Epigenome-wide analysis across the development span of pediatric acute lymphoblastic leukemia: backtracking to birth

Akram Ghantous; Semira Gonseth Nussle; Farah J. Nassar; Natalia Spitz; Alexei Novoloaca; Olga Krali; Eric Nickels; Vincent Cahais; Cyrille Cuenin; Ritu Roy; Shaobo Li; Maxime Caron; Dilys Lam; Peter Daniel  Fransquet; John Casement; Gordon Strathdee; Mark S. Pearce; Helen M. Hansen; Hwi-Ho Lee; Young Sun  Lee; Adam J. de Smith; Daniel  Sinnett; Siri Eldevik Haberg; Jill A. McKay; Jessica Nordlund; Per Magnus; Terence Dwyer; Richard Saffery; Joseph Leo Wiemels; Monica Cheng Munthe-Kaas; Zdenko Herceg

doi:10.1186/s12943-024-02118-4

Epigenome-wide analysis across the development span of pediatric acute lymphoblastic leukemia: backtracking to birth

Akram Ghantous^*, Semira Gonseth Nussle, Farah J. Nassar, Natalia Spitz, Alexei Novoloaca, Olga Krali, Eric Nickels, Vincent Cahais, Cyrille Cuenin, Ritu Roy, Shaobo Li, Maxime Caron, Dilys Lam, Peter Daniel Fransquet, John Casement, Gordon Strathdee, Mark S. Pearce, Helen M. Hansen, Hwi-Ho Lee, Young Sun LeeAdam J. de Smith, Daniel Sinnett, Siri Eldevik Haberg, Jill A. McKay, Jessica Nordlund, Per Magnus, Terence Dwyer, Richard Saffery, Joseph Leo Wiemels, Monica Cheng Munthe-Kaas, Zdenko Herceg^*

^*Corresponding author for this work

Applied Sciences Department

Research output: Contribution to journal › Article › peer-review

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Abstract

Background

Cancer is the leading cause of disease-related mortality in children. Causes of leukemia, the most common form, are largely unknown. Growing evidence points to an origin in-utero, when global redistribution of DNA methylation occurs driving tissue differentiation.

Methods

Epigenome-wide DNA methylation was profiled in surrogate (blood) and target (bone marrow) tissues at birth, diagnosis, remission and relapse of pediatric pre-B acute lymphoblastic leukemia (pre-B ALL) patients. Double-blinded analyses was performed between prospective cohorts extending from birth to diagnosis and retrospective studies backtracking from clinical disease to birth. Validation was carried out using independent technologies and populations.

Results

The imprinted and immuno-modulating VTRNA2-1 was hypermethylated (FDR<0.05) at birth in nested cases relative to controls in all tested populations (totaling 317 cases and 483 controls), including European and Hispanic ancestries. VTRNA2-1 methylation was stable over follow-up years after birth and across surrogate, target and other tissues (n=5,023 tissues; 30 types). When profiled in leukemic tissues from two clinical cohorts (totaling 644 cases), VTRNA2-1 methylation exhibited higher levels at diagnosis relative to controls, it reset back to normal levels at remission, and then re-increased to above control levels at relapse. Hypermethylation was significantly associated with worse pre-B ALL patient survival and with reduced VTRNA2-1 expression (n=2,294 tissues; 26 types), supporting a functional and translational role for VTRNA2-1 methylation.

Conclusion

This study provides proof-of-concept to detect at birth epigenetic precursors of pediatric pre-B ALL. These alterations were reproducible with different technologies, in three continents and in two ethnicities, and can offer biomarkers for early detection and prognosis as well as actionable targets for therapy.

Original language	English
Article number	238
Number of pages	8
Journal	Molecular Cancer
Volume	23
Issue number	1
DOIs	https://doi.org/10.1186/s12943-024-02118-4
Publication status	Published - 23 Oct 2024

Keywords

Pediatric leukemia
epigenetics
DNA methylation
VTRNA2-1
birth cohort
neonatal bloods spots

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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s12943-024-02118-4Final published version, 2.14 MBLicence: CC BY-NC-ND

Cite this

Ghantous, A., Gonseth Nussle, S., Nassar, F. J., Spitz, N., Novoloaca, A., Krali, O., Nickels, E., Cahais, V., Cuenin, C., Roy, R., Li, S., Caron, M., Lam, D., Fransquet, P. D., Casement, J., Strathdee, G., Pearce, M. S., Hansen, H. M., Lee, H.-H., ... Herceg, Z. (2024). Epigenome-wide analysis across the development span of pediatric acute lymphoblastic leukemia: backtracking to birth. Molecular Cancer, 23(1), Article 238. https://doi.org/10.1186/s12943-024-02118-4

