Germline mutations in predisposition genes in pediatric cancer

Jinghui Zhang, Michael F. Walsh, Gang Wu, Michael N. Edmonson, Tanja A. Gruber, John Easton, Dale Hedges, Xiaotu Ma, Xin Zhou, Donald A. Yergeau, Mark R. Wilkinson, Bhavin Vadodaria, Xiang Chen, Rose B. McGee, Stacy Hines Dowell, Regina Nuccio, Emily Quinn, Sheila A. Shurtleff, Michael Rusch, Aman Patel & 12 others Jared B. Becksfort, Shuoguo Wang, Meaghann S Weaver, Li Ding, Elaine R. Mardis, Richard K. Wilson, Amar Gajjar, David W. Ellison, Alberto S. Pappo, Ching Hon Pui, Kim E. Nichols, James R. Downing

Research output: Contribution to journalArticle

294 Citations (Scopus)

Abstract

BACKGROUND The prevalence and spectrum of predisposing mutations among children and adolescents with cancer are largely unknown. Knowledge of such mutations may improve the understanding of tumorigenesis, direct patient care, and enable genetic counseling of patients and families. METHODS In 1120 patients younger than 20 years of age, we sequenced the whole genomes (in 595 patients), whole exomes (in 456), or both (in 69). We analyzed the DNA sequences of 565 genes, including 60 that have been associated with autosomal dominant cancerpredisposition syndromes, for the presence of germline mutations. The pathogenicity of the mutations was determined by a panel of medical experts with the use of cancerspecific and locus-specific genetic databases, the medical literature, computational predictions, and second hits identified in the tumor genome. The same approach was used to analyze data from 966 persons who did not have known cancer in the 1000 Genomes Project, and a similar approach was used to analyze data from an autism study (from 515 persons with autism and 208 persons without autism). RESULTS Mutations that were deemed to be pathogenic or probably pathogenic were identified in 95 patients with cancer (8.5%), as compared with 1.1% of the persons in the 1000 Genomes Project and 0.6% of the participants in the autism study. The most commonly mutated genes in the affected patients were TP53 (in 50 patients), APC (in 6), BRCA2 (in 6), NF1 (in 4), PMS2 (in 4), RB1 (in 3), and RUNX1 (in 3). A total of 18 additional patients had protein-truncating mutations in tumor-suppressor genes. Of the 58 patients with a predisposing mutation and available information on family history, 23 (40%) had a family history of cancer. CONCLUSIONS Germline mutations in cancer-predisposing genes were identified in 8.5% of the children and adolescents with cancer. Family history did not predict the presence of an underlying predisposition syndrome in most patients.

Original languageEnglish (US)
Pages (from-to)2336-2346
Number of pages11
JournalNew England Journal of Medicine
Volume373
Issue number24
DOIs
StatePublished - Dec 10 2015

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Germ-Line Mutation
Pediatrics
Autistic Disorder
Genes
Neoplasms
Mutation
Genome
Exome
Genetic Databases
Neoplasm Genes
Genetic Counseling
Tumor Suppressor Genes
Virulence
Patient Care
Carcinogenesis

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Zhang, J., Walsh, M. F., Wu, G., Edmonson, M. N., Gruber, T. A., Easton, J., ... Downing, J. R. (2015). Germline mutations in predisposition genes in pediatric cancer. New England Journal of Medicine, 373(24), 2336-2346. https://doi.org/10.1056/NEJMoa1508054

Germline mutations in predisposition genes in pediatric cancer. / Zhang, Jinghui; Walsh, Michael F.; Wu, Gang; Edmonson, Michael N.; Gruber, Tanja A.; Easton, John; Hedges, Dale; Ma, Xiaotu; Zhou, Xin; Yergeau, Donald A.; Wilkinson, Mark R.; Vadodaria, Bhavin; Chen, Xiang; McGee, Rose B.; Dowell, Stacy Hines; Nuccio, Regina; Quinn, Emily; Shurtleff, Sheila A.; Rusch, Michael; Patel, Aman; Becksfort, Jared B.; Wang, Shuoguo; Weaver, Meaghann S; Ding, Li; Mardis, Elaine R.; Wilson, Richard K.; Gajjar, Amar; Ellison, David W.; Pappo, Alberto S.; Pui, Ching Hon; Nichols, Kim E.; Downing, James R.

In: New England Journal of Medicine, Vol. 373, No. 24, 10.12.2015, p. 2336-2346.

