174 results found
Garner IM, Brown R, 2022, Is there a role for epigenetic therapies in modulating dna damage repair pathways to enhance chemotherapy and overcome drug resistance?, Cancers (Basel), Vol: 14, ISSN: 2072-6694
Epigenetic therapies describe drug molecules such as DNA methyltransferase, histone methyltransferase and histone acetylase/deacetylase inhibitors, which target epigenetic mechanisms such as DNA methylation and histone modifications. Many DNA damage response (DDR) genes are epigenetically regulated in cancer leading to transcriptional silencing and the loss of DNA repair capacity. Epigenetic marks at DDR genes, such as DNA methylation at gene promoters, have the potential to be used as stratification biomarkers, identifying which patients may benefit from particular chemotherapy treatments. For genes such as MGMT and BRCA1, promoter DNA methylation is associated with chemosensitivity to alkylating agents and platinum coordination complexes, respectively, and they have use as biomarkers directing patient treatment options. In contrast to epigenetic change leading to chemosensitivity, DNA methylation of DDR genes involved in engaging cell death responses, such as MLH1, are associated with chemoresistance. This contrasting functional effect of epigenetic modification on chemosensitivity raises challenges in using DNA-demethylating agents, and other epigenetic approaches, to sensitise tumours to DNA-damaging chemotherapies and molecularly targeted agents. Demethylation of MGMT/BRCA1 could lead to drug resistance whereas demethylation of MLH1 could sensitise cells to chemotherapy. Patient selection based on a solid understanding of the disease pathway will be one means to tackle these challenges. The role of epigenetic modification of DDR genes during tumour development, such as causing a mutator phenotype, has different selective pressures and outcomes compared to epigenetic adaptation during treatment. The prevention of epigenetic adaptation during the acquisition of drug resistance will be a potential strategy to improve the treatment of patients using epigenetic therapies.
McNeish I, Spiliopoulou P, Spear S, et al., 2022, Dual G9A/EZH2 inhibition stimulates anti-tumour immune response in ovarian high-grade serous carcinoma, Molecular Cancer Therapeutics, Vol: 21, Pages: 522-534, ISSN: 1535-7163
Ovarian high-grade serous carcinoma (HGSC) prognosis correlates directly with presence of intratumoral lymphocytes. However, cancer immunotherapy has yet to achieve meaningful survival benefit in patients with HGSC. Epigenetic silencing of immunostimulatory genes is implicated in immune evasion in HGSC and re-expression of these genes could promote tumour immune clearance. We discovered that simultaneous inhibition of the histone methyltransferases G9A and EZH2 activates the CXCL10-CXCR3 axis and increases homing of intratumoral effector lymphocytes and natural killer cells whilst suppressing tumour-promoting FoxP3+ CD4 T cells. The dual G9A/EZH2 inhibitor HKMTI-1-005 induced chromatin changes that resulted in the transcriptional activation of immunostimulatory gene networks, including the re-expression of elements of the ERV-K endogenous retroviral family. Importantly, treatment with HKMTI-1-005 improved the survival of mice bearing Trp53-/- null ID8 ovarian tumours and resulted in tumour burden reduction. These results indicate that inhibiting G9A and EZH2 in ovarian cancer alters the immune microenvironment and reduces tumour growth and therefore positions dual inhibition of G9A/EZH2 as a strategy for clinical development.
Garner IM, Su Z, Hu S, et al., 2021, Modulation of homologous recombination repair pathway gene expression by a dual EZH2 and EHMT2 histone methyltransferase inhibitor and synergy with PARP inhibitors in ovarian cancer., Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Gallon J, Curry E, Loomis E, et al., 2021, Chromatin accessibility changes at intergenic regions associate with ovarian cancer drug resistance, Clinical Epigenetics, Vol: 13, Pages: 1-15, ISSN: 1868-7083
BackgroundResistance to DNA damaging chemotherapies leads to cancer treatment failure and poor patient prognosis. We investigated how genomic distribution of accessible chromatin sites is altered during acquisition of cisplatin resistance using matched ovarian cell lines from high grade serous ovarian cancer (HGSOC) patients before and after becoming clinically resistant to platinum-based chemotherapy.ResultsResistant lines show altered chromatin accessibility at intergenic regions, but less so at gene promoters. Clusters of cis-regulatory elements at these intergenic regions show chromatin changes that are associated with altered expression of linked genes, with enrichment for genes involved in the Fanconi anemia/BRCA DNA damage response pathway. Further, genome-wide distribution of platinum adducts associates with the chromatin changes observed and distinguish sensitive from resistant lines. In the resistant line, we observe fewer adducts around gene promoters and more adducts at intergenic regions.ConclusionsChromatin changes at intergenic regulators of gene expression are associated with in vivo derived drug resistance and Pt-adduct distribution in patient-derived HGSOC drug resistance models.
