Genomic characterization of advanced and recurrent endometrial carcinoma: KRAS and TP53 co-mutation as a biomarker for adverse prognosis and therapeutic failure.

OBJECTIVES

The survival outcomes of advanced or recurrent endometrial cancer (EC) have not improved markedly despite the expanding therapeutic options. We performed molecular characterization of EC to identify therapeutic targets and prognostic biomarkers.

METHODS

Whole-exome sequencing (WES)-based somatic mutation profiling was performed in tumor samples obtained from 67 EC patients (41 early-stage and 26 advanced/recurrent cases). The frequencies of somatic mutations were compared between early and advanced/recurrent EC. Copy number variation analysis was also performed. Survival outcomes and recurrences according to mutational status were analyzed.

RESULTS

TP53 and KRAS mutations tended to be more frequent in advanced/recurrent disease than early-stage EC. Deletions were also more common in advanced EC (42.3% vs. 17.1%). Among the advanced EC patients (n=26), 16 patients recurred. Recurrent cases had significantly higher TP53 mutation rates (56.3% versus 10%) and lower PTEN mutation rates (25% versus 80%) than non-recurrent cases. KRAS and CTNNB1 mutations also tended to be enriched. Although KRAS mutation alone only showed a trend of shorter OS (p=0.179) in advanced EC, KRAS-TP53 co-mutation exhibited the worst survival outcomes (p=0.011). KRAS-TP53 co-mutation was associated with chemoresistance: all the co-mutated cases were chemoresistant, whereas patients without either mutation were chemosensitive. Among copy-number low (CNL) and microsatellite instability-high (MSI-H) tumors (n=46), KRAS-TP53 co-mutation was strongly associated with adverse survival outcomes (p=0.003).

CONCLUSIONS

KRAS-TP53 co-mutation represents a potential molecular biomarker of poor prognosis and chemoresistance in advanced EC. It may enable refinement of TCGA classification, especially for CNL and MSI-H subgroups, and support investigation of KRAS-targeted therapeutic strategies.