Fast Facts: Refining Endometrial Carcinoma Subclassification with NGS
Author: Dr Nicole Rossum
Overview
Endometrial carcinoma (EC) is the 5th most common cancer affecting women in South Africa. Its subclassification has evolved significantly with the integration of molecular diagnostics into routine clinical practice.
The most notable advancement is the recognition of four non-overlapping molecular categories, which allow for more accurate prediction of clinical outcomes and tailored therapeutic strategies.
Molecular Subtypes of EC
- POLE-mutated EC
- Involves mutations in the exonuclease domain of the DNA Polymerase epsilon gene (POLE).
- Known as ultramutated due to exceptionally high mutation rates in tumour cells.
- MMRd EC
- Characterised by mismatch repair deficiency.
- Also referred to as hypermutated, with high mutation rates in tumour cells.
- p53 Abnormal EC
- Involves mutations in the TP53 oncogene.
- Known as copy number-high due to numerous somatic copy number alterations.
- NSMP EC (No Specific Molecular Profile)
- Lacks the three molecular defects above.
- Considered a diagnosis of exclusion.
NGS-Based Profiling at Ampath
Ampath now offers a Next Generation Sequencing (NGS) panel specifically for the molecular subclassification of endometrial carcinomas. This panel includes:
- Genes tested: POLE, TP53, CTNNB1
- MMRd status: Assessed via immunohistochemical staining
- Specimen type: Formalin Fixed Paraffin Embedded Tissue (FFPE)
- Requirements: 6–8 normal slides with 10-micron thick unstained recuts
- Turnaround time: 7–10 working days
Although CTNNB1 mutations do not define a distinct molecular category, they are associated with higher recurrence rates and lower overall survival.
Clinical Guidelines
Both the European Society for Medical Oncology (ESMO) and the European Society of Gynaecological Oncology (ESGO) now recommend molecular classification as standard practice in the management of endometrial carcinoma.