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


CONCLUSIONS
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.
Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB20RE, UK.
S L
SL
Cooke
J
J
Temple
S
S
Macarthur
M A
MA
Zahra
L T
LT
Tan
R A F
RA
Crawford
C K Y
CK
Ng
M
M
Jimenez-Linan
E
E
Sala
J D
JD
Brenton
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D005260:Female; D018740:Genetic Heterogeneity; D006801:Humans; D008875:Middle Aged; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000532:radiotherapy
D000970:Antineoplastic Agents