Research output: Contribution to journalArticle

Zhang, J, Walsh, MF, Wu, G, Edmonson, MN, Gruber, TA, Easton, J, Hedges, D, Ma, X, Zhou, X, Yergeau, DA, Wilkinson, MR, Vadodaria, B, Chen, X, McGee, RB, Dowell, SH, Nuccio, R, Quinn, E, Shurtleff, SA, Rusch, M, Patel, A, Becksfort, JB, Wang, S, Weaver, MS, Ding, L, Mardis, ER, Wilson, RK, Gajjar, A, Ellison, DW, Pappo, AS, Pui, CH, Nichols, KE & Downing, JR 2015, 'Germline mutations in predisposition genes in pediatric cancer', New England Journal of Medicine, vol. 373, no. 24, pp. 2336-2346. https://doi.org/10.1056/NEJMoa1508054
Zhang J, Walsh MF, Wu G, Edmonson MN, Gruber TA, Easton J et al. Germline mutations in predisposition genes in pediatric cancer. New England Journal of Medicine. 2015 Dec 10;373(24):2336-2346. https://doi.org/10.1056/NEJMoa1508054
Zhang, Jinghui ; Walsh, Michael F. ; Wu, Gang ; Edmonson, Michael N. ; Gruber, Tanja A. ; Easton, John ; Hedges, Dale ; Ma, Xiaotu ; Zhou, Xin ; Yergeau, Donald A. ; Wilkinson, Mark R. ; Vadodaria, Bhavin ; Chen, Xiang ; McGee, Rose B. ; Dowell, Stacy Hines ; Nuccio, Regina ; Quinn, Emily ; Shurtleff, Sheila A. ; Rusch, Michael ; Patel, Aman ; Becksfort, Jared B. ; Wang, Shuoguo ; Weaver, Meaghann S ; Ding, Li ; Mardis, Elaine R. ; Wilson, Richard K. ; Gajjar, Amar ; Ellison, David W. ; Pappo, Alberto S. ; Pui, Ching Hon ; Nichols, Kim E. ; Downing, James R. / Germline mutations in predisposition genes in pediatric cancer. In: New England Journal of Medicine. 2015 ; Vol. 373, No. 24. pp. 2336-2346.
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title = "Germline mutations in predisposition genes in pediatric cancer",
abstract = "BACKGROUND The prevalence and spectrum of predisposing mutations among children and adolescents with cancer are largely unknown. Knowledge of such mutations may improve the understanding of tumorigenesis, direct patient care, and enable genetic counseling of patients and families. METHODS In 1120 patients younger than 20 years of age, we sequenced the whole genomes (in 595 patients), whole exomes (in 456), or both (in 69). We analyzed the DNA sequences of 565 genes, including 60 that have been associated with autosomal dominant cancerpredisposition syndromes, for the presence of germline mutations. The pathogenicity of the mutations was determined by a panel of medical experts with the use of cancerspecific and locus-specific genetic databases, the medical literature, computational predictions, and second hits identified in the tumor genome. The same approach was used to analyze data from 966 persons who did not have known cancer in the 1000 Genomes Project, and a similar approach was used to analyze data from an autism study (from 515 persons with autism and 208 persons without autism). RESULTS Mutations that were deemed to be pathogenic or probably pathogenic were identified in 95 patients with cancer (8.5{\%}), as compared with 1.1{\%} of the persons in the 1000 Genomes Project and 0.6{\%} of the participants in the autism study. The most commonly mutated genes in the affected patients were TP53 (in 50 patients), APC (in 6), BRCA2 (in 6), NF1 (in 4), PMS2 (in 4), RB1 (in 3), and RUNX1 (in 3). A total of 18 additional patients had protein-truncating mutations in tumor-suppressor genes. Of the 58 patients with a predisposing mutation and available information on family history, 23 (40{\%}) had a family history of cancer. CONCLUSIONS Germline mutations in cancer-predisposing genes were identified in 8.5{\%} of the children and adolescents with cancer. Family history did not predict the presence of an underlying predisposition syndrome in most patients.",
author = "Jinghui Zhang and Walsh, {Michael F.} and Gang Wu and Edmonson, {Michael N.} and Gruber, {Tanja A.} and John Easton and Dale Hedges and Xiaotu Ma and Xin Zhou and Yergeau, {Donald A.} and Wilkinson, {Mark R.} and Bhavin Vadodaria and Xiang Chen and McGee, {Rose B.} and Dowell, {Stacy Hines} and Regina Nuccio and Emily Quinn and Shurtleff, {Sheila A.} and Michael Rusch and Aman Patel and Becksfort, {Jared B.} and Shuoguo Wang and Weaver, {Meaghann S} and Li Ding and Mardis, {Elaine R.} and Wilson, {Richard K.} and Amar Gajjar and Ellison, {David W.} and Pappo, {Alberto S.} and Pui, {Ching Hon} and Nichols, {Kim E.} and Downing, {James R.}",
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T1 - Germline mutations in predisposition genes in pediatric cancer

AU - Zhang, Jinghui

AU - Walsh, Michael F.