Gallon J, Loomis E, Curry E, et al., 2021, Chromatin accessibility changes at intergenic regions associates with ovarian cancer drug resistance, Clinical Epigenetics, ISSN: 1868-7083
<jats:title>Abstract</jats:title><jats:p>We have investigated how genomic distribution of chromatin accessibilities alter during acquisition of resistance to carboplatin-based chemotherapy using matched ovarian cell lines from high grade serous ovarian cancer (HGSOC) patients before and after becoming clinically resistant to platinum-based chemotherapy. Resistant lines show altered chromatin accessibility at intergenic regions, but less so at gene promoters. Super-enhancers, as defined by clusters of cis-regulatory elements, at these intergenic regions show chromatin changes that are associated with altered expression of linked genes, with enrichment for genes involved in the Fanconi anemia/BRCA DNA damage response pathway. Further, genome-wide distribution of platinum adducts associates with the chromatin changes observed and distinguish sensitive from resistant lines. In the resistant line, we observe fewer adducts around gene promoters and more adducts at intergenic regions. Thus, chromatin changes at intergenic regulators of gene expression are associated with <jats:italic>in vivo</jats:italic> derived drug resistance and Pt-adduct distribution in patient-derived HGSOC drug resistance models.</jats:p>
Hoppe MM, Jaynes P, Wardyn JD, et al., 2021, Quantitative imaging of RAD51 expression as a marker of platinum resistance in ovarian cancer, EMBO MOLECULAR MEDICINE, Vol: 13, ISSN: 1757-4676
Kaur H, Salles D, Murali S, et al., 2021, Homologous Recombination Deficiency (HRD) Score in Germline BRCA2-Versus ATM-Altered Prostate Cancer, Publisher: SPRINGERNATURE, Pages: 575-576, ISSN: 0023-6837
Kaur H, Salles D, Murali S, et al., 2021, Homologous Recombination Deficiency (HRD) Score in Germline BRCA2-Versus ATM-Altered Prostate Cancer, Publisher: SPRINGERNATURE, Pages: 575-576, ISSN: 0893-3952
Lotan TL, Kaur HB, Salles DC, et al., 2021, Homologous recombination deficiency (HRD) score in germline BRCA2- versus ATM-altered prostate cancer, MODERN PATHOLOGY, Vol: 34, Pages: 1185-1193, ISSN: 0893-3952
Natoli M, Gallon J, Lu H, et al., 2021, Transcriptional analysis of multiple ovarian cancer cohorts reveals prognostic and immunomodulatory consequences of ERV expression, Journal for ImmunoTherapy of Cancer, Vol: 9, ISSN: 2051-1426
Background Endogenous retroviruses (ERVs) play a role in a variety of biological processes, including embryogenesis and cancer. DNA methyltransferase inhibitors (DNMTi)-induced ERV expression triggers interferon responses in ovarian cancer cells via the viral sensing machinery. Baseline expression of ERVs also occurs in cancer cells, though this process is poorly understood and previously unexplored in epithelial ovarian cancer (EOC). Here, the prognostic and immunomodulatory consequences of baseline ERV expression was assessed in EOC.Methods ERV expression was assessed using EOC transcriptional data from The Cancer Genome Atlas (TCGA) and from an independent cohort (Hammersmith Hospital, HH), as well as from untreated or DNMTi-treated EOC cell lines. Least absolute shrinkage and selection operator (LASSO) logistic regression defined an ERV expression score to predict patient prognosis. Immunohistochemistry (IHC) was conducted on the HH cohort. Combination of DNMTi treatment with γδ T cells was tested in vitro, using EOC cell lines and patient-derived tumor cells.Results ERV expression was found to define clinically relevant subsets of EOC patients. An ERV prognostic score was successfully generated in TCGA and validated in the independent cohort. In EOC patients from this cohort, a high ERV score was associated with better survival (log-rank p=0.0009) and correlated with infiltration of CD8+PD1+T cells (r=0.46, p=0.0001). In the TCGA dataset, a higher ERV score was found in BRCA1/2 mutant tumors, compared to wild type (p=0.015), while a lower ERV score was found in CCNE1 amplified tumors, compared to wild type (p=0.019). In vitro, baseline ERV expression dictates the level of ERV induction in response to DNMTi. Manipulation of an ERV expression threshold by DNMTi resulted in improved EOC cell killing by cytotoxic immune cells.Conclusions These findings uncover the potential for baseline ERV expression to robustly inform EOC patient prognosis, influence
