110 results found
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.
Bowden S, Bodinier B, Kalliala I, et al., 2021, Genetic variation in cervical preinvasive and invasive disease: a genome-wide association study, The Lancet Oncology, Vol: 22, Pages: 548-557, ISSN: 1213-9432
Background: Most uterine cervical high-risk HPV infections (hrHPV) are transient, with only a small 3fraction developing into cervical cancer. Family aggregation studies and heritability estimates suggest 4a significant inherited genetic component. Candidate gene studies and previous genome-wide 5association studies (GWAS) report associations between the human leukocyte antigen (HLA) region 6and cervical cancer. 78Methods: Adopting a genome-wide approach, we compared the genetic variation in women with 9invasive cervical cancer (ICC) and cervical intra-epithelial neoplasia (CIN) grade 3, to that in healthy 10controls using the largest reported cohort of unrelated European individuals (N=150,314)to date. We 11sought for replication in a second large independent dataset (N=128,123). We further performed a two-12sample Mendelian Randomisation approach to explore the role of risk factors in the genetic risk of 13cervical cancer.1415Findings: In our analysis (N=4,769 CIN3 and ICC cases; N=145,545 controls), of the (N=9,600,464) 16assayed and imputed SNPs, six independent variants were found associated with CIN3and ICC. These 17included novel loci rs10175462(PAX8; OR=0.87(95%CI=0.84-0.91); P=1.07x10-9) and rs27069 18(CLPTM1L;OR=0.88(95%CI=0.84-0.92); P=2.51x10-9), and previously reported signals at rs9272050 19(HLA-DQA1;OR=1.27(95%CI=1.21-1.32); P=2.51x10-28), rs6938453 (MICA;OR=0.7920(95%CI=0.75-0.83); P=1.97x10-17), rs55986091 (HLA-DQB1;OR=0.66(95%CI=0.60-0.72); 21P=6.42x10-22) and rs9266183 (HLA-B;OR=0.73(95%CI=0.64-0.83); P=1.53x10-6). Mendelian 22randomisation further supported the complementary role of smoking, age at first pregnancy, and number 23of sexual partners in the risk of developing cervical cancer.2425Interpretation: Our results provide substantial new evidence for genetic susceptibility to cervical cancer, 26including PAX8, CLPTM1LandHLA genes, suggesting disruption in apoptotic and immun
Glubb DM, Thompson DJ, Aben KKH, et al., 2021, Cross-Cancer Genome-Wide Association Study of Endometrial Cancer and Epithelial Ovarian Cancer Identifies Genetic Risk Regions Associated with Risk of Both Cancers, CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION, Vol: 30, Pages: 217-228, ISSN: 1055-9965
Shenker NS, Perdones-Montero A, Burke A, et al., 2020, Metabolomic and Metataxonomic Fingerprinting of Human Milk Suggests Compositional Stability over a Natural Term of Breastfeeding to 24 Months, NUTRIENTS, Vol: 12
Brewer H, Hirst Y, Sudha S, et al., 2020, Cancer Loyalty Card Study (CLOCS): protocol for an observational case-control study focusing on the patient interval in ovarian cancer diagnosis, BMJ Open, Vol: 10, Pages: 1-9, ISSN: 2044-6055
IntroductionOvarian Cancer is the eighth most common cancer in women worldwide, and about one infive women with ovarian cancer do not receive treatment, because they are too unwell by thetime they are diagnosed. Symptoms of ovarian cancer are non-specific or can be associatedwith other common conditions, and women experiencing these symptoms have been shownto self-manage them using over-the-counter medication. Results from a recent proof ofconcept study suggest there may be an increase in the purchases of pain killers andindigestion medication 10-12 months before ovarian cancer diagnosis. We propose a casecontrol study, as part of a larger project called the Cancer Loyalty Card Study (CLOCS), toinvestigate whether a significant change in medication purchases could be an indication forearly signs of ovarian cancer, using data already collected through store loyalty cards.Methods and AnalysisUsing a retrospective case-control design, we aim to recruit 500 women diagnosed withovarian cancer (cases) and 500 women without ovarian cancer (controls) in the UnitedKingdom who hold a loyalty card with at least one participating high street retailer. We willuse pre-existing loyalty card data to compare past purchase patterns of cases with those ofcontrols. In order to assess ovarian cancer risk in participants and their purchase patterns, wewill collect information from participants on ovarian cancer risk factors and clinical dataincluding symptoms experienced before diagnosis from recruited women with ovariancancer.Ethics and disseminationCLOCS was reviewed and approved by the North West - Greater Manchester South ResearchEthics Committee (19/NW/0427). Study outcomes will be disseminated through academicpublications, the study website, social media, and a report to the research sites that supportthe study once results are published.Study Registration NumbersCLOCS is registered with ISRCTN (14897082), NIHR portfolio (CPMS 43323), andclinicaltrials.gov (NCT03994653).
