Whole genome, transcriptome and methylome profiling enhances actionable target discovery in high-risk pediatric cancer

Marie Wong; Chelsea Mayoh; Loretta M.S. Lau; Dong Anh Khuong-Quang; Mark Pinese; Amit Kumar; Paulette Barahona; Emilie E. Wilkie; Patricia Sullivan; Rachel Bowen-James; Mustafa Syed; Iñigo Martincorena; Federico Abascal; Alexandra Sherstyuk; Noemi A. Bolanos; Jonathan Baber; Peter Priestley; M. Emmy M. Dolman; Emmy D.G. Fleuren; Marie Emilie Gauthier; Emily V.A. Mould; Velimir Gayevskiy; Andrew J. Gifford; Dylan Grebert-Wade; Patrick A. Strong; Elodie Manouvrier; Meera Warby; David M. Thomas; Judy Kirk; Katherine Tucker; Tracey O’Brien; Frank Alvaro; Geoffry B. McCowage; Luciano Dalla-Pozza; Nicholas G. Gottardo; Heather Tapp; Paul Wood; Seong Lin Khaw; Jordan R. Hansford; Andrew S. Moore; Murray D. Norris; Toby N. Trahair; Richard B. Lock; Vanessa Tyrrell; Michelle Haber; Glenn M. Marshall; David S. Ziegler; Paul G. Ekert; Mark J. Cowley

doi:10.1038/s41591-020-1072-4

Whole genome, transcriptome and methylome profiling enhances actionable target discovery in high-risk pediatric cancer

Marie Wong, Chelsea Mayoh, Loretta M.S. Lau, Dong Anh Khuong-Quang, Mark Pinese, Amit Kumar, Paulette Barahona, Emilie E. Wilkie, Patricia Sullivan, Rachel Bowen-James, Mustafa Syed, Iñigo Martincorena, Federico Abascal, Alexandra Sherstyuk, Noemi A. Bolanos, Jonathan Baber, Peter Priestley, M. Emmy M. Dolman, Emmy D.G. Fleuren, Marie Emilie GauthierEmily V.A. Mould, Velimir Gayevskiy, Andrew J. Gifford, Dylan Grebert-Wade, Patrick A. Strong, Elodie Manouvrier, Meera Warby, David M. Thomas, Judy Kirk, Katherine Tucker, Tracey O’Brien, Frank Alvaro, Geoffry B. McCowage, Luciano Dalla-Pozza, Nicholas G. Gottardo, Heather Tapp, Paul Wood, Seong Lin Khaw, Jordan R. Hansford, Andrew S. Moore, Murray D. Norris, Toby N. Trahair, Richard B. Lock, Vanessa Tyrrell, Michelle Haber, Glenn M. Marshall, David S. Ziegler, Paul G. Ekert, Mark J. Cowley

UWA Centre for Child Health Research (affiliated with the The Kids Research Institute Australia)

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

238 Citations (Scopus)

Abstract

The Zero Childhood Cancer Program is a precision medicine program to benefit children with poor-outcome, rare, relapsed or refractory cancer. Using tumor and germline whole genome sequencing (WGS) and RNA sequencing (RNAseq) across 252 tumors from high-risk pediatric patients with cancer, we identified 968 reportable molecular aberrations (39.9% in WGS and RNAseq, 35.1% in WGS only and 25.0% in RNAseq only). Of these patients, 93.7% had at least one germline or somatic aberration, 71.4% had therapeutic targets and 5.2% had a change in diagnosis. WGS identified pathogenic cancer-predisposing variants in 16.2% of patients. In 76 central nervous system tumors, methylome analysis confirmed diagnosis in 71.1% of patients and contributed to a change of diagnosis in two patients (2.6%). To date, 43 patients have received a recommended therapy, 38 of whom could be evaluated, with 31% showing objective evidence of clinical benefit. Comprehensive molecular profiling resolved the molecular basis of virtually all high-risk cancers, leading to clinical benefit in some patients.