Timms K, Mills G, Perry M, et al., 2020, COMPARISON OF GENOMIC INSTABILITY TEST SCORES USED FOR PREDICTING PARP ACTIVITY IN OVARIAN CANCER, Publisher: BMJ PUBLISHING GROUP, Pages: A111-A111, ISSN: 1048-891X
McNeish I, Ennis D, Stronach E, 2020, Development and validation of the gene-expression Predictor of high-grade-serous Ovarian carcinoma molecular subTYPE (PrOTYPE), Clinical Cancer Research, Vol: 26, Pages: 5411-5423, ISSN: 1078-0432
Purpose: Gene expression–based molecular subtypes of high-grade serous tubo-ovarian cancer (HGSOC), demonstrated across multiple studies, may provide improved stratification for molecularly targeted trials. However, evaluation of clinical utility has been hindered by nonstandardized methods, which are not applicable in a clinical setting. We sought to generate a clinical grade minimal gene set assay for classification of individual tumor specimens into HGSOC subtypes and confirm previously reported subtype-associated features.Experimental Design: Adopting two independent approaches, we derived and internally validated algorithms for subtype prediction using published gene expression data from 1,650 tumors. We applied resulting models to NanoString data on 3,829 HGSOCs from the Ovarian Tumor Tissue Analysis consortium. We further developed, confirmed, and validated a reduced, minimal gene set predictor, with methods suitable for a single-patient setting.Results: Gene expression data were used to derive the predictor of high-grade serous ovarian carcinoma molecular subtype (PrOTYPE) assay. We established a de facto standard as a consensus of two parallel approaches. PrOTYPE subtypes are significantly associated with age, stage, residual disease, tumor-infiltrating lymphocytes, and outcome. The locked-down clinical grade PrOTYPE test includes a model with 55 genes that predicted gene expression subtype with >95% accuracy that was maintained in all analytic and biological validations.Conclusions: We validated the PrOTYPE assay following the Institute of Medicine guidelines for the development of omics-based tests. This fully defined and locked-down clinical grade assay will enable trial design with molecular subtype stratification and allow for objective assessment of the predictive value of HGSOC molecular subtypes in precision medicine applications.
Millstein J, Budden T, Goode EL, et al., 2020, Prognostic gene expression signature for high-grade serous ovarian cancer, Annals of Oncology, Vol: 31, Pages: 1240-1250, ISSN: 0923-7534
BackgroundMedian overall survival (OS) for women with high-grade serous ovarian cancer (HGSOC) is approximately four years, yet survival varies widely between patients. There are no well-established, gene expression signatures associated with prognosis. The aim of this study was to develop a robust prognostic signature for overall survival in HGSOC patients.Patients and methodsExpression of 513 genes, selected from a meta-analysis of 1455 tumours and other candidates, were measured using NanoString technology from formalin-fixed, paraffin-embedded (FFPE) tumour tissue from 3,769 women with HGSOC from multiple studies. Elastic net regularization for survival analysis was applied to develop a prognostic model for 5-year OS, trained on 2702 tumours from fifteen studies and evaluated on an independent set of 1067 tumours from six studies.ResultsExpression levels of 276 genes were associated with OS [false discovery rate (FDR) < 0.05] in covariate-adjusted single gene analyses. The top five genes were TAP1, ZFHX4, CXCL9, FBN1, and PTGER3 (P < 0.001). The best performing prognostic signature included 101 genes enriched in pathways with treatment implications. Each gain of one standard deviation in the gene expression score (GES) conferred a greater than two-fold increase in risk of death [HR = 2.35 (2.02, 2.71); P < 0.001]. Median survival by GES quintile was 9.5 (8.3, --), 5.4 (4.6, 7.0), 3.8 (3.3, 4.6), 3.2 (2.9, 3.7) and 2.3 (2.1, 2.6) years.ConclusionThe OTTA-SPOT (Ovarian Tumor Tissue Analysis consortium - Stratified Prognosis of Ovarian Tumours) gene expression signature may improve risk stratification in clinical trials by identifying patients who are least likely to achieve 5-year survival. The identified novel genes associated with the outcome may also yield opportunities for the development of targeted therapeutic approaches.
Timms KM, Mills GB, Perry M, et al., 2020, Comparison of genomic instability test scores used for predicting PARP activity in ovarian cancer., Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO), Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0732-183X
Brunton H, Caligiuri G, Cunningham R, et al., 2020, HNF4A and GATA6 Loss Reveals Therapeutically Actionable Subtypes in Pancreatic Cancer, CELL REPORTS, Vol: 31, ISSN: 2211-1247
Spiliopoulou P, Spear S, Dowson S, et al., 2019, Inhibiting Ehmt2 and Ezh2 histone methyltransferases alters the immune microenvironment in a Trp53(-/-) murine ovarian cancer model, Cancer Conference of the National-Cancer-Research-Institute (NCRI), Publisher: NATURE PUBLISHING GROUP, Pages: 1-1, ISSN: 0007-0920
Scott AJ, Alexander JL, Merrifield CA, et al., 2019, International Cancer Microbiome Consortium consensus statement on the role of the human microbiome in carcinogenesis, Gut, Vol: 68, Pages: 1624-1632, ISSN: 0017-5749
Objective In this consensus statement, an international panel of experts deliver their opinions on key questions regarding the contribution of the human microbiome to carcinogenesis.Design International experts in oncology and/or microbiome research were approached by personal communication to form a panel. A structured, iterative, methodology based around a 1-day roundtable discussion was employed to derive expert consensus on key questions in microbiome-oncology research.Results Some 18 experts convened for the roundtable discussion and five key questions were identified regarding: (1) the relevance of dysbiosis/an altered gut microbiome to carcinogenesis; (2) potential mechanisms of microbiota-induced carcinogenesis; (3) conceptual frameworks describing how the human microbiome may drive carcinogenesis; (4) causation versus association; and (5) future directions for research in the field.The panel considered that, despite mechanistic and supporting evidence from animal and human studies, there is currently no direct evidence that the human commensal microbiome is a key determinant in the aetiopathogenesis of cancer. The panel cited the lack of large longitudinal, cohort studies as a principal deciding factor and agreed that this should be a future research priority. However, while acknowledging gaps in the evidence, expert opinion was that the microbiome, alongside environmental factors and an epigenetically/genetically vulnerable host, represents one apex of a tripartite, multidirectional interactome that drives carcinogenesis.Conclusion Data from longitudinal cohort studies are needed to confirm the role of the human microbiome as a key driver in the aetiopathogenesis of cancer.
Kubler K, Karlic R, Haradhvala NJ, et al., 2019, The premalignant state captured in the landscape of somatic mutations can reveal the cancer cell-of-origin, Annual Meeting of the American-Association-for-Cancer-Research (AACR), Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Stronach EA, Paul J, Timms KM, et al., 2018, Biomarker assessment of HR deficiency, tumor BRCA1/2 mutations and CCNE1 copy number in ovarian cancer: associations with clinical outcome following platinum monotherapy, Molecular Cancer Research, Vol: 16, Pages: 1103-1111, ISSN: 1541-7786
The current study evaluated three biomarkers [homologous recombination deficiency (HRD), tumor BRCA1/2 (tBRCA) mutations, and CCNE1 copy number variation (CNV)] in ovarian tumors from patients enrolled on the SCOTROC4 clinical trial for associations with outcome following carboplatinum monotherapy. Ovarian tumors (n=250), with high-grade serous (HGSOC) subgroup analysis (n=179), were classified as HRD positive (HRD score ≥42 or tBRCA mutation) and as CCNE1 amplification positive (CCNE1 CNV score >2.4). Seventy-four (30%) tumors were HRD positive, including 34 (14%) with tBRCA mutations. Forty-seven (19%) were CCNE1 amplification positive, all of which were tBRCA wild-type. HRD and tBRCA, but not CCNE1 amplification, were significantly associated with CA125 complete response in the entire cohort (HRD, p=0.00015; tBRCA p=0.0096), and the HGSOC subgroup (HRD, p= 0.0016; tBRCA p=0.032). HRD and lack of CCNE1 amplification were associated with improved progression free survival (PFS) and overall survival (OS) in the full cohort and HGSOC subgroup (HRD, p=0.00021; CCNE1 status p=0.038). HRD remained significant for OS and PFS after adjusting for clinical factors, while CCNE1 status only remained significant for PFS. Patients with HRD positive tumors had greater PFS and OS benefit from platinum dose intensification than HRD negative tumors (p=0.049 and p=0.035, respectively). An alternative exploratory HRD score threshold (≥33 or tBRCA mutation) was also significantly associated with both PFS and OS in the HGSOC subset. IMPLICATIONS: HRD, tumor BRCA1/2 mutations and absence of CCNE1 amplification are associated with improved survival of ovarian cancer patients treated with platinum monotherapy and HRD positive patients may benefit from platinum dose intensification.
