||1R01CA242218-01 Interpret this number
||Beckman Research Institute/City Of Hope
||Precision Approaches to Refining Tp53-Associated Cancer Risk
Pathogenic TP53 gene variants underlie 70% of Li-Fraumeni Syndrome (LFS), a hereditary cancer syndrome
classically associated with predisposition to multiple primary neoplasms, particularly sarcoma, brain, breast,
adrenocortical and other malignancies at unusually early ages. Traditionally, clinical TP53 testing was limited to
individuals and families who met specific criteria. With the introduction of NGS-based multi-gene panel testing
(MGPT), TP53 testing is now being performed on large numbers of people who do not meet LFS criteria. Broader
MGPT testing for TP53 mutations has raised concerns about:1) a broader phenotypic spectrum for mutation
carriers; and 2) the clinical relevance of TP53 variants identified in blood or saliva with allele frequencies below
the 50% expected frequency for a germline carrier. We demonstrated that aberrant clonal expansions (ACE) of
hematopoietic cells (clonal hematopoiesis CH) with an acquired pathogenic TP53 variant is responsible for many
such cases. ACE/CH, which is observed at increasing frequency with advancing age in healthy populations, and
after exposure to chemotherapy in cancer survivors, has been associated with increased risk of hematologic
malignancy. Clinically, it is critical to discern true germline from somatic TP53 variants (ACE), since the clinical
implications differ substantially. Carriers of true germline TP53 mutations may bear the psychological, medical
and financial costs of striking personal and family cancer risks, the burden of intensive surveillance, the high
risks of cancer deaths at disproportionately young ages and the weight of possibly passing TP53 variants to
offspring. Those with ACE/CH may be followed for increased risk of hematologic malignancy or heart disease.
More research is needed to better quantify TP53 associated risks to clarify optimal management.
The investigators will partner with colleagues from the Li-Fraumeni Exploration Consortium (LiFE), and others
with patients ascertained through broader, more agnostic approaches to testing: commercial genetic testing
laboratories, the Geisinger MyCode® project, the PROMPT study of individuals with germline mutations, and the
ORIEN tumor/germline sequencing project, to assemble the largest cohort of individuals with a TP53 mutation
in blood or saliva and their relatives. Given the rarity of LFS, acquiring this cohort through other means would be
cost prohibitive and impracticable. In aim 1, we will estimate the TP53-related site-specific cancer risks in families
identified through agnostic testing approaches and study tumor genomic characteristics in their collected tumor
specimens. In aim 2, we will investigate the roles of TP53 allelic heterogeneity and specific genetic variation as
modifiers of these cancer risks. ACE will be characterized separately as described in aim 3, and we will exclude
probands with ACE rather than germline TP53 mutations from Aim 1 and 2 analyses.
These studies will improve our ability to distinguish between germline TP53 variants and those associated
with ACE, and the genotype-phenotype correlations elucidated will better define the TP53-associated tumor
spectrum and cancer risks to help refine clinical management recommendations for both groups.
Suggested application of HER2+ breast tumor phenotype for germline TP53 variant classification within ACMG/AMP guidelines.
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