Study Identifies Potential Genomic Markers for Residual Ovarian Cancer Following Resection

Whether a patient has residual disease following primary surgery is an important factor in ovarian cancer outcomes, and a recent study published in Genomic Medicine found that certain gene variants may be prognostic for residual disease following resection in this patient population.

Epithelial ovarian cancer (EOC) is a leading cause of death from cancer in women, and most who are diagnosed cannot be cured due to advanced disease at diagnosis or because their tumors develop resistance to systemic therapies. Cytoreductive surgery is a key treatment strategy for patients diagnosed with EOC, and the quality of care and residual disease status following surgery have been strongly associated with outcomes. Research has shown that patients whose tumors are completely resected experience better outcomes compared with incomplete resections, the authors noted.

AI image of microscope looking at ovarian cancer cells | Image credit: Justlight - stock.adobe.com

Despite progress in surgical techniques, complete cytoreduction is not always possible, and even approximately 30% of patients at specialty centers show macroscopic residual disease following resection.

“The main reason for residual disease is disseminated miliary carcinomatosis scattered over the viscera and the meso of the small bowel,” the authors explained. “Such residual disease is apparently due to local tumor spread, which might be influenced by biological features, and some have proposed gene expression variations associated with residual disease.” Whether genetic factors influence residual disease status after surgery has not been previously determined, however.

The researchers aimed to identify possible genetic variants impacting residual disease post resection, conducting genome-wide association study (GWAS) analyses in a large case series of 7705 patients with ovarian cancer from the Ovarian Cancer Association Consortium. Genes identified in the analyses were then tested for methylation and expression in another series of samples with debulking status and survival information available from the AGO-OVAR 11 study, as well as evaluated for their correlations with progression-free survival (PFS) in patients with no macroscopic residual disease vs those with residual disease. The results were validated with data from The Cancer Genome Atlas Program (TCGA), which is publicly available.

Using this approach, the variant rs72845444, which is located upstream of the MGMT gene, was found to be strongly associated with debulking status in patients with high-grade serous ovarian cancer (HGSOC) (OR, 2.11; 95%CI, 1.61-2.74; P = 3.9 × 10⁻⁸). The association remained but was slightly reduced after adjusting for International Federation of Gynecology and Obstetrics (FIGO) stage (OR, 2.11; 95% CI, 1.58-2.82; P = 4.9 × 10⁻⁷). After adjustment for FIGO stage, no other variants were strongly associated with debulking status.

A gene-based analysis to identify the cumulative effects of single nucleotide polymorphisms in and around single genes found that, after stage adjustment, PPP2R5C was the gene most strongly associated with resection status in HGSOC. Specific genes in PPP2R5C were also associated with its transcript levels, which partially depended on resection status, the authors added. In both the AGO-OVAR11 and TCGA datasets, PPP2R5C also showed potential to predict progression-free survival.

Although the study included a large patient series, a limitation was the inability to stratify for neoadjuvant chemotherapy due to insufficient data. Results for both MGMT and PPP2R5C were also below genome-wide significance, so replicating the findings in additional studies is needed, the authors noted.

“Our GWAS provided strong evidence for candidate genomic loci associated with resection status in patients with EOC undergoing primary debulking surgery and identified a potential role for inherited variants at two genes involved in DNA repair, MGMT and PPP2R5C, in modulating gene expression, debulking outcome and progression-free survival. Future prospective studies should test genomic markers at these genes as predictive factors for resection status and prognostic factors for survival in patients with epithelial ovarian cancer.”

Reference

Ramachandran D, Tyrer JP, Kommoss S, et al. Genome-wide association analyses of ovarian cancer patients undergoing primary debulking surgery identify candidate genes for residual disease. NPJ Genom Med. Published online March 5, 2024. doi:10.1038/s41525-024-00395-y