Gallon J, Loomis E, Martin N, et al., 2018, The chromatin context and consequence of cisplatin-adduct DNA damage, Annual Meeting of the American-Association-for-Cancer-Research (AACR), Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Brown R, Curry E, Zeller C, et al., 2018, Genes predisposed to DNA hypermethylation during acquired resistance to chemotherapy are identified in ovarian tumors by bivalent chromatin domains at initial diagnosis, Cancer Research, Vol: 78, Pages: 1383-1391, ISSN: 1538-7445
Bivalent chromatin domains containing both active H3K4me3 and repressive H3K27me3 histone marks define gene sets poised for expression or silencing in differentiating embryonic stem (ES) cells. In cancer cells, aberrantly poised genes may facilitate changes in transcriptional states after exposure to anticancer drugs. In this study, we used ChIP-seq to characterize genome-wide positioning of H3K4me3- and H3K27me3-associated chromatin in primary high-grade serous ovarian carcinomas and in normal ovarian surface and fallopian tube tissue. Gene sets with proximal bivalent marks defined in this manner were evaluated subsequently as signatures of systematic change in DNA methylation and gene expression, comparing pairs of tissue samples taken from patients at primary presentation and relapse following chemotherapy. We found that gene sets harboring bivalent chromatin domains at their promoters in tumor tissue, but not normal epithelia, overlapped with Polycomb-repressive complex target genes as well as transcriptionally silenced genes in normal ovarian and tubal stem cells. The bivalently marked genes we identified in tumors before chemotherapy displayed increased promoter CpG methylation and reduced gene expression at relapse after chemotherapy of ovarian cancer. Overall, our results support the hypothesis that preexisting histone modifications at genes in a poised chromatin state may lead to epigenetic silencing during acquired drug resistance.
tutt A, tovey H, Cheang MCU, et al., 2018, Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT Trial, Nature Medicine, Vol: 24, Pages: 628-637, ISSN: 1078-8956
Germline mutations in BRCA1/2 predispose individuals to breast cancer (termed germline-mutated BRCA1/2 breast cancer, gBRCA-BC) by impairing homologous recombination (HR) and causing genomic instability. HR also repairs DNA lesions caused by platinum agents and PARP inhibitors. Triple-negative breast cancers (TNBCs) harbor subpopulations with BRCA1/2 mutations, hypothesized to be especially platinum-sensitive. Cancers in putative ‘BRCAness’ subgroups—tumors with BRCA1 methylation; low levels of BRCA1 mRNA (BRCA1 mRNA-low); or mutational signatures for HR deficiency and those with basal phenotypes—may also be sensitive to platinum. We assessed the efficacy of carboplatin and another mechanistically distinct therapy, docetaxel, in a phase 3 trial in subjects with unselected advanced TNBC. A prespecified protocol enabled biomarker–treatment interaction analyses in gBRCA-BC and BRCAness subgroups. The primary endpoint was objective response rate (ORR). In the unselected population (376 subjects; 188 carboplatin, 188 docetaxel), carboplatin was not more active than docetaxel (ORR, 31.4% versus 34.0%, respectively; P = 0.66). In contrast, in subjects with gBRCA-BC, carboplatin had double the ORR of docetaxel (68% versus 33%, respectively; biomarker, treatment interaction P = 0.01). Such benefit was not observed for subjects with BRCA1 methylation, BRCA1 mRNA-low tumors or a high score in a Myriad HRD assay. Significant interaction between treatment and the basal-like subtype was driven by high docetaxel response in the nonbasal subgroup. We conclude that patients with advanced TNBC benefit from characterization of BRCA1/2 mutations, but not BRCA1 methylation or Myriad HRD analyses, to inform choices on platinum-based chemotherapy. Additionally, gene expression analysis of basal-like cancers may also influence treatment selection.
