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Low-frequency variation near common germline susceptibility loci are associated with risk of Ewing sarcoma.

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  • معلومة اضافية
    • المصدر:
      Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: eCollection Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE
    • بيانات النشر:
      Original Publication: San Francisco, CA : Public Library of Science
    • الموضوع:
      Genetic Loci* ; Genetic Predisposition to Disease* ; Genetic Variation*; Germ Cells/*metabolism ; Sarcoma, Ewing/*genetics; Genome-Wide Association Study ; Humans ; Linkage Disequilibrium/genetics ; Odds Ratio ; Polymorphism, Single Nucleotide/genetics
    • نبذة مختصرة :
      Background: Ewing sarcoma (EwS) is a rare, aggressive solid tumor of childhood, adolescence and young adulthood associated with pathognomonic EWSR1-ETS fusion oncoproteins altering transcriptional regulation. Genome-wide association studies (GWAS) have identified 6 common germline susceptibility loci but have not investigated low-frequency inherited variants with minor allele frequencies below 5% due to limited genotyped cases of this rare tumor.
      Methods: We investigated the contribution of rare and low-frequency variation to EwS susceptibility in the largest EwS genome-wide association study to date (733 EwS cases and 1,346 unaffected controls of European ancestry).
      Results: We identified two low-frequency variants, rs112837127 and rs2296730, on chromosome 20 that were associated with EwS risk (OR = 0.186 and 2.038, respectively; P-value < 5×10-8) and located near previously reported common susceptibility loci. After adjusting for the most associated common variant at the locus, only rs112837127 remained a statistically significant independent signal (OR = 0.200, P-value = 5.84×10-8).
      Conclusions: These findings suggest rare variation residing on common haplotypes are important contributors to EwS risk.
      Impact: Motivate future targeted sequencing studies for a comprehensive evaluation of low-frequency and rare variation around common EwS susceptibility loci.
      Competing Interests: The authors have read the journal's policy and the authors of this manuscript have the following competing interests: Leidos Biomedical Research Inc. and Information Management Services, Inc. provided salaries for authors J.M., E.K., C.L.D., L.B., K.J., M.M., K.W., and W.Z. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products to declare.
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    • Grant Information:
      U24 CA055727 United States CA NCI NIH HHS
    • الموضوع:
      Date Created: 20200904 Date Completed: 20201020 Latest Revision: 20220728
    • الموضوع:
      20240628
    • الرقم المعرف:
      PMC7470401
    • الرقم المعرف:
      10.1371/journal.pone.0237792
    • الرقم المعرف:
      32881892