Mutational spectrum of cell proliferation genes as early predictive markers for aggressive disease in endometrial cancers.

e15034 Background: Endometrial cancer (EC) illustrates diverse nucleotide substitution and chromosomal re-arrangement signatures like other cancers. Namely, four molecular types are identified, replicative polymerases, microsatellite stable, copy number high/serous-like, and microsatellite instability characterized by mutations in mismatch repair genes. With advances in molecular techniques, early prediction of disease aggressiveness can be revealed using comprehension in ECs. Although few cell proliferative genes have been documented, a complete molecular landscaping is essential for effective treatment planning and decision-making. We report, the association between clinical disease status and corresponding molecular findings to establish the role of the latter in the early prediction of disease aggression in endometrial cancer. Methods: Retrospectively, we investigated the association of genomic mutational profiles of 40 endometrial cancer patients and their clinical disease status from PET scans and HPE reports. Next Generation Sequencing (NGS) test was performed using a comprehensive genomic panel (CGP) OncoIndx assay. Results: Amongst 40 patients, 65% (n = 26/40) of patients had progressive and metastatic disease from PET scans and HPE reports indicative of disease aggressiveness. Almost 80% (n = 20/26) of the aggressive disease cohort were detected to have a minimum of one genomic alteration. Their mutational profiles showed a diverse spectrum of pathway-related aberrations from cell proliferation, progression, double-strand DNA (dsDNA) repair, mismatch repair (MMR), and tumor suppression constituting a total of 83 genomic alterations detected in the whole cohort. Further, the cell proliferation and dsDNA repair pathways exhibited the highest mutational load of 57.8% (n = 48/83) and 14.5% (n = 12/83) respectively in the cohort. Likewise, tumor suppressor genes constituted the lowest frequency at 6% (n = 5/83).In addition, five patients were detected with high MSI scores and one patient with an intermediate MSI score of which two MSI-high patients were also found to harbor MMR gene mutations (MSH3:p.K383Rfs*32, p.D403H, p.E456* and p.E512*, MSH6:p.F1088Sfs*2). Conclusions: Using CGP, we observed mutational frequencies of cell proliferation and dsDNA repair pathways that act as crucial markers for disease aggression in EC. We also noted that high MSI scores were not always concordant with mutations in the classical MMR genes and vice versa. This also indicates the individual significance of estimating MSI scores in these patients for clinical decision-making. Since the identified landscape of mutations well correlated with the disease states categorized from their clinical findings, they could potentially transform into molecular attributes for early prediction of progression and metastasis aiding treatment planning and decision making.