Evolutionary mode and timing of dissemination of high-grade serous carcinomas.

Dissemination within the peritoneal cavity is a main determinant of poor patient outcomes from high-grade serous carcinomas (HGSCs). The dissemination process is poorly understood from a cancer evolutionary perspective. We reconstructed the evolutionary trajectories across a median of five tumor sites and regions from each of 23 patients (n=108 samples) based on deep whole-exome sequencing. Polyclonal cancer origin was detected in one patient. Ovarian tumors had more complex subclonal architectures than other intra-peritoneal tumors in each patient, which indicated that tumors developed earlier in the ovaries. Three common modes of dissemination were identified, including monoclonal (27%) or polyclonal dissemination of monophyletic (linear; 50%) or polyphyletic (branched; 23%) subclones. Mutation profiles of initial or disseminated clones varied greatly among cancers, but recurrent mutations were found in seven cancer-critical genes, such as TP53, BRCA1, BRCA2, DNMT3A, and in the PI3K/AKT1 pathway. Disseminated clones developed late in the evolutionary trajectory models of most cancers, in particular in cancers with DNA damage repair deficiency. Polyclonal dissemination was predicted to occur predominantly as a single and rapid wave, but chemotherapy exposure was associated with higher genomic diversity of disseminated clones. In conclusion, we described three common evolutionary dissemination modes across HGSCs and proposed factors associated with dissemination diversity.