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 1

Mutation profiles across multiple tumors and tumor regions from disseminated high-grade serous carcinomas.

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Mutation profiles across multiple tumors and tumor regions from dissemin...
(A) Mutation burden from whole-exome sequencing of 108 tumor or ascites samples from 23 patients with disseminated high-grade serous carcinoma. Samples are grouped by patient and colored according to tumor site. The black dashed lines indicate the median mutation burden per patient, and patients are ranked in order of a decreasing median mutation burden. The asterisk marks a patient with polyclonal cancer origin. (B–D) Selected (B) clinicopathological and (C and D) molecular characteristics per patient. Color labels and scales are defined to the right of each parameter. The proportion of each base substitution signature represents the median per patient. Split boxes indicate intrapatient heterogeneity between the ovarian (left) and extraovarian (right) samples. Remaining molecular characteristics were homogeneous in all samples from each patient. (E) Three modes of cancer dissemination were determined by clonality modeling, as illustrated in Figure 3. dBER, deficient base excision repair; dMMR, deficient mismatch repair; IDS, interval debulking surgery (with neoadjuvant chemotherapy); LOH, loss of heterozygosity; Mb, megabase; nd, not determined; PDS, primary debulking surgery (with adjuvant chemotherapy); PFS1, progression-free survival after first-line therapy; sig, signature.