Molecular Characterization of Endometrial Carcinoma

Endometrial carcinoma comprises a spectrum of tumours whose prognosis and response to therapy are governed by distinct molecular alterations. The current molecular classification divides tumours into four major subgroups: POLE-ultramutated, characterised by exonuclease domain mutations in the polymerase epsilon gene and exceptionally high mutation rates; mismatch repair-deficient (MMRd), which exhibit microsatellite instability and moderate mutational burden; p53 abnormal (p53abn), associated with extensive copy-number alterations and poor outcome; and non-specific molecular profile (NSMP), lacking the defining aberrations of the other three groups. These categories have been shown to outperform traditional histological grading in predicting recurrence risk and guiding adjuvant treatment. Integrative genomic analyses have also uncovered co-occurring defects, such as ‘multiple-classifier’ tumours harbouring combinations of POLE mutations, MMR deficiency and TP53 alterations, revealing tumour evolution pathways and subclonal architecture. Advances in high-throughput sequencing, immunohistochemistry and bioinformatic scoring have facilitated routine clinical implementation of this histomolecular approach, enabling personalised risk stratification and opening avenues for targeted therapies directed at PI3K-AKT, homologous recombination and chromatin-remodelling pathways. Ongoing trials are now assessing molecular profile–based adjuvant regimens with the aim of reducing overtreatment and improving quality of life without compromising disease control.

Research from Nature Portfolio

Whole-exome sequencing of rare gynaecological carcinosarcomas has revealed recurrent mutations in chromatin-remodelling genes, including ARID1A, ARID1B, MLL3 and SPOP, in addition to frequent TP53 and KRAS alterations. This work demonstrated that two-thirds of cases carry defects in chromatin-assembly factors and histone modifiers, suggesting a pivotal role for epigenetic dysregulation in tumourigenesis. Moreover, actionable alterations in PI3-kinase and homologous DNA-repair pathways were identified in over three-quarters of samples, highlighting potential targets for personalised therapy. The study established a paradigm for molecular dissection of mixed Müllerian tumours, underscoring the importance of genome-wide profiling to uncover novel therapeutic vulnerabilities and refine subtype-specific treatment strategies.

Molecular Characterization of Endometrial Carcinoma publication trend

The graph below shows the total number of articles in molecular characterization of endometrial carcinoma across all publications each year (not limited to Nature Index journals).

Technical terms

POLE-ultramutated: Tumours with exonuclease domain mutations in the DNA polymerase epsilon gene, resulting in exceptionally high single-nucleotide variant rates.

Mismatch repair-deficient (MMRd): Tumours with inactivation of DNA mismatch repair proteins, exhibiting microsatellite instability and intermediate mutational burden.

p53 abnormal (p53abn): Tumours with TP53 mutations or aberrant p53 immunostaining, associated with widespread copy-number alterations and aggressive behaviour.

Non-specific molecular profile (NSMP): Tumours lacking POLE, MMRd or p53 abnormalities, often showing lower overall mutational load and intermediate prognosis.

Tumour mutational burden (TMB): The total number of mutations per megabase of tumour DNA, used as a marker for neoantigen load and potential immunotherapy response.

References

1. Incorporation of molecular characteristics into endometrial cancer management. Histopathology (2019).
2. Molecular Classification of the PORTEC-3 Trial for High-Risk Endometrial Cancer: Impact on Prognosis and Benefit From Adjuvant Therapy. Journal of Clinical Oncology (2020).
3. Clinicopathological and molecular characterisation of ‘multiple‐classifier’ endometrial carcinomas. The Journal of Pathology (2020).
4. Genomic analyses of gynaecologic carcinosarcomas reveal frequent mutations in chromatin remodelling genes. Nature Communications (2014).
5. PORTEC-4a: international randomized trial of molecular profile-based adjuvant treatment for women with high-intermediate risk endometrial cancer. International Journal of Gynecological Cancer (2020).