed to the overall risk of childhood ALL. Methods: Whole-exome sequencing of an index family with several cases of ALL was done to identify causal variants for ALL predisposition. Targeted sequencing of ETV6 was done in children from the Children's Oncology Group and St Jude Children's Research Hospital front-line ALL trials. Patients were included in this study on the basis of their enrolment in these clinical trials and the availability of germline DNA. ETV6 variant genotypes were compared with non-ALL controls to define ALL-related germline risk variants. ETV6 variant function was characterised bioinformatically and correlated with clinical and demographic features in children with ALL. Findings: We identified a novel non-sense ETV6 variant (p.Arg359X) with a high penetrance in an index family. Subsequent targeted sequencing of ETV6 in 4405 childhood ALL cases identified 31 exonic variants (four non-sense, 21 missense, one splice site, and five frameshift variants) that were potentially related to ALL risk in 35 cases (1%). 15 (48%) of 31 ALL-related ETV6 variants clustered in the erythroblast transformation specific domain and were predicted to be highly deleterious. Children with ALL-related ETV6 variants were significantly older at leukaemia diagnosis than those without (10·2 years [IQR 5·3-13·8] vs 4·7 years [3·0-8·7]; p=0·017). The hyperdiploid leukaemia karyotype was highly over-represented in ALL cases harbouring germline ETV6 risk variants compared with the wild-type group (nine [64%] of 14 cases vs 538 [27%] of 2007 cases; p=0·0050). Interpretation: Our findings indicated germline ETV6 variations as the basis of a novel genetic syndrome associated with predisposition to childhood ALL. The development of recommendations for clinical interventions and surveillance for individuals harbouring ALL-related ETV6 variants are needed. Funding: US National Institutes of Health and American Lebanese Syrian Associated Charities.

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