Genomic analysis of genetic heterogeneity and evolution in high-grade serous ovarian carcinoma

Resistance to chemotherapy in ovarian cancer is poorly understood. Evolutionary models of cancer predict that, following treatment, resistance emerges either because of outgrowth of an intrinsically resistant sub-clone or evolves in residual disease under the selective pressure of treatment. To investigate genetic evolution in high-grade serous (HGS) ovarian cancers, we first analysed cell line series derived from three cases of HGS carcinoma before and after platinum resistance had developed (PEO1, PEO4 and PEO6; PEA1 and PEA2; and PEO14 and PEO23). Analysis with 24-colour fluorescence in situ hybridisation and single nucleotide polymorphism (SNP) array comparative genomic hybridisation (CGH) showed mutually exclusive endoreduplication and loss of heterozygosity events in clones present at different time points in the same individual. This implies that platinum-sensitive and -resistant disease was not linearly related, but shared a common ancestor at an early stage of tumour development. Array CGH analysis of six paired pre- and post-neoadjuvant treatment HGS samples from the CTCR-OV01 clinical study did not show extensive copy number differences, suggesting that one clone was strongly dominant at presentation. These data show that cisplatin resistance in HGS carcinoma develops from pre-existing minor clones but that enrichment for these clones is not apparent during short-term chemotherapy treatment.

[1]  T. Herzog,et al.  Ovarian cancer: a focus on management of recurrent disease , 2006, Nature Clinical Practice Oncology.

[2]  D. Huntsman,et al.  Critical molecular abnormalities in high-grade serous carcinoma of the ovary , 2008, Expert Reviews in Molecular Medicine.

[3]  A. Ashworth,et al.  Hallmarks of 'BRCAness' in sporadic cancers , 2004, Nature Reviews Cancer.

[4]  Ryan D. Morin,et al.  Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution , 2009, Nature.

[5]  F. Couch,et al.  Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers , 2008, Nature.

[6]  D J Porteous,et al.  WWOX: A candidate tumor suppressor gene involved in multiple tumor types , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[7]  A. McClatchey,et al.  Nf2/Merlin: a coordinator of receptor signalling and intercellular contact , 2007, British Journal of Cancer.

[8]  Robert C. Bast,et al.  The biology of ovarian cancer: new opportunities for translation , 2009, Nature Reviews Cancer.

[9]  Noam Harpaz,et al.  Molecular phenotype of inflammatory bowel disease-associated neoplasms with microsatellite instability. , 2005, Gastroenterology.

[10]  T. Herzog.  Recurrent Ovarian Cancer , 2004, Clinical Cancer Research.

[11]  D J Ruiter,et al.  HISTOLOGICAL GRADE HETEROGENEITY IN MULTIFOCAL PROSTATE CANCER. BIOLOGICAL AND CLINICAL IMPLICATIONS , 1996, The Journal of pathology.

[12]  Thomas J. Hardcastle,et al.  Chromosomal instability determines taxane response , 2009, Proceedings of the National Academy of Sciences.

[13]  P. Edwards,et al.  Distribution of breakpoints on chromosome 18 in breast, colorectal, and pancreatic carcinoma cell lines. , 2006, Cancer genetics and cytogenetics.

[14]  S. Kitano,et al.  Identification and Cloning of Human G-Protein γ 7, Down-regulated in Pancreatic Cancer , 1998 .

[15]  N. Kley,et al.  A novel moesin-, ezrin-, radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor. , 1993, Cell.

[16]  Carlos Caldas,et al.  Driver mutations in TP53 are ubiquitous in high grade serous carcinoma of the ovary , 2010, The Journal of pathology.

[17]  Monique Albert,et al.  Parallel analysis of sporadic primary ovarian carcinomas by spectral karyotyping, comparative genomic hybridization, and expression microarrays. , 2002, Cancer research.

[18]  C. Cordon-Cardo,et al.  A multigenic program mediating breast cancer metastasis to bone. , 2003, Cancer cell.

[19]  D. Hanahan,et al.  The Hallmarks of Cancer , 2000, Cell.