Phelps DL, Balog J, Gildea LF, et al., 2018, The surgical intelligent knife distinguishes normal, borderline and malignant gynaecological tissues using rapid evaporative ionisation mass spectrometry (REIMS), British Journal of Cancer, Vol: 118, Pages: 1349-1358, ISSN: 0007-0920
BackgroundSurvival from ovarian cancer (OC) is improved with surgery, but surgery can be complex and tumour identification, especially for borderline ovarian tumours (BOT), is challenging. The Rapid Evaporative Ionisation Mass Spectrometric (REIMS) technique reports tissue histology in real-time by analysing aerosolised tissue during electrosurgical dissection.MethodsAerosol produced during diathermy of tissues was sampled with the REIMS interface. Histological diagnosis and mass spectra featuring complex lipid species populated a reference database on which principal component, linear discriminant and leave-one-patient-out cross-validation analyses were performed.ResultsA total of 198 patients provided 335 tissue samples, yielding 3384 spectra. Cross-validated OC classification vs separate normal tissues was high (97·4% sensitivity, 100% specificity). BOT were readily distinguishable from OC (sensitivity 90.5%, specificity 89.7%). Validation with fresh tissue lead to excellent OC detection (100% accuracy). Histological agreement between iKnife and histopathologist was very good (kappa 0.84, P < 0.001, z = 3.3). Five predominantly phosphatidic acid (PA(36:2)) and phosphatidyl-ethanolamine (PE(34:2)) lipid species were identified as being significantly more abundant in OC compared to normal tissue or BOT (P < 0.001, q < 0.001).ConclusionsThe REIMS iKnife distinguishes gynaecological tissues by analysing mass-spectrometry-derived lipidomes from tissue diathermy aerosols. Rapid intra-operative gynaecological tissue diagnosis may improve surgical care when histology is unknown, leading to personalised operations tailored to the individual.
Hoppe MM, Tan DSP, Lim DGZ, et al., 2017, RAD51 expression as a biomarker of homologous recombination deficiency in ovarian cancer, AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer, Publisher: American Association for Cancer Research, ISSN: 1535-7163
Martyn M, Liu X, Wilhelm-Benartzi C, et al., 2017, Issues with over-fitting in predictive models produced for stratified medicine: a case study on an ovarian cancer trial, Publisher: BIOMED CENTRAL LTD, ISSN: 1745-6215
Flanagan JM, Wilson A, Koo C, et al., 2017, Platinum-based chemotherapy induces methylation changes in blood DNA associated with overall survival in ovarian cancer patients, Clinical Cancer Research, Vol: 23, Pages: 2213-2222, ISSN: 1557-3265
PURPOSE: DNA damage repair can lead to epigenetic changes. DNA mismatch repair proteins bind to platinum DNA adducts and at sites of DNA damage can recruit the DNA methylating enzyme DNMT1, resulting in aberrant methylation. We hypothesised that DNA damage repair during platinum-based chemotherapy may cause aberrant DNA methylation in normal tissues of patients such as blood. EXPERIMENTAL DESIGN: We used Illumina 450k methylation arrays and bisulphite pyrosequencing to investigate methylation at presentation and relapse in blood DNA from ovarian cancer patients enrolled in the SCOTROC1 trial (n=247) and in a cohort of ovarian tumour DNA samples collected at first relapse (n=46). We used an ovarian cancer cell line model to investigate the role of the DNA mismatch repair gene MLH1 in platinum induced methylation changes. RESULTS: Specific CpG methylation changes in blood at relapse are observed following platinum-based chemotherapy and are associated with patient survival, independent of other clinical factors (HR=3.7; 95%CI 1.8-7.6, p=2.8x10-4). Similar changes occur in ovarian tumours at relapse, also associate with patient survival (HR=2.6; 95%CI 1.0-6.8, p=0.048). Using an ovarian cancer cell line model, we demonstrate that functional mismatch repair (MMR) increases the frequency of platinum-induced methylation. CONCLUSION: DNA methylation in blood at relapse following chemotherapy, and not at presentation, is informative about ovarian cancer patient survival. Functional DNA mismatch repair increases the frequency of DNA methylation changes induced by platinum. DNA methylation in blood following chemotherapy could provide a non-invasive means of monitoring patients' epigenetic responses to treatment without requiring a tumour biopsy.
