Spatial and temporal heterogeneity in high-grade serous XXXX : a phylogenetic analysis.

@entity43 @entity1 @entity2214 @entity5 @entity1265 @entity902 @entity1349
BACKGROUND: The major clinical challenge in the treatment of high-grade serous @entity43 (HGSOC) is the development of progressive resistance to @entity902 -based chemotherapy. The objective of this study was to determine whether @entity5 genetic heterogeneity resulting from @entity2214 and the emergence of @entity5 populations in HGSOC was associated with the development of resistant disease. METHODS AND FINDINGS: Evolutionary inference and phylogenetic quantification of heterogeneity was performed using the MEDICC algorithm on high-resolution whole genome copy number profiles and selected genome-wide sequencing of 135 spatially and temporally separated samples from 14 @entity1 with HGSOC who received @entity902 -based chemotherapy. Samples were obtained from the clinical CTCR-OV03/04 studies, and @entity1 were enrolled between 20 July 2007 and 22 October 2009. Median follow-up of the cohort was 31 mo (interquartile range 22-46 mo), censored after 26 October 2013. Outcome measures were @entity1349 ( @entity1349 ) and progression-free survival (PFS). There were marked differences in the degree of @entity2214 ( @entity2214 ) between @entity1 (median 0.74, interquartile range 0.66-1.15), and dichotimization by median @entity2214 showed worse survival in @entity2214 -high cases (PFS 12.7 versus 10.1 mo, p = 0.009; @entity1349 42.6 versus 23.5 mo, p = 0.003). Bootstrap analysis with resampling showed that the 95% confidence intervals for the hazard ratios for PFS and @entity1349 in the @entity2214 -high group were greater than 1.0. These data support a relationship between heterogeneity and survival but do not precisely determine its effect size. Relapsed tissue was available for two @entity1 in the @entity2214 -high group, and phylogenetic analysis showed that the prevalent clonal population at clinical recurrence arose from early divergence events. A subclonal population marked by a @entity1265 deletion showed a progressive @entity5 allele fraction during chemotherapy. CONCLUSIONS: This study demonstrates that quantitative measures of @entity5 heterogeneity may have predictive value for survival after chemotherapy treatment in HGSOC. @entity5 populations are present in pre-treatment biopsies in HGSOC and can undergo expansion during chemotherapy, causing clinical relapse.
