Evolutionary mode and timing of dissemination of high-grade serous carcinomas
Anita Sveen, Bjarne Johannessen, Solveig M.K. Klokkerud, Sigrid M. Kraggerud, Leonardo A. Meza-Zepeda, Merete Bjørnslett, Katharina Bischof, Ola Myklebost, Kjetil Taskén, Rolf I. Skotheim, Anne Dørum, Ben Davidson, Ragnhild A. Lothe
Anita Sveen, Bjarne Johannessen, Solveig M.K. Klokkerud, Sigrid M. Kraggerud, Leonardo A. Meza-Zepeda, Merete Bjørnslett, Katharina Bischof, Ola Myklebost, Kjetil Taskén, Rolf I. Skotheim, Anne Dørum, Ben Davidson, Ragnhild A. Lothe
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Research Article Genetics Oncology

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

Abstract

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 5 tumor sites and regions from each of 23 patients based on deep whole-exome sequencing. Polyclonal cancer origin was detected in 1 patient. Ovarian tumors had more complex subclonal architectures than other intraperitoneal tumors in each patient, which indicated that tumors developed earlier in the ovaries. Three common modes of dissemination were identified, including monoclonal or polyclonal dissemination of monophyletic (linear) or polyphyletic (branched) subclones. Mutation profiles of initial or disseminated clones varied greatly among cancers, but recurrent mutations were found in 7 cancer-critical genes, including TP53, BRCA1, BRCA2, and 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.

Authors

Anita Sveen, Bjarne Johannessen, Solveig M.K. Klokkerud, Sigrid M. Kraggerud, Leonardo A. Meza-Zepeda, Merete Bjørnslett, Katharina Bischof, Ola Myklebost, Kjetil Taskén, Rolf I. Skotheim, Anne Dørum, Ben Davidson, Ragnhild A. Lothe

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Figure 3

Three common modes of cancer dissemination.

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Three common modes of cancer dissemination. The 3 categories of cancer d...
The 3 categories of cancer dissemination are illustrated by example cases, including (A) dissemination of a single clone, (B) polyclonal dissemination of monophyletic subclones of a linear evolutionary lineage (related subclones), and (C) polyclonal dissemination of polyphyletic subclones of a branched evolutionary lineage (independent subclones). Fish plots illustrate the subclonal architecture of each cancer, with the estimated cellular prevalence of each subclone at each tumor site indicated along the vertical axis (white lines). Bar plots show the number of mutations (nonsilent and silent) per subclone, and nonsilent mutations in oncogenes and tumor suppressor genes (defined by the Cancer Gene Census) are indicated. White boxes with black outlines illustrate the phylogeny of each cancer, with dots representing subclones, dashed lines indicating a linear evolutionary lineage, and the horizontal axis representing the relative mutation time for development of each clone, plotted as the proportion of mutations in each clone relative to the total number of mutations in the cancer model. Charts with arrows illustrate the direction of seeding between tumor sites, with two parallel arrows indicating bidirectional seeding and a bidirectional arrow indicating that the direction is undetermined. Subclones have consistent colors in all plots per cancer. Disseminated subclones are marked by black outlines in the bar plots and phylogenetic representations. None of the illustrated cancers were exposed to neoadjuvant chemotherapy or refractory to first-line treatment. The cancer in B had bidirectional seeding of the pink subclone from the left to the right ovary, followed by the purple subclone in the opposite direction. There were several possible models for the relationship of the red, yellow, and orange subclones in this cancer, but this had no effect on the designated mode of dissemination.