Fachal L, Aschard H, Beesley J, et al., 2020, Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes, Nature Genetics, Vol: 52, Pages: 56-73, ISSN: 1061-4036
Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (expression quantitative trait loci), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways were over-represented among the highest-confidence target genes.
Bowden SJ, Kalliala I, Veroniki AA, et al., 2019, The use of Human Papillomavirus DNA Methylation in cervical intraepithelial neoplasia: a systematic review and meta-analysis, EBioMedicine, Vol: 50, Pages: 246-259, ISSN: 2352-3964
BackgroundMethylation of viral DNA has been proposed as a novel biomarker for triage of human papillomavirus(HPV) positive women at screening. This systematic review and meta-analysis aims to assess how methylation levels change with disease severity and to determine diagnostic test accuracy (DTA) in detectinghigh-grade cervical intra-epithelial neoplasia (CIN).MethodsWe performed searches in MEDLINE, EMBASE and CENTRAL from inception to October 2019. Studies were eligible if they explored HPV methylation levels in HPV positive women. Data were extracted induplicate and requested from authors where necessary. Random-effects models and a bivariate mixed-effectsbinary regression model were applied to determine pooled effect estimates.Findings44 studies with 8819 high-risk HPV positive women were eligible. The pooled estimates for positive methylation rate in HPV16 L1 gene were higher for high-grade CIN (≥CIN2/high-grade squamousintra-epithelial lesion (HSIL) (95% confidence interval (95%CI:72·7% (47·8–92·2))) vs. low-grade CIN(≤CIN1/low-grade squamous intra-epithelial lesion (LSIL) (44·4% (95%CI:16·0–74·1))). Pooled differencein mean methylation level was significantly higher in ≥CIN2/HSIL vs. ≤CIN1/LSIL for HPV16 L1 (11·3%(95%CI:6·5–16·1)). Pooled odds ratio of HPV16 L1 methylation was 5·5 (95%CI:3·5–8·5) for ≥CIN2/HSIL vs. ≤CIN1/LSIL (p < 0·0001). HPV16 L1/L2 genes performed best in predicting CIN2 or worse(pooled sensitivity 77% (95%CI:63–87), specificity 64% (95%CI:55–71), area under the curve (0·73(95%CI:0·69–0·77)).InterpretationHigher HPV methylation is associated with increased disease severity, whilst HPV16 L1/L2 genes demonstrated high diagnostic accuracy to detect high-grade CIN in HPV16 positive women. Direct clinical use islimited by the need for a multi-genotype and standardised ass
Li A, Geyer FC, Blecua P, et al., 2019, Homologous recombination DNA repair defects in PALB2-associated breast cancers (vol 5, 23, 2019), NPJ BREAST CANCER, Vol: 5
Figlioli G, Bogliolo M, Catucci I, et al., 2019, The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer, npj Breast Cancer, Vol: 5, ISSN: 2374-4677
ArticleOpen AccessPublished: 01 November 2019The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancerGisella Figlioli, Massimo Bogliolo, […]Paolo Peterlongo npj Breast Cancer volume 5, Article number: 38 (2019) Cite this articleArticle metrics937 Accesses22 AltmetricMetricsdetailsAbstractBreast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of trunca
Bowden S, Kalliala I, Wielscher M, et al., 2019, CERVICAL INTRAEPITHELIAL NEOPLASIA AND CERVICAL CANCER: A GENOME WIDE ASSOCIATION STUDY (GWAS) OF THE UK BIOBANK COHORT, Publisher: BMJ PUBLISHING GROUP, Pages: A59-A60, ISSN: 1048-891X
Bowden S, Kalliala I, Veroniki A, et al., 2019, THE USE OF HUMAN PAPILLOMAVIRUS DNA METHYLATION IN CERVICAL INTRAEPITHