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Related Concept Videos

Abnormal Proliferation02:23

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Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
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Genes usually encode proteins necessary for the proper functioning of a healthy cell. Mutations can often cause changes to the gene expression pattern, thereby altering the phenotype.
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Copy Number-low/TP53-mutated Endometrial Cancer With Wild-type p53 Immunoexpression: Implications for Risk

Joseph T Rabban1, Rebecca J Wolsky2, Neslihan Kayraklioglu1

  • 1Department of Pathology, University of California, San Francisco, California.

Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc
|April 23, 2026
PubMed
Summary
This summary is machine-generated.

A rare endometrial cancer subtype with TP53 mutation but low copy number alterations and wild-type p53 expression has a favorable prognosis. This finding highlights the complexity of TP53 mutations in endometrial cancer.

Keywords:
TP53endometrial cancermolecular classification

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Area of Science:

  • Gynecologic Oncology
  • Genomic Medicine
  • Cancer Genomics

Background:

  • Endometrial cancers (ECs) with specific Cancer Genome Atlas (TCGA) profiles, such as TP53-mutated, POLE-wild type, and microsatellite-stable, typically show high copy number (CN) alterations and poor outcomes.
  • Conversely, TP53 mutations co-occurring with POLE mutations or microsatellite instability are associated with better prognoses, similar to ultramutated or hypermutated cancers.
  • The clinical significance of TP53 mutations in EC is complex and influenced by co-existing molecular alterations.

Purpose of the Study:

  • To characterize a rare molecular subtype of endometrial cancer defined by TP53 mutation but a low burden of CN alterations, wild-type p53 immunoexpression (IHC), and low TP53 variant allele frequency (VAF).
  • To evaluate the clinical behavior and prognosis of this distinct molecular subgroup.
  • To assess the detectability of this subtype using current classification methods.

Main Methods:

  • Next-generation sequencing (NGS) was used to prospectively classify 723 consecutive endometrial cancers.
  • TP53 mutation status, POLE status, microsatellite stability, CN alterations, p53 IHC, and TP53 VAF were analyzed.
  • A retrospective cohort was used for additional case identification and analysis.

Main Results:

  • 16 out of 723 (2.2%) prospective cases met the criteria for CN-Low/TP53-mutated/p53 wild-type IHC; two additional cases were found in a retrospective cohort, totaling 18 cases.
  • These tumors predominantly affected post-menopausal patients, were low-grade endometrioid histotype, and largely confined to the uterus without lymphovascular invasion.
  • The recurrence rate was low (6.25% in the prospective cohort), and no deaths occurred, indicating a prognosis closer to CN-Low cancers.

Conclusions:

  • NGS-based TCGA classification requires further evaluation with CN analysis and/or p53 IHC to identify this rare TP53-mutated, POLE-wild type, microsatellite-stable EC subtype with TP53 VAF <50%.
  • Immunohistochemistry-based classifications (e.g., ProMisE protocol) may miss these cases due to wild-type p53 IHC and lack of distinct morphological features.
  • Long-term outcome studies are necessary to refine risk stratification and treatment strategies for this unique molecular class of endometrial cancer.