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Frequency of Pathogenic Germline Variants in Cancer-Susceptibility Genes in the Childhood Cancer Survivor Study

  1. Author:
    Kim, Jung
    Gianferante, Matthew
    Karyadi, Danielle M.
    Hartley, Stephen W.
    Frone, Megan N.
    Luo,Wen
    Robison, Leslie L.
    Armstrong, Gregory T.
    Bhatia, Smita
    Dean,Michael
    Yeager,Meredith
    Zhu,Bin
    Song, Lei
    Sampson, Joshua N.
    Yasui, Yutaka
    Leisenring, Wendy M.
    Brodie,Seth
    de Andrade, Kelvin C.
    Fortes, Fernanda P.
    Goldstein, Alisa M.
    Khincha, Payal P.
    Machiela, Mitchell J.
    McMaster, Mary L.
    Nickerson, Michael L.
    Oba, Leatrisse
    Pemov, Alexander
    Pinheiro, Maisa
    Rotunno, Melissa
    Santiago, Karina
    Wegman-Ostrosky, Talia
    Diver, W. Ryan
    Teras, Lauren
    Freedman, Neal D.
    Hicks,Belynda
    Wang,Mingyi
    Jones,Kristine
    Hutchinson,Amy
    Dagnall,Casey
    Savage, Sharon A.
    Tucker, Margaret A.
    Chanock, Stephen J.
    Morton, Lindsay M.
    Stewart, Douglas R.
    Mirabello, Lisa

  2. Author Address

    NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA.Frederick Natl Lab Canc Res, Canc Genom Res Lab, Frederick, MD USA.St Jude Childrens Res Hosp, Dept Epidemiol & Canc Control, 332 N Lauderdale St, Memphis, TN 38105 USA.Univ Alabama Birmingham, Inst Canc Outcomes & Survivorship, Birmingham, AL USA.Fred Hutchinson Canc Res Ctr, Canc Prevent Program, 1124 Columbia St, Seattle, WA 98104 USA.Fred Hutchinson Canc Res Ctr, Clin Stat Program, 1124 Columbia St, Seattle, WA 98104 USA.AC Camargo Canc Ctr, Int Res Ctr, Sao Paulo, Brazil.NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA.Inst Nacl Cancerol INCan, Basic Res Subdirect, Mexico City, DF, Mexico.Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA.
    1. Year: 2021
    2. Date: Apr
    3. Epub Date: 2021 01 23
  2. Journal: JNCI cancer spectrum
  3. OXFORD UNIV PRESS,
    1. 5
    2. 2
  5. Type of Article: Article
  6. Article Number: pkab007
  7. ISSN: 2515-5091
  1. Abstract:

    Background: Pediatric cancers are the leading cause of death by disease in children despite improved survival rates overall. The contribution of germline genetic susceptibility to pediatric cancer survivors has not been extensively characterized. We assessed the frequency of pathogenic or likely pathogenic (P/LP) variants in 5451 long-term pediatric cancer survivors from the Childhood Cancer Survivor Study. Methods: Exome sequencing was conducted on germline DNA from 5451 pediatric cancer survivors (cases who survived >= 5 years from diagnosis; n = 5105 European) and 597 European cancer-free adults (controls). Analyses focused on comparing the frequency of rare P/LP variants in 237 cancer-susceptibility genes and a subset of 60 autosomal dominant high-to-moderate penetrance genes, for both case-case and case-control comparisons. Results: Of European cases, 4.1% harbored a P/LP variant in high-to-moderate penetrance autosomal dominant genes compared with 1.3% in controls (2-sided P = 3 x 10(-4)). The highest frequency of P/LP variants was in genes typically associated with adult onset rather than pediatric cancers, including BRCA1/2, FH, PALB2, PMS2, and CDKN2A. A statistically significant excess of P/LP variants, after correction for multiple tests, was detected in patients with central nervous system cancers (NF1, SUFU, TSC1, PTCH2), Wilms tumor (WT1, REST), non-Hodgkin lymphoma (PMS2), and soft tissue sarcomas (SDHB, DICER1, TP53, ERCC4, FGFR3) compared with other pediatric cancers. Conclusion: In long-term pediatric cancer survivors, we identified P/LP variants in cancer-susceptibility genes not previously associated with pediatric cancer as well as confirmed known associations. Further characterization of variants in these genes in pediatric cancer will be important to provide optimal genetic counseling for patients and their families.

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External Sources

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  2. DOI: 10.1093/jncics/pkab007
  3. PMID: 34308104
  4. PMCID: PMC8023430
  5. View record in Web of Science®
  6. WOS: 000661527500004

Library Notes

  1. Fiscal Year: FY2020-2021
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