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title = "Epigenome-wide analysis across the development span of pediatric acute lymphoblastic leukemia: backtracking to birth",

abstract = "BackgroundCancer is the leading cause of disease-related mortality in children. Causes of leukemia, the most common form, are largely unknown. Growing evidence points to an origin in-utero, when global redistribution of DNA methylation occurs driving tissue differentiation.MethodsEpigenome-wide DNA methylation was profiled in surrogate (blood) and target (bone marrow) tissues at birth, diagnosis, remission and relapse of pediatric pre-B acute lymphoblastic leukemia (pre-B ALL) patients. Double-blinded analyses was performed between prospective cohorts extending from birth to diagnosis and retrospective studies backtracking from clinical disease to birth. Validation was carried out using independent technologies and populations.ResultsThe imprinted and immuno-modulating VTRNA2-1 was hypermethylated (FDR<0.05) at birth in nested cases relative to controls in all tested populations (totaling 317 cases and 483 controls), including European and Hispanic ancestries. VTRNA2-1 methylation was stable over follow-up years after birth and across surrogate, target and other tissues (n=5,023 tissues; 30 types). When profiled in leukemic tissues from two clinical cohorts (totaling 644 cases), VTRNA2-1 methylation exhibited higher levels at diagnosis relative to controls, it reset back to normal levels at remission, and then re-increased to above control levels at relapse. Hypermethylation was significantly associated with worse pre-B ALL patient survival and with reduced VTRNA2-1 expression (n=2,294 tissues; 26 types), supporting a functional and translational role for VTRNA2-1 methylation.ConclusionThis study provides proof-of-concept to detect at birth epigenetic precursors of pediatric pre-B ALL. These alterations were reproducible with different technologies, in three continents and in two ethnicities, and can offer biomarkers for early detection and prognosis as well as actionable targets for therapy.",

keywords = "Pediatric leukemia, epigenetics, DNA methylation, VTRNA2-1, birth cohort, neonatal bloods spots",

author = "Akram Ghantous and {Gonseth Nussle}, Semira and Nassar, {Farah J.} and Natalia Spitz and Alexei Novoloaca and Olga Krali and Eric Nickels and Vincent Cahais and Cyrille Cuenin and Ritu Roy and Shaobo Li and Maxime Caron and Dilys Lam and Fransquet, {Peter Daniel} and John Casement and Gordon Strathdee and Pearce, {Mark S.} and Hansen, {Helen M.} and Hwi-Ho Lee and Lee, {Young Sun} and {de Smith}, {Adam J.} and Daniel Sinnett and Haberg, {Siri Eldevik} and McKay, {Jill A.} and Jessica Nordlund and Per Magnus and Terence Dwyer and Richard Saffery and Wiemels, {Joseph Leo} and Munthe-Kaas, {Monica Cheng} and Zdenko Herceg",

year = "2024",

month = oct,

day = "23",

doi = "10.1186/s12943-024-02118-4",

language = "English",

volume = "23",

journal = "Molecular Cancer",

issn = "1476-4598",

publisher = "BioMed Central",

number = "1",

}

Ghantous, A, Gonseth Nussle, S, Nassar, FJ, Spitz, N, Novoloaca, A, Krali, O, Nickels, E, Cahais, V, Cuenin, C, Roy, R, Li, S, Caron, M, Lam, D, Fransquet, PD, Casement, J, Strathdee, G, Pearce, MS, Hansen, HM, Lee, H-H, Lee, YS, de Smith, AJ, Sinnett, D, Haberg, SE, McKay, JA, Nordlund, J, Magnus, P, Dwyer, T, Saffery, R, Wiemels, JL, Munthe-Kaas, MC & Herceg, Z 2024, 'Epigenome-wide analysis across the development span of pediatric acute lymphoblastic leukemia: backtracking to birth', Molecular Cancer, vol. 23, no. 1, 238. https://doi.org/10.1186/s12943-024-02118-4

TY - JOUR

T1 - Epigenome-wide analysis across the development span of pediatric acute lymphoblastic leukemia

T2 - backtracking to birth

AU - Ghantous, Akram

AU - Gonseth Nussle, Semira

AU - Nassar, Farah J.

AU - Spitz, Natalia

AU - Novoloaca, Alexei

AU - Krali, Olga

AU - Nickels, Eric

AU - Cahais, Vincent

AU - Cuenin, Cyrille

AU - Roy, Ritu

AU - Li, Shaobo

AU - Caron, Maxime

AU - Lam, Dilys

AU - Fransquet, Peter Daniel

AU - Casement, John

AU - Strathdee, Gordon

AU - Pearce, Mark S.

