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Somatic TP53 variants frequently confound germ-line testing results.

Jeffrey N Weitzel1, Elizabeth C Chao2,3, Bita Nehoray4

  • 1Division of Clinical Cancer Genomics, City of Hope, Duarte, California, USA. jweitzel@coh.org.

Genetics in Medicine : Official Journal of the American College of Medical Genetics
|December 1, 2017
PubMed
Summary

Acquired clonal expansions (ACEs) with TP53 variants can be mistaken for germline mutations, complicating cancer risk assessment. Ancillary testing is crucial to differentiate ACE from true germline status before managing Li-Fraumeni syndrome.

Keywords:
Li-Fraumeni syndromeTP53aberrant clonal expansionclonal hematopoiesissomatic variant

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Area of Science:

  • Genetics
  • Oncology
  • Molecular Diagnostics

Background:

  • Germline DNA from blood or saliva is standard for cancer risk assessment.
  • Pathogenic TP53 variants detected via multigene panels can be discordant with Li-Fraumeni syndrome diagnoses.
  • This discordance raises concerns about acquired aberrant clonal expansions (ACEs) being misinterpreted as germline results.

Discussion:

  • This study analyzed TP53 variants with abnormal next-generation sequencing metrics from a CLIA laboratory.
  • Ancillary testing on alternate tissues or relatives was used to distinguish ACE from germline status.
  • Clinical data and Li-Fraumeni syndrome criteria were reviewed.

Key Insights:

  • Abnormal sequencing metrics were found in 20% of TP53-positive results, with 91% confirmed as ACE, often due to clonal hematopoiesis.
  • Individuals with ACE were older (50 vs. 33.7 years) and more frequently identified through multigene panel testing (23.2%) than TP53-specific tests (8.8%).
  • Only four cases met Chompret criteria for Li-Fraumeni syndrome.

Outlook:

  • ACE can interfere with accurate germline diagnosis and may indicate an increased risk of hematologic malignancy.
  • Unwarranted clinical interventions may result from misinterpreting ACE as a germline finding.
  • Confirming germline status through ancillary testing is essential before initiating Li-Fraumeni syndrome management.