Ovarian Cancer Disseminates via Distinct Modes of Intraperitoneal Spread

High-grade serous ovarian cancers exhibit frequent widespread intraperitoneal spreading to other organs, facilitated by the lack of physical barriers to metastasis in the peritoneal cavity. However, it is not clear if local peritoneal spread arises from monoclonal seeding and expansion or from a polyclonal population of cells. To better understand the modes of intraperitoneal spread and high-grade serous ovarian cancer progression, McPherson, Roth, and colleagues performed sequencing and phylogenetic analyses of 68 spatially distinct samples obtained from 7 patients that included samples from the ovary, omentum, fallopian tube, peritoneum, and distant metastases. Among the 7 patients, a total of 44 clonal genotypes were identified by single-nucleus sequencing or deep sequencing, ranging from 3 to 9 genotypes per patient. The patient samples were classified as clonally pure or polyclonal (either monophyletic—from the same phylogenetic clade—or polyphyletic—from different clades). The majority of samples were monophyletic or clonally pure, but each of the patients had at least one polyphyletic sample, indicating either branched clonal evolution or a site having been seeded by multiple clones. Characterization of clonal composition across samples revealed that most of the intraperitoneal spread in patients was characterized by clonally pure or monophyletic clones, not repeated reseeding of multiple clones, with only a limited number of sites being permissive of coexisting clones, though there were exceptions to this trend. Across the 7 patients, two types of intraperitoneal mixing were observed: monoclonal seeding at a single tumor site permissive of clonal diversity, and polyclonal mixing and reseeding. These results provide insight into mechanisms of high-grade serous ovarian cancer evolution and modes of intraperitoneal spreading and suggest that microenvironmental niches reduce clonal mixing in the peritoneal cavity, leading to monoclonal seeding.

McPherson A, Roth A, Laks E, Masud T, Bashashati A, Zhang AW, et al. Divergent modes of clonal spread and intraperitoneal mixing in high-grade serous ovarian cancer. Nat Genet 2016 May 16 [Epub ahead of print].