Supplementary Figure S1. Representative images of hematoxylin and eosin (H&E) staining and computed tomography from each patients.Supplementary Figure S2. Distribution of cancer-predisposition genes in each patient. Blue: splice site; dark gray: single nucleotide variations; light gray: absent. Supplementary Figure S3. SciClone analysis of sequenced tumor samples from RJOC12. Supplementary Figure S4. Circos plot displays the copy number variations and inter- and intra-chromosal translocations. Supplementary Figure S5. Heat maps display the Cancer Cell Fraction (CCF) of all mutations in both ovarian lesions of RJOC1-11 (up). Phylogenetic tree of both ovarian tumors were constructed from all somatic mutations. Supplementary Figure S6. Mutation signatures of SNVs in early and late stages. Supplementary Figure S7. Mutational signatures of SBOCs. Supplementary Figure S8. SciClone analysis of 11 SBOC patients. Supplementary Figure S9. Pyclone analysis of 11 SBOC patients.Supplementary Figure S10. Germline and somatic alterations of DNA repair genes.
Funding
National Natural Science Foundation of China
State Key Laboratory of Oncogenes and Related Genes
Shanghai Jiao Tong University
Shanghai Municipal Education Commission
Shanghai Institutions of Higher Learning
Shanghai Rising-Star Program
Shanghai Municipal Commission of Health and Family Planning
Shanghai Key Laboratory of Gynecologic Oncology
Science and Technology Commission of Shanghai Municipality
ARTICLE ABSTRACT
Synchronous bilateral ovarian cancer (SBOC) represents a relatively frequent occurrence and clinically relevant diagnostic dilemma. Delineation of its clonal architecture, genetic heterogeneity, and evolutionary trajectories may have important implications for prognosis and management of patients with SBOC. Here, we describe the results of next-generation whole-exome or whole-genome sequencing of specimens from 12 SBOC cases and report that bilateral tumors from each individual display a comparable number of genomic abnormalities and similar mutational signatures of single-nucleotide variations. Clonality indices based on tumor-specific alterations supported monoclonal origins of SBOC. Each of the ovarian lesions was nevertheless oligoclonal, with inferred metastatic tumors harboring more subclones than their primary counterparts. The phylogenetic structure of SBOC indicated that most cancer cell dissemination occurred early, when the primary carcinoma was still relatively small (<100 million cells). Accordingly, the mutation spectra and mutational signatures of somatic variants exhibited pronounced spatiotemporal differences in each patient. Overall, these findings suggest that SBOCs are clonally related and form through pelvic spread rather than independent multifocal oncogenesis. Metastatic dissemination is often an early event, with dynamic mutational processes leading to divergent evolution and intratumor and intertumor heterogeneity, ultimately contributing substantially to phenotypic plasticity and diverse clinical course in SBOC. Cancer Res; 77(23); 6551–61. ©2017 AACR.
