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Advances in Diagnosis and Management of TP53 Associated Cancer Risk: Germline and Somatic Insights

13 Mar 2024
Venue: MTCC
Meeting Room: 718
Cancer Genetics and Therapeutics
  • Accredited:
    • Accredited
  • Primary Categories:
    • Cancer
  • Secondary Categories:
    • Cancer
  • Level of Learner:
    • Intermediate
Pathogenic (and likely pathogenic) TP53 gene variants (PVs) underlie Li-Fraumeni Syndrome (LFS), a rare inherited cancer susceptibility syndrome. Although LFS has been recognized for over 50 years, many questions about germline TP53 PV-associated disease remain unanswered, including variant prevalence, penetrance and the spectrum of the phenotype. Although classic LFS includes predisposition to multiple and diverse primary neoplasms, the major associations include sarcoma, brain, lung, breast, adrenocortical, multiple primary and other cancers at unusually early ages, although almost any cancer type has been observed. Lifetime cancer risks have been reported between 70- 100%, depending on sex. Compared to ascertainment based on TP53 testing criteria, more agnostic ascertainment of cancer risk, for example through next generation sequencing (NGS) multi-gene panel testing (MGPT), often leads to identification of PVs in individuals and families who share limited features with classic LFS, raising questions about established penetrance estimates. As MGPT, WES/WGS become increasingly prevalent, single gene testing outside of cascade testing will become progressively rarer, so that cohorts identified through those testing approaches will soon include the entire penetrance spectrum of TP53-associated disease including classic LFS.  Innovation in tools and rules for variant curation has also proved challenging, with frequent missense PVs and recognition of hypomorphs.

Recognition of acquired PVs, usually associated with clonal hematopoiesis (CH) point out the importance of discerning true germline/constitutional PVs (including post-zygotic mosaicism of one or more embryonic layers: “true mosaicism”) from entirely somatic acquired events that may or may not be associated with the development of neoplasia.

There is increasing evidence from studies of TP53 carriers and of other inherited cancer-predisposing genes such as BRCA1, that allelic variation and other genetic loci affect cancer risks. Analysis by variant type (loss of function [LOF], dominant negative [DN], other) and data from TP53 locus architecture in tumors is helping to uncover biologic insights.  Ultimately, advances will allow us to better estimate individual cancer risks and provide more power to individualize risk prediction. Demonstrated efficacy of intensive surveillance provide immediate clinical implications for clarifying risks. Advances in cell-free/plasma DNA analyses have revolutionized non-invasive prenatal testing, and lead to tools for ‘liquid biopsy’, molecular residual disease detection, and multi-cancer early detection (MCED).  With such pleomorphic cancer risks, the setting of LFS has the greatest need and perhaps the most challenging test for MCED assays.  Paired tumor and germline analyses are also illuminating how TP53 PVs may affect cellular processes, with implications about the potential clinical impact therapies on future cancer risks.

Learning Objectives

  1. Explain how to distinguish the clinical and molecular features of LFS and TP53-associated cancer risk
  2. Increase diagnostic competence by discerning somatic and germline TP53 PVs
  3. Recognize how consortia and international databases are illuminating genotype-phenotype correlations
  4. Discuss the data shifting the paradigm from LFS to TP53-associated diseases
  5. Apply state of the art clinico-genomic evidence to the challenges of TP53 variant curation
  6. Identify emerging and evolving ctDNA and imaging approaches to cancer surveillance
  7. Interpret how genomics and international collaboration represent a paradigm to address rare hereditary cancer disorders

Agenda

  • Jeffrey N.. Weitzel, MD, FACMG
    Moderator
    4:00 PM – 4:00 PM
  • Sharon A. Savage, MD
    Defining a New Paradigm of TP53-Associated Disease: Leveraging Consortia, Databases and Advocacy
    4:00 PM – 4:15 PM
  • Huma Q. Rana, MD, MPH, FACMG
    Defining a New Paradigm of TP53-Associated Disease: Stratifying Ascertainment and Commercial Laboratory Collaboration to Illustrate Differences in Age-Specific Penetrance and Expressivity
    4:15 PM – 4:30 PM
  • Jeffrey N.. Weitzel, MD, FACMG
    Know Before you Go: Clonal Hematopoiesis and Mosaicism Revealed by a Multi-Tissue Analysis of Constitutional TP53 Status
    4:30 PM – 4:45 PM
  • Kara N. Maxwell, MD, PhD
    Presenting Evidence and Wrangling Committees: Evolving TP53/LFS Diagnostic (Variant Curation) and Management
    4:45 PM – 5:00 PM
  • David Malkin, MD, FRCPC, FRSC
    Leveraging Historical Lessons from LFS Discovery to State-of-the Art Imaging, Molecular Tools and Priorities for Research
    5:00 PM – 5:15 PM
  • Panel Discussion
    Panel Discussion and Q&A
    5:15 PM – 5:30 PM

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