New Discoveries in Ovarian Cancer: The Role of Whole-Genome Doubling in Treatment Development

Recent research by Memorial Sloan Kettering Cancer Center has provided significant insights into the progression of ovarian cancer, particularly focusing on the phenomenon known as whole-genome doubling (WGD). This process involves the duplication of a cell's entire set of chromosomes and appears to play a dual role in cancer dynamics—driving tumor progression while also acting as a potential barrier depending on the context.

Ovarian cancer remains a leading cause of cancer-related mortality among women globally, largely because it often spreads at a microscopic level within the abdomen well before a diagnosis can be made, making early detection and treatment challenging. The study centered on high-grade serous ovarian carcinoma (HGSOC), the most common and aggressive form of ovarian cancer.

Utilizing advanced single-cell sequencing techniques, researchers examined over 30,000 cells from 70 tumor samples across 41 patients who had not yet received treatment. They discovered that more than 65% of these tumors exhibited high levels of WGD, meaning a majority of cells in these tumors had undergone genome duplication. These WGD-high tumors were observed to better suppress the immune response of the patient, notably by repressing the STING pathway, which is typically responsible for activating immune defenses against tumors.

Interestingly, WGD-low tumors appeared more recognizable to the immune system and more likely to trigger inflammatory responses. This immune evasion in WGD-high tumors suggests that the process of genome doubling may contribute to increased resistance to current therapies and greater tumor adaptability.

Mapping the evolutionary timeline of these tumors revealed that WGD is an ongoing and dynamic event, occurring at different stages and in different groups of cancer cells within the same tumor. This ongoing process underscores the complexity of ovarian cancer evolution and highlights the importance of understanding how environmental factors in the fallopian tubes, where many ovarian cancers originate, influence WGD events.

The collaborative effort involved researchers, surgeons, oncologists, and specialists in genomics, emphasizing the multidisciplinary approach needed to tackle such a complex disease. The development of single-cell sequencing protocols was particularly challenging but essential for capturing the heterogeneity of tumor cell populations.

These findings open new avenues for targeted therapies, especially those aimed at inhibiting WGD or improving the immune system's ability to detect and attack WGD-high tumors. Future research will focus on understanding the triggers for WGD and how it can be effectively targeted to improve outcomes for patients with advanced ovarian cancer.