OCRA-Funded Research Reveals How Distinct Mutational Processes May Affect HGSOC Tumor Growth

Research News

OCRA grantees Ignacio Vázquez-García, PhD and Sohrab Shah, PhD, of Memorial Sloan Kettering Cancer Center, along with colleagues, have found that distinct mutational processes determine the different mechanisms by which certain ovarian cancer tumors are able to evade the immune system and continue to grow. These learnings may lead the way to future immunotherapeutic approaches that can more effectively treat high-grade serous ovarian cancer (HGSOC).

HGSOC is the most common type of ovarian cancer, with approximately 75% of epithelial ovarian cancers classified in this category. It remains difficult to treat, with even the newer class of drugs known as immunotherapy agents proving largely ineffective thus far. Immunotherapy drugs are designed to boost the body’s defenses so that the cancer-fighting cells can more effectively attack the tumor cells, but HGSOC tumors typically remain resistant to this type of treatment.  

Up until recently, it was thought that ovarian cancers originate in the cells lining the surface of the ovaries. However, it is now understood that many cases of HGSOC start in the fallopian tubes. The disease is often advanced by the time it is diagnosed. Researchers believe that because this particular cancer typically goes undetected for such a long time, it allows for broad periods of genomic instability, which is the increased tendency for mutations to occur when cells multiply.

“Genomic instability is a hallmark of human cancer, which often occurs due to impaired DNA repair mechanisms such as homologous recombination (HR), leading to chromosomal copy number alterations and structural genomic rearrangements. The nature of genomic instability has fundamental relevance to cancer etiology and evolution, and anti-tumor immune responses,” according to the study’s authors. 

The researchers sought to investigate whether the type of mutational process driving the particular genomic instability associated with each HGSOC subtype impacts the body’s immune response to the tumor. They studied 160 tissue biopsies from 42 pre-treatment patients who had been newly diagnosed with HGSOC and were undergoing laparoscopy or primary debulking surgeries.

They used numerous data modalities to profile the tissue samples and the study’s authors concluded that the specific type of mutational process associated with each HGSOC subtype does impact how the tumor is able to evade detection and destruction by the body’s immune system. “Most notably, our study demonstrates that different mutational processes associated with HGSOC engender distinct immune evasion mechanisms. Our findings implicate distinct immune resistance mechanisms across HGSOC subtypes which can inform future immunotherapeutic strategies.”

Read more at bioRxiv.

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