When cancer spreads in time and space, it can also spread branches in a kind of family tree. Such is the case with ovarian cancer. In high-grade serious ovarian cancer (HGSOC), which often develops progressive resistance to chemotherapy, different groups of tumor cells diversify genetically, with dire consequences. According to a recent study conducted by Cancer Research UK, HSOC is more deadly if it consists of a patchwork of different groups of cells.

Serous ovarian cancers containing a variety of genetically different cells were more likely to become resistant to treatment and come back again than cancers made of more similar cells. Women with this type of tumour also died sooner than those with less varied tumors.

These findings appeared February 24 in PLOS Medicine, in an article entitled, “Spatial and Temporal Heterogeneity in High-Grade Serous Ovarian Cancer: A Phylogenetic Analysis.” The article described how Cancer Research UK scientists evaluated solid tumors for genetic variety, or tumor heterogeneity, and subsequently linked measures of tumor heterogeneity to cancer survival.

The link is a matter of clonal expansion (CE), a process by which tumor subpopulations that possess an evolutionary advantage such as faster growth or chemotherapy resistance come to dominate a tumor.

To address their hypothesis that quantitative measures of intratumour heterogeneity could predict outcome in HGSOC, the Cancer Research UK scientists collected multiple spatially and temporally separated tumor samples from 14 women undergoing chemotherapy for HGSOC, and used formal methods to reconstruct the evolutionary history of the disease within each patient from whole genome copy number profiles.

“Our analyses showed marked differences in CE between patients and negative effects of high CE on survival. In two patients with very high CE, we demonstrated that clonal populations detected at relapse arose from early branching events, followed by divergent evolution and CE,” wrote the authors. “We further showed that HGSOC generally evolves and spreads in a branching process with frequently changing rates of evolution. Taken together, these findings are consistent with previous data from cell-based studies and circulating tumor DNA assays that suggested that CE occurs between diagnosis and relapse in HGSOC.”

The team also found that gene faults contributing to drug resistance were present in some parts of tumors before treatment began, replacing the previous belief that chemotherapy caused these genetic changes.

Lead researcher James Brenton, Ph.D., from the Cancer Research UK Cambridge Institute, said: “Our research is important because it helps make sense of the genetic chaos inside tumors. It's another step closer to cracking the code on cancer biology so that we can understand sooner how patients will respond to treatment—and how to develop better drugs for this hard to treat cancer in the future.”








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