AU - Wu, Gang

AU - Edmonson, Michael N.

AU - Gruber, Tanja A.

AU - Easton, John

AU - Hedges, Dale

AU - Ma, Xiaotu

AU - Zhou, Xin

AU - Yergeau, Donald A.

AU - Wilkinson, Mark R.

AU - Vadodaria, Bhavin

AU - Chen, Xiang

AU - McGee, Rose B.

AU - Dowell, Stacy Hines

AU - Nuccio, Regina

AU - Quinn, Emily

AU - Shurtleff, Sheila A.

AU - Rusch, Michael

AU - Patel, Aman

AU - Becksfort, Jared B.

AU - Wang, Shuoguo

AU - Weaver, Meaghann S

AU - Ding, Li

AU - Mardis, Elaine R.

AU - Wilson, Richard K.

AU - Gajjar, Amar

AU - Ellison, David W.

AU - Pappo, Alberto S.

AU - Pui, Ching Hon

AU - Nichols, Kim E.

AU - Downing, James R.

PY - 2015/12/10

Y1 - 2015/12/10

N2 - BACKGROUND The prevalence and spectrum of predisposing mutations among children and adolescents with cancer are largely unknown. Knowledge of such mutations may improve the understanding of tumorigenesis, direct patient care, and enable genetic counseling of patients and families. METHODS In 1120 patients younger than 20 years of age, we sequenced the whole genomes (in 595 patients), whole exomes (in 456), or both (in 69). We analyzed the DNA sequences of 565 genes, including 60 that have been associated with autosomal dominant cancerpredisposition syndromes, for the presence of germline mutations. The pathogenicity of the mutations was determined by a panel of medical experts with the use of cancerspecific and locus-specific genetic databases, the medical literature, computational predictions, and second hits identified in the tumor genome. The same approach was used to analyze data from 966 persons who did not have known cancer in the 1000 Genomes Project, and a similar approach was used to analyze data from an autism study (from 515 persons with autism and 208 persons without autism). RESULTS Mutations that were deemed to be pathogenic or probably pathogenic were identified in 95 patients with cancer (8.5%), as compared with 1.1% of the persons in the 1000 Genomes Project and 0.6% of the participants in the autism study. The most commonly mutated genes in the affected patients were TP53 (in 50 patients), APC (in 6), BRCA2 (in 6), NF1 (in 4), PMS2 (in 4), RB1 (in 3), and RUNX1 (in 3). A total of 18 additional patients had protein-truncating mutations in tumor-suppressor genes. Of the 58 patients with a predisposing mutation and available information on family history, 23 (40%) had a family history of cancer. CONCLUSIONS Germline mutations in cancer-predisposing genes were identified in 8.5% of the children and adolescents with cancer. Family history did not predict the presence of an underlying predisposition syndrome in most patients.

AB - BACKGROUND The prevalence and spectrum of predisposing mutations among children and adolescents with cancer are largely unknown. Knowledge of such mutations may improve the understanding of tumorigenesis, direct patient care, and enable genetic counseling of patients and families. METHODS In 1120 patients younger than 20 years of age, we sequenced the whole genomes (in 595 patients), whole exomes (in 456), or both (in 69). We analyzed the DNA sequences of 565 genes, including 60 that have been associated with autosomal dominant cancerpredisposition syndromes, for the presence of germline mutations. The pathogenicity of the mutations was determined by a panel of medical experts with the use of cancerspecific and locus-specific genetic databases, the medical literature, computational predictions, and second hits identified in the tumor genome. The same approach was used to analyze data from 966 persons who did not have known cancer in the 1000 Genomes Project, and a similar approach was used to analyze data from an autism study (from 515 persons with autism and 208 persons without autism). RESULTS Mutations that were deemed to be pathogenic or probably pathogenic were identified in 95 patients with cancer (8.5%), as compared with 1.1% of the persons in the 1000 Genomes Project and 0.6% of the participants in the autism study. The most commonly mutated genes in the affected patients were TP53 (in 50 patients), APC (in 6), BRCA2 (in 6), NF1 (in 4), PMS2 (in 4), RB1 (in 3), and RUNX1 (in 3). A total of 18 additional patients had protein-truncating mutations in tumor-suppressor genes. Of the 58 patients with a predisposing mutation and available information on family history, 23 (40%) had a family history of cancer. CONCLUSIONS Germline mutations in cancer-predisposing genes were identified in 8.5% of the children and adolescents with cancer. Family history did not predict the presence of an underlying predisposition syndrome in most patients.

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