Endometrial Carcinoma Genomic Profiling- Focusing on POLE

Keerthi Ranganathan

Scientific Content Developer
4baseCare

Endometrial carcinoma (EC) also known as Uterine Cancer is one of the most frequent gynecological malignancy that is predominantly associated with industrialized countries with a high standard of living and food surplus.

Statistically, 69% of EC are diagnosed at an early age and about >80% of them cross the mark of 5 years of their survival.

Determining the proper sub-type is very important to avail the optimal outcome for ECs. So, the scientific community widely agrees that molecular classification will be the key to endometrial carcinoma therapeutic strategies in the future. Previously ECs were classified as Type 1 (estrogen-dependent with good prognosis) and Type 2 (estrogen negative worst prognosis) based on Estrogen dependency.

But now replacing the current type I and type II terminology, four molecular subtypes have been established, each of them reflecting underlying molecular aberrations (based on NGS analysis) and distinct clinical behavior. Future research is focusing on how to integrate these new findings into clinical practice with the ultimate goal to drive personalized endometrial carcinoma patient care forward.

The Cancer Genome Atlas (TCGA) Project an integrated genomic characterization of endometrioid and serous endometrial cancer. This led to molecular classification of endometrial cancer in two types defined by their nucleotide substitutions and patterns, microsatellite instability (MSI) status, and copy number alterations: POLE (ultra-mutated), MSI (hypermutated), copy number low (endometrioid), and copy number high (serous-like). The serous and serous-like endometrioid tumors are characterized by frequent mutations in TP53, extensive copy number alterations, and few DNA methylation changes. In contrast, the majority of endometrioid tumors demonstrate few copy number alterations and rare mutations in TP53 but frequent mutations in PTEN and KRAS. 

It could be demonstrated that four molecular subtypes, namely POLE mutant (POLE mut), mismatch repair deficient (dMMR), p53 abnormal (p53abn), and no specific molecular profile (NSMP), are independent factors for outcome and survival and could provide guidance in the future for individual treatment like fertility-sparing.

The Le Gallo eta al has also identified Clear cell endometrial cancer (CCEC) as another subtype that was not well documented in TCGA. CCEC is an uncommon but aggressive histologic type that accounts for 1%-6% of endometrial cancer. and much less is known about the molecular drivers of this malignancy. The study by Le Gallo et al2 in this issue of Cancer represents the largest effort to date to characterize the mutational landscape of CCEC. 

The genes that cause the MSI are associated with Lynch Syndrome which increases the risk of Colorectal Cancer. It’s been documented that women with Lynch Syndrome can benefit from screening and preventions strategies to prevent the development of second cancer that is Endometrial cancer

The HRR genes have significantly contributed to the treatment decision for the management of the ECs along-with other HRR pathway deficient cancers. BRIP1 gene (BRCA1 interacting Protein 1) alterations occur in the frequency of 0.14% in type 2 ECs. 

Several studies have shown durable responses with fewer side effects in BRIP1 altered ECs with Olaparib treatment.

So, it clearly defines that along with POLE gene other genes (HRR genes, MMR genes) plays a crucial role in the management of Endometrial cancer and comprehensive NGS analysis is the ultimate technology to give accurate single nucleotide level genomic information for precise targeted treatment of this cancer. Both Targeted and Immunotherapy decisions can be made based on the molecular classification that has been made by Comprehensive NGS analysis of the genomic landscape of ECs.