AU - Hansen, Helen M.

AU - Lee, Hwi-Ho

AU - Lee, Young Sun

AU - de Smith, Adam J.

AU - Sinnett, Daniel

AU - Haberg, Siri Eldevik

AU - McKay, Jill A.

AU - Nordlund, Jessica

AU - Magnus, Per

AU - Dwyer, Terence

AU - Saffery, Richard

AU - Wiemels, Joseph Leo

AU - Munthe-Kaas, Monica Cheng

AU - Herceg, Zdenko

PY - 2024/10/23

Y1 - 2024/10/23

N2 - BackgroundCancer is the leading cause of disease-related mortality in children. Causes of leukemia, the most common form, are largely unknown. Growing evidence points to an origin in-utero, when global redistribution of DNA methylation occurs driving tissue differentiation.MethodsEpigenome-wide DNA methylation was profiled in surrogate (blood) and target (bone marrow) tissues at birth, diagnosis, remission and relapse of pediatric pre-B acute lymphoblastic leukemia (pre-B ALL) patients. Double-blinded analyses was performed between prospective cohorts extending from birth to diagnosis and retrospective studies backtracking from clinical disease to birth. Validation was carried out using independent technologies and populations.ResultsThe imprinted and immuno-modulating VTRNA2-1 was hypermethylated (FDR<0.05) at birth in nested cases relative to controls in all tested populations (totaling 317 cases and 483 controls), including European and Hispanic ancestries. VTRNA2-1 methylation was stable over follow-up years after birth and across surrogate, target and other tissues (n=5,023 tissues; 30 types). When profiled in leukemic tissues from two clinical cohorts (totaling 644 cases), VTRNA2-1 methylation exhibited higher levels at diagnosis relative to controls, it reset back to normal levels at remission, and then re-increased to above control levels at relapse. Hypermethylation was significantly associated with worse pre-B ALL patient survival and with reduced VTRNA2-1 expression (n=2,294 tissues; 26 types), supporting a functional and translational role for VTRNA2-1 methylation.ConclusionThis study provides proof-of-concept to detect at birth epigenetic precursors of pediatric pre-B ALL. These alterations were reproducible with different technologies, in three continents and in two ethnicities, and can offer biomarkers for early detection and prognosis as well as actionable targets for therapy.

AB - BackgroundCancer is the leading cause of disease-related mortality in children. Causes of leukemia, the most common form, are largely unknown. Growing evidence points to an origin in-utero, when global redistribution of DNA methylation occurs driving tissue differentiation.MethodsEpigenome-wide DNA methylation was profiled in surrogate (blood) and target (bone marrow) tissues at birth, diagnosis, remission and relapse of pediatric pre-B acute lymphoblastic leukemia (pre-B ALL) patients. Double-blinded analyses was performed between prospective cohorts extending from birth to diagnosis and retrospective studies backtracking from clinical disease to birth. Validation was carried out using independent technologies and populations.ResultsThe imprinted and immuno-modulating VTRNA2-1 was hypermethylated (FDR<0.05) at birth in nested cases relative to controls in all tested populations (totaling 317 cases and 483 controls), including European and Hispanic ancestries. VTRNA2-1 methylation was stable over follow-up years after birth and across surrogate, target and other tissues (n=5,023 tissues; 30 types). When profiled in leukemic tissues from two clinical cohorts (totaling 644 cases), VTRNA2-1 methylation exhibited higher levels at diagnosis relative to controls, it reset back to normal levels at remission, and then re-increased to above control levels at relapse. Hypermethylation was significantly associated with worse pre-B ALL patient survival and with reduced VTRNA2-1 expression (n=2,294 tissues; 26 types), supporting a functional and translational role for VTRNA2-1 methylation.ConclusionThis study provides proof-of-concept to detect at birth epigenetic precursors of pediatric pre-B ALL. These alterations were reproducible with different technologies, in three continents and in two ethnicities, and can offer biomarkers for early detection and prognosis as well as actionable targets for therapy.

KW - Pediatric leukemia

KW - epigenetics

KW - DNA methylation

KW - VTRNA2-1

KW - birth cohort

KW - neonatal bloods spots

U2 - 10.1186/s12943-024-02118-4

DO - 10.1186/s12943-024-02118-4

M3 - Article

SN - 1476-4598

VL - 23

JO - Molecular Cancer

JF - Molecular Cancer

IS - 1

M1 - 238

ER -