High-grade serous ovarian cancer: the clone wars

Abstract

BackgroundThe last 5 years’ studies using next-generation sequencing provided evidences that many types of solid tumors present spatial and temporal genetic heterogeneity and are composed of multiple populations of genetically distinct subclones that evolve over time following a pattern of branched evolution. The evolutionary nature of cancer has been proposed as the major contributor to drug resistance and treatment failure. In this review, we present the current state of knowledge about the clonal evolution of high-grade serous ovarian cancer and discuss the challenge that clonal evolution poses for efforts to achieve an optimal cancer control.MethodsA systemic search of peer-reviewed articles published between August 2007 and October 2016 was performed using PUBMED and Google Scholar database.Results and conclusionsRecent studies using next-generation sequencing have allowed us to look inside the evolutionary nature of high-grade serous ovarian cancer, which in the light of current evidence can explain the relapsing course of the disease frequently observed in the clinical practice. Since only minimal improvement in the survival of patients treated with standard therapy has been observed in the last decade, novel molecular targeted therapies are of great interest in high-grade serous ovarian cancer. However, both spatial and temporal intratumoral genetic heterogeneity is a major challenge for personalized medicine, and greater knowledge of the molecular rules that drive tumor evolution through space and time is required to achieve a long-term clinical benefit from personalized therapy.

Multi-omic analysis of subtype evolution and heterogeneity in high-grade serous ovarian carcinoma

“…It seems initially counterintuitive that the proliferative subtype displayed a lower risk than the mesenchymal subtype with respect to overall survival [8]. However, this is in agreement with several previous studies that found an extreme level of genomic instability associated with improved outcome compared to intermediate levels [26,27]. A recent analysis of transcriptome subtypes in colorectal cancer generally questioned the existence of discrete subtypes, and proposed a continuum of transcriptomes instead [28].…”

“…A subtype model based on HGSOC tumor evolution: our observations are consistent with a model that places the differentiated and the proliferative subtype at opposite ends of the timeline of HGSOC tumor developement; with the differentiated subtype being an early subtype, the proliferative a late subtype, and the immunoreactive and the mesenchymal being intermediate subtypes. HGSOC development along this timeline is thereby reportedly characterized by an increasing level of genomic instability and subclonal expansion [25,26]. Several previous findings support this model: (i) mean age at diagnosis was lowest for patients of differentiated subtype, but significantly increased for patients of proliferative subtype [8], and (ii) tumors of differentiated subtype displayed a high level of infiltrating immune cells, indicating an active immune response at an early time point of tumor development, whereas tumors of proliferative subtype displayed a negligible level of infiltrating immune cells, consistent with an adapted tumor successfully evading the immune response at a late point in tumor evolution [27].…”

Epithelial ovarian cancer risk: A review of the current genetic landscape

“…However, conversely, higher levels of genomic instability can enable the acquisition of pathogenic variants with a selective disadvantage, by limiting tumour growth or increasing response to chemotherapy. 14…”

“…Notch and FOXM1 signalling pathways are also implicated . The genomic instability present in HGSOC promotes the development of further variants, increases genetic diversity and development of genetically distinct subclones within a tumour . Genomic instability can be associated with treatment resistance and poor prognosis if subclones develop genomic characteristics that benefit tumour survival.…”

“…Genomic instability can be associated with treatment resistance and poor prognosis if subclones develop genomic characteristics that benefit tumour survival. However, conversely, higher levels of genomic instability can enable the acquisition of pathogenic variants with a selective disadvantage, by limiting tumour growth or increasing response to chemotherapy . In HGSOC, higher levels of genomic instability are associated with higher platinum‐based chemotherapy and poly ADP ribose polymerase (PARP) inhibitor response rates, and improved survival outcomes …”