Distinct evolutionary trajectories of primary high‐grade serous ovarian cancers revealed through spatial mutational profiling

Abstract

High-grade serous ovarian cancer (HGSC) is characterized by poor outcome, often attributed to the emergence of treatment-resistant subclones. We sought to measure the degree of genomic diversity within primary, untreated HGSCs to examine the natural state of tumour evolution prior to therapy. We performed exome sequencing, copy number analysis, targeted amplicon deep sequencing and gene expression profiling on 31 spatially and temporally separated HGSC tumour specimens (six patients), including ovarian masses, distant metastases and fallopian tube lesions. We found widespread intratumoural variation in mutation, copy number and gene expression profiles, with key driver alterations in genes present in only a subset of samples (eg PIK3CA, CTNNB1, NF1). On average, only 51.5% of mutations were present in every sample of a given case (range 10.2–91.4%), with TP53 as the only somatic mutation consistently present in all samples. Complex segmental aneuploidies, such as whole-genome doubling, were present in a subset of samples from the same individual, with divergent copy number changes segregating independently of point mutation acquisition. Reconstruction of evolutionary histories showed one patient with mixed HGSC and endometrioid histology, with common aetiologic origin in the fallopian tube and subsequent selection of different driver mutations in the histologically distinct samples. In this patient, we observed mixed cell populations in the early fallopian tube lesion, indicating that diversity arises at early stages of tumourigenesis. Our results revealed that HGSCs exhibit highly individual evolutionary trajectories and diverse genomic tapestries prior to therapy, exposing an essential biological characteristic to inform future design of personalized therapeutic solutions and investigation of drug-resistance mechanisms.

Assessing intratumor heterogeneity and tracking longitudinal and spatial clonal evolutionary history by next-generation sequencing

“…Through simulations, we explore the effects of various parameters on deconvolution accuracy and compare Canopy against existing methods. Canopy is then applied to four datasets with different sequencing designs: the whole-exome sequencing (WES) of a heterogeneous triple-negative breast carcinoma cell line MDA-MB-231 and its derived sublines with single and mixed cell populations, the whole-genome sequencing (WGS) of breast cancer patient xenografts from Eirew et al (10), the WGS of leukemia patients, each at two time points from Ding et al (7) (SI Appendix, SI Results), and the multiregion sequencing of an ovarian cancer patient from Bashashati et al (8) (SI Appendix, SI Results).…”

“…Recently, there have been increasing efforts to sequence the tumor from the same patient at multiple time points and/or from multiple spatially separated resections (7)(8)(9)(10)(11)(12). Multiple snapshots of the same tumor have proved invaluable for identifying subclonal populations and for inferring the tumor's evolutionary history.…”

“…High-throughput sequencing technologies have made possible the large-scale, high-resolution analysis of tumor genomes. A recurring finding of these studies is the high degree of heterogeneity-both intertumor heterogeneity among patients with the same clinical diagnosis (4,5), as well as intratumor heterogeneity between tumor cells derived from the same patient (summarized in SI Appendix, Table S1) (6)(7)(8)(9)(10)(11)(12). Heterogeneity, at all levels, confound diagnosis and treatment.…”

PyClone: statistical inference of clonal population structure in cancer

“…We specified the priors for cellularity estimation in PICNIC based on quantitative pathology estimates. Allelic count data was obtained from Bashashati et al 14 . We obtained count data from additional mutations not validated as somatic from the authors.…”

“…We next compared results from multi-sample BeBin-PCN and IBBMM in the cancer setting, using recently published mutational profiles of multiple samples from a high grade serous ovarian cancer (HGSOC) 14 . Four spatially separated samples were taken from a primary, untreated ovarian tumour (study case 2).…”