Phelps DL, Borley J, Flower K, et al., 2017, Methylation of MYLK3 gene promoter region: a biomarker to stratify surgical care in ovarian cancer in a multi-centre study, British Journal of Cancer, Vol: 116, Pages: 1287-1293, ISSN: 1532-1827
BackgroundSurvival benefit from surgical debulking of ovarian cancer (OC) is well established but some women, despite total macroscopic clearance of disease, still have poor prognosis. We aimed to identify biomarkers to predict benefit from conventional surgery.MethodsClinical data from women debulked for high-stage OC was analysed (Hammersmith Hospital, London, UK; 2001-2014). Infinium’s HumanMethylation27 array interrogated tumour-DNA for differentially-methylated CpG sites, correlated to survival, in patients with the least residual disease (RD) (Hammersmith Array). Validation was performed using bisulphite pyrosequencing (Charité Hospital, Berlin, Germany cohort) and The Cancer Genome Atlas’ (TCGA) methylation dataset. Kaplan-Meier curves and Cox models tested survival.ResultsAltogether 803 women with serous ovarian cancer were studied. No RD was associated with significantly improved overall- (OS) (hazard ratio [HR] 1.25, 95% CI 1.06-1.47; P=0.0076) and progression-free survival (PFS) (HR 1.23, 1.05-1.43; P=0.012) (Hammersmith database n=430). Differentially-methylated loci within FGF4, FGF21, MYLK2, MYLK3, MYL7, and ITGAE associated with survival. Patients with the least RD had significantly better OS with higher methylation of MYLK3 (Hammersmith (HR 0.51, 0.31-0.84; P=0.01), Charité (0.46, 0.21-1.01; P=0.05), TCGA (0.64, 0.44-0.93; P=0.02)). ConclusionMYLK3 methylation is associated with improved OS in patients with the least RD, which could potentially be used to determine response to surgery.
Weinberg PD, Hernandez ADR, Brown R, 2017, Engineering solutions for cancer, CONVERGENT SCIENCE PHYSICAL ONCOLOGY, Vol: 3, ISSN: 2057-1739
Flower KJ, Ghaem-Maghami S, Brown R, 2017, Is there a role for epigenetic enhancement of immunomodulatory approaches to cancer treatment?, Current Cancer Drug Targets, Vol: 17, ISSN: 1873-5576
The efficacy of cancer immunotherapy relies on the ability of the host immune system to recognise the cancer as non-self and eliminate it from the body. Whilst this is an extremely fertile area of medical research, with positive clinical trials showing durable responses, attention must be paid to the subset of patients that do not respond to these treatments. Immune surveillance and immunoediting by the host could itself select for immune-evasive tumour cells during tumour development leading to immunotherapy resistance. One such mechanism of non-efficacy or resistance is the epigenetic silencing of a specific gene required in the immunotherapy response pathway. Epigenetics is the study of the control of expression patterns in a cell via mechanisms not involving a change in DNA sequence. All tumour types show aberrant epigenetic regulation of genes involved in all the hallmarks of cancer, including immunomodulation. Inhibition of key enzymes involved in maintenance of epigenetic states is another important area of research for new treatment strategies for cancer. Could epigenetic therapies be used to successfully enhance the action of immunomodulatory agents in cancer, and are they acting in the way we imagine? An understanding of the effects of epigenetic therapies on immunological pathways in both the tumour and host cells, especially the tumour microenvironment, will be essential to further develop such combination approaches.
Tutt A, Cheang MCU, Kilburn L, et al., 2017, BRCA1 methylation status, silencing and treatment effect in the TNT trial: A randomized phase III trial of carboplatin compared with docetaxel for patients with metastatic or recurrent locally advanced triple negative or BRCA1/2 breast cancer (CRUK/07/012), San Antonio Breast Cancer Symposium, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
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