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 2

Clonal designations of recurrent mutations and mutation signatures.

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Clonal designations of recurrent mutations and mutation signatures. (A) ...
(A) The vertical axes show the mutation frequency (calculated patient-wise among 23 patients) of all oncogenes and tumor suppressor genes (defined by the Cancer Gene Census) with recurrent nonsilent SNVs or indels across the cancers. Mutations are colored according to designations of clonality based on MutationTimeR (top part) or PyClone and ClonEvol (bottom part; reverse vertical axes orientation). Mutations were considered clonal according to MutationTimeR if designated as such in at least 1 sample per patient, and subclonal mutations were divided according to their homogeneous (pink) or heterogeneous (green) presence across samples per patient. Results from PyClone and ClonEvol are from clonality modeling across all samples per patient. Two polyclonal cancers in 1 patient were analyzed separately and summarized patient-wise. (B) The sample-wise proportions of 3 selected base substitution signatures of deficient DNA damage repair, calculated separately for clonal (black) and subclonal (pink) mutations, as designated by MutationTimeR. Results are presented per patient (separated by white spaces) in the same order as in Figure 1 (ranked according to a decreasing median tumor mutation burden) and per sample ordered by tumor site. The two top rows indicate the type of DNA damage repair deficiency detected in each patient (Repair) and the tumor site of each sample (Sample). c, clonal; dBER, deficient base excision repair; dMMR, deficient mismatch repair; nd, not determined; s, subclonal.