Intra-tumour genetic heterogeneity and poor chemoradiotherapy response in cervical cancer

Abstract

Background:Intra-tumour genetic heterogeneity has been reported in both leukaemias and solid tumours and is implicated in the development of drug resistance in CML and AML. The role of genetic heterogeneity in drug response in solid tumours is unknown.Methods:To investigate intra-tumour genetic heterogeneity and chemoradiation response in advanced cervical cancer, we analysed 10 cases treated on the CTCR-CE01 clinical study. Core biopsies for molecular profiling were taken from four quadrants of the cervix pre-treatment, and weeks 2 and 5 of treatment. Biopsies were scored for cellularity and profiled using Agilent 180k human whole genome CGH arrays. We compared genomic profiles from 69 cores from 10 patients to test for genetic heterogeneity and treatment effects at weeks 0, 2 and 5 of treatment.Results:Three patients had two or more distinct genetic subpopulations pre-treatment. Subpopulations within each tumour showed differential responses to chemoradiotherapy. In two cases, there was selection for a single intrinsically resistant subpopulation that persisted at detectable levels after 5 weeks of chemoradiotherapy. Phylogenetic analysis reconstructed the order in which genomic rearrangements occurred in the carcinogenesis of these tumours and confirmed gain of 3q and loss of 11q as early events in cervical cancer progression.Conclusion:Selection effects from chemoradiotherapy cause dynamic changes in genetic subpopulations in advanced cervical cancers, which may explain disease persistence and subsequent relapse. Significant genetic heterogeneity in advanced cervical cancers may therefore be predictive of poor outcome.

Empirical chemosensitivity testing in a spheroid model of ovarian cancer using a microfluidics-based multiplex platform

“…[25][26][27] ITH has been identified in a number of human cancer types including acute lymphoblastic leukemia, prostate, melanoma, pancreatic, gastric, uterine, and ovarian carcinomas. [28][29][30][31][32][33][34] In the past, most common in vitro methods to test tumor chemotherapeutic responses have relied on dissociating solid tumors explanted into monolayer (2D) cultures, but this approach has proven unsatisfactory as only a limited and highly selected cell population is able to explant and grow. In addition, there is ample evidence to suggest that 2D monolayers lack many of the physical characteristics found in tissues, resulting in dramatically different therapeutic responses to that observed in patients.…”

Insight into the heterogeneity of breast cancer through next-generation sequencing

“…Some subtypes seem to have greater intratumoral hetero-geneity than others (69), but the clinical importance of each given subpopulation is not yet clear. Intratumor heterogeneity is likely to play an important role in responsiveness to chemotherapy (5,96,97), and results from adjuvant-treated ovary, cervical, and tongue cancer suggest that resistant tumor subpopulations pre-exist and expand after treatment (98)(99)(100). The study of Jones et al illustrates how such information can be used to determine the next level of treatment in an adjuvant setting (100).…”

The evolution of tumour phylogenetics: principles and practice

“…Higher intra-tumour heterogeneity has been associated with poorer prognosis 8,56–58 and linked with the ability of the tumour to resist immune surveillance and therapy 3,59,60 . Progression, metastasis, and therapeutic resistance frequently proceed from clones that were rare at earlier progression stages 41,43,49,61 .…”