[20]  W. Hofmann,et al.  Presence of the BCR-ABL mutation Glu255Lys prior to STI571 (imatinib) treatment in patients with Ph+ acute lymphoblastic leukemia. , 2003, Blood.

[21]  M. Toyoda,et al.  jumonji downregulates cardiac cell proliferation by repressing cyclin D1 expression. , 2003, Developmental cell.

[22]  Joshy George,et al.  Integrated Genome-Wide DNA Copy Number and Expression Analysis Identifies Distinct Mechanisms of Primary Chemoresistance in Ovarian Carcinomas , 2009, Clinical Cancer Research.

[23]  James R. Downing,et al.  Genomic Analysis of the Clonal Origins of Relapsed Acute Lymphoblastic Leukemia , 2008, Science.

[24]  J. McAlpine,et al.  Tumor heterogeneity in ovarian cancer as demonstrated by in vitro chemoresistance assays. , 2008, Gynecologic oncology.

[25]  R. Agarwal,et al.  Ovarian cancer: strategies for overcoming resistance to chemotherapy , 2003, Nature Reviews Cancer.

[26]  R. Weichselbaum,et al.  The Breast Cancer Susceptibility Gene BRCA1 Is Required for Subnuclear Assembly of Rad51 and Survival following Treatment with the DNA Cross-linking Agent Cisplatin* , 2000, The Journal of Biological Chemistry.

[27]  L. Foroni,et al.  Mechanisms of relapse in acute leukaemia: involvement of p53 mutated subclones in disease progression in acute lymphoblastic leukaemia , 1999, British Journal of Cancer.

[28]  J. Andersen,et al.  Intratumor genomic heterogeneity in breast cancer with clonal divergence between primary carcinomas and lymph node metastases , 2007, Breast Cancer Research and Treatment.

[29]  B. Karlan,et al.  Secondary BRCA1 mutations in BRCA1-mutated ovarian carcinomas with platinum resistance. , 2008, Cancer research.

[30]  C. Maley,et al.  Cancer is a disease of clonal evolution within the body1–3. This has profound clinical implications for neoplastic progression, cancer prevention and cancer therapy. Although the idea of cancer as an evolutionary problem , 2006 .

[31]  C. Caldas,et al.  The Extracellular Matrix Protein TGFBI Induces Microtubule Stabilization and Sensitizes Ovarian Cancers to Paclitaxel , 2007, Cancer cell.

[32]  S. Rubin,et al.  Second-line platinum therapy in patients with ovarian cancer previously treated with cisplatin. , 1991, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[33]  A. Schäffer,et al.  Stable karyotypes in epithelial cancer cell lines despite high rates of ongoing structural and numerical chromosomal instability. , 2002, Neoplasia.

[34]  I. Jacobs,et al.  Genetic intra‐tumour heterogeneity in epithelial ovarian cancer and its implications for molecular diagnosis of tumours , 2007, The Journal of pathology.

[35]  M. Skolnick,et al.  A cell cycle regulator potentially involved in genesis of many tumor types. , 1994, Science.

[36]  J. Brenton,et al.  Regulators of mitotic arrest and ceramide metabolism are determinants of sensitivity to paclitaxel and other chemotherapeutic drugs. , 2007, Cancer cell.

[37]  P. Nowell.  The clonal evolution of tumor cell populations. , 1976, Science.

[38]  A. Mes-Masson,et al.  Characterization of three new serous epithelial ovarian cancer cell lines , 2008, BMC Cancer.

[39]  Jun Luo,et al.  Copy Number Analysis Indicates Monoclonal Origin of Lethal Metastatic Prostate Cancer , 2009, Nature Medicine.

[40]  S. Kitano,et al.  Identification and cloning of human G-protein gamma 7, down-regulated in pancreatic cancer. , 1998, Biochemical and biophysical research communications.

[41]  J. Smyth,et al.  Characterization and properties of nine human ovarian adenocarcinoma cell lines. , 1988, Cancer research.

[42]  F. Couch,et al.  Edinburgh Research Explorer Functional restoration of BRCA2 protein by secondary BRCA2 mutations in BRCA2-mutated ovarian carcinoma , 2022 .

[43]  J. Haines,et al.  A novel moesin-, ezrin-, radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor , 1993, Cell.