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Cited by 1,345BRCA gene mutations in cancerCancer Genomics and DiagnosticsGenomics and Rare Diseases

The DOI matches its Crossref record; 54 of the 56 references it cites were found in a registry or an index.

Germline Mutations in Predisposition Genes in Pediatric Cancer

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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., Hines-Dowell, Stacy, 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.·2015·New England Journal of Medicine
DOI 10.1056/nejmoa1508054PMC PMC4734119
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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 cancer-predisposition syndromes, for the presence of germline mutations. The pathogenicity of the mutations was determined by a panel of medical experts with the use of cancer-specific 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. (Funded by the American Lebanese Syrian Associated Charities and the National Cancer Institute.).

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  1. Lindor NM, 2008, J Natl Cancer Inst Monogr, 1
  2. Meldrum C, 2011, Clin Biochem Rev, 32, 177
  3. Armes JE, 1999, Cancer Res, 59, 2011

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Metadata

Authors
Zhang, J., Walsh, M. F., Wu, G., Edmonson, M. N., Gruber, T. A., Easton, J., Hedges, D., Ma, X., Zhou, X., Yergeau, D. A., Wilkinson, M. R., Vadodaria, B., Chen, X., McGee, R. B., Hines-Dowell, S., Nuccio, R., Quinn, E., Shurtleff, S. A., Rusch, M., Patel, A., Becksfort, J. B., Wang, S., Weaver, M. S., Ding, L., Mardis, E. R., Wilson, R. K., Gajjar, A., Ellison, D. W., Pappo, A. S., Pui, C.-H., Nichols, K. E., & Downing, J. R.
Affiliations
  • St. Jude Children's Research Hospital (US)
  • Washington University in St. Louis (US)
ORCID
Venue
New England Journal of Medicine
Publisher
Massachusetts Medical Society
Published
2015-12-10
Volume
373
Issue
24
Pages
2336-2346
ISSN
  • 0028-4793 (ISSN-L)
  • 1533-4406
DOI
10.1056/nejmoa1508054
PMC
PMC4734119
OpenAlex
W2303408208
Cited by
1,345
References
56
Citations by year
2026: 90 · 2025: 113 · 2024: 151 · 2023: 132 · 2022: 134 · 2021: 161 · 2020: 141 · 2019: 122 · 2018: 113 · 2017: 101 · 2016: 76 · 2015: 5
FWCI
67.59
Type
journal article
Language
en
Open access
Locations
  • New England Journal of Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
Funders
  • St. Jude Children's Research Hospital (CA21765)
  • American Lebanese Syrian Associated Charities (CA 21765)
  • National Cancer Institute (R01CA180006, CA21765, P30CA021765)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
Keywords
germline mutations, cancer susceptibility genes, childhood cancer, children and adolescents, TP53, APC, BRCA2, neurofibromatosis type 1, PMS2, RB1, RUNX1, tumor suppressor, pathogenicity assessment, family history of cancer, genetic counseling, autism spectrum disorder
MeSH terms
Adolescent, Autistic Disorder, Child, Female, Genes, Dominant, Humans, Male, Neoplasms, Genome, Human, Sequence Analysis, DNA, Germ-Line Mutation, SEER Program, Genetic Predisposition to Disease, Genes, Neoplasm, Young Adult

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