Original language	English
Pages (from-to)	1742-1753
Number of pages	12
Journal	Nature Medicine
Volume	26
Issue number	11
DOIs	https://doi.org/10.1038/s41591-020-1072-4
Publication status	Published - Nov 2020

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Wong, M., Mayoh, C., Lau, L. M. S., Khuong-Quang, D. A., Pinese, M., Kumar, A., Barahona, P., Wilkie, E. E., Sullivan, P., Bowen-James, R., Syed, M., Martincorena, I., Abascal, F., Sherstyuk, A., Bolanos, N. A., Baber, J., Priestley, P., Dolman, M. E. M., Fleuren, E. D. G., ... Cowley, M. J. (2020). Whole genome, transcriptome and methylome profiling enhances actionable target discovery in high-risk pediatric cancer. Nature Medicine, 26(11), 1742-1753. https://doi.org/10.1038/s41591-020-1072-4

@article{48e0aecf9b9b4e80ad6ae9d139be7f37,

title = "Whole genome, transcriptome and methylome profiling enhances actionable target discovery in high-risk pediatric cancer",

abstract = "The Zero Childhood Cancer Program is a precision medicine program to benefit children with poor-outcome, rare, relapsed or refractory cancer. Using tumor and germline whole genome sequencing (WGS) and RNA sequencing (RNAseq) across 252 tumors from high-risk pediatric patients with cancer, we identified 968 reportable molecular aberrations (39.9% in WGS and RNAseq, 35.1% in WGS only and 25.0% in RNAseq only). Of these patients, 93.7% had at least one germline or somatic aberration, 71.4% had therapeutic targets and 5.2% had a change in diagnosis. WGS identified pathogenic cancer-predisposing variants in 16.2% of patients. In 76 central nervous system tumors, methylome analysis confirmed diagnosis in 71.1% of patients and contributed to a change of diagnosis in two patients (2.6%). To date, 43 patients have received a recommended therapy, 38 of whom could be evaluated, with 31% showing objective evidence of clinical benefit. Comprehensive molecular profiling resolved the molecular basis of virtually all high-risk cancers, leading to clinical benefit in some patients.",

author = "Marie Wong and Chelsea Mayoh and Lau, {Loretta M.S.} and Khuong-Quang, {Dong Anh} and Mark Pinese and Amit Kumar and Paulette Barahona and Wilkie, {Emilie E.} and Patricia Sullivan and Rachel Bowen-James and Mustafa Syed and I{\~n}igo Martincorena and Federico Abascal and Alexandra Sherstyuk and Bolanos, {Noemi A.} and Jonathan Baber and Peter Priestley and Dolman, {M. Emmy M.} and Fleuren, {Emmy D.G.} and Gauthier, {Marie Emilie} and Mould, {Emily V.A.} and Velimir Gayevskiy and Gifford, {Andrew J.} and Dylan Grebert-Wade and Strong, {Patrick A.} and Elodie Manouvrier and Meera Warby and Thomas, {David M.} and Judy Kirk and Katherine Tucker and Tracey O{\textquoteright}Brien and Frank Alvaro and McCowage, {Geoffry B.} and Luciano Dalla-Pozza and Gottardo, {Nicholas G.} and Heather Tapp and Paul Wood and Khaw, {Seong Lin} and Hansford, {Jordan R.} and Moore, {Andrew S.} and Norris, {Murray D.} and Trahair, {Toby N.} and Lock, {Richard B.} and Vanessa Tyrrell and Michelle Haber and Marshall, {Glenn M.} and Ziegler, {David S.} and Ekert, {Paul G.} and Cowley, {Mark J.}",

year = "2020",

month = nov,

doi = "10.1038/s41591-020-1072-4",

language = "English",

volume = "26",

pages = "1742--1753",

journal = "Nature Medicine",

issn = "1078-8956",

publisher = "Nature Publishing Group - Macmillan Publishers",

number = "11",

}

Wong, M, Mayoh, C, Lau, LMS, Khuong-Quang, DA, Pinese, M, Kumar, A, Barahona, P, Wilkie, EE, Sullivan, P, Bowen-James, R, Syed, M, Martincorena, I, Abascal, F, Sherstyuk, A, Bolanos, NA, Baber, J, Priestley, P, Dolman, MEM, Fleuren, EDG, Gauthier, ME, Mould, EVA, Gayevskiy, V, Gifford, AJ, Grebert-Wade, D, Strong, PA, Manouvrier, E, Warby, M, Thomas, DM, Kirk, J, Tucker, K, O’Brien, T, Alvaro, F, McCowage, GB, Dalla-Pozza, L, Gottardo, NG, Tapp, H, Wood, P, Khaw, SL, Hansford, JR, Moore, AS, Norris, MD, Trahair, TN, Lock, RB, Tyrrell, V, Haber, M, Marshall, GM, Ziegler, DS, Ekert, PG & Cowley, MJ 2020, 'Whole genome, transcriptome and methylome profiling enhances actionable target discovery in high-risk pediatric cancer', Nature Medicine, vol. 26, no. 11, pp. 1742-1753. https://doi.org/10.1038/s41591-020-1072-4

TY - JOUR

T1 - Whole genome, transcriptome and methylome profiling enhances actionable target discovery in high-risk pediatric cancer

AU - Wong, Marie

AU - Mayoh, Chelsea

AU - Lau, Loretta M.S.

AU - Khuong-Quang, Dong Anh

AU - Pinese, Mark

AU - Kumar, Amit

AU - Barahona, Paulette

AU - Wilkie, Emilie E.

AU - Sullivan, Patricia

AU - Bowen-James, Rachel

AU - Syed, Mustafa

AU - Martincorena, Iñigo

AU - Abascal, Federico

AU - Sherstyuk, Alexandra

AU - Bolanos, Noemi A.

AU - Baber, Jonathan

AU - Priestley, Peter

AU - Dolman, M. Emmy M.

AU - Fleuren, Emmy D.G.

AU - Gauthier, Marie Emilie

AU - Mould, Emily V.A.

AU - Gayevskiy, Velimir

AU - Gifford, Andrew J.

AU - Grebert-Wade, Dylan

AU - Strong, Patrick A.

AU - Manouvrier, Elodie

AU - Warby, Meera

AU - Thomas, David M.

AU - Kirk, Judy

AU - Tucker, Katherine

AU - O’Brien, Tracey

AU - Alvaro, Frank

AU - McCowage, Geoffry B.

AU - Dalla-Pozza, Luciano

AU - Gottardo, Nicholas G.

AU - Tapp, Heather

AU - Wood, Paul

AU - Khaw, Seong Lin

AU - Hansford, Jordan R.

AU - Moore, Andrew S.

AU - Norris, Murray D.

AU - Trahair, Toby N.

AU - Lock, Richard B.

AU - Tyrrell, Vanessa

AU - Haber, Michelle

AU - Marshall, Glenn M.

AU - Ziegler, David S.

AU - Ekert, Paul G.

AU - Cowley, Mark J.

PY - 2020/11

Y1 - 2020/11

N2 - The Zero Childhood Cancer Program is a precision medicine program to benefit children with poor-outcome, rare, relapsed or refractory cancer. Using tumor and germline whole genome sequencing (WGS) and RNA sequencing (RNAseq) across 252 tumors from high-risk pediatric patients with cancer, we identified 968 reportable molecular aberrations (39.9% in WGS and RNAseq, 35.1% in WGS only and 25.0% in RNAseq only). Of these patients, 93.7% had at least one germline or somatic aberration, 71.4% had therapeutic targets and 5.2% had a change in diagnosis. WGS identified pathogenic cancer-predisposing variants in 16.2% of patients. In 76 central nervous system tumors, methylome analysis confirmed diagnosis in 71.1% of patients and contributed to a change of diagnosis in two patients (2.6%). To date, 43 patients have received a recommended therapy, 38 of whom could be evaluated, with 31% showing objective evidence of clinical benefit. Comprehensive molecular profiling resolved the molecular basis of virtually all high-risk cancers, leading to clinical benefit in some patients.

AB - The Zero Childhood Cancer Program is a precision medicine program to benefit children with poor-outcome, rare, relapsed or refractory cancer. Using tumor and germline whole genome sequencing (WGS) and RNA sequencing (RNAseq) across 252 tumors from high-risk pediatric patients with cancer, we identified 968 reportable molecular aberrations (39.9% in WGS and RNAseq, 35.1% in WGS only and 25.0% in RNAseq only). Of these patients, 93.7% had at least one germline or somatic aberration, 71.4% had therapeutic targets and 5.2% had a change in diagnosis. WGS identified pathogenic cancer-predisposing variants in 16.2% of patients. In 76 central nervous system tumors, methylome analysis confirmed diagnosis in 71.1% of patients and contributed to a change of diagnosis in two patients (2.6%). To date, 43 patients have received a recommended therapy, 38 of whom could be evaluated, with 31% showing objective evidence of clinical benefit. Comprehensive molecular profiling resolved the molecular basis of virtually all high-risk cancers, leading to clinical benefit in some patients.

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U2 - 10.1038/s41591-020-1072-4

DO - 10.1038/s41591-020-1072-4

M3 - Article

C2 - 33020650

AN - SCOPUS:85092107957

SN - 1078-8956

VL - 26

SP - 1742

EP - 1753

JO - Nature Medicine

JF - Nature Medicine

IS - 11

ER -

Whole genome, transcriptome and methylome profiling enhances actionable target discovery in high-risk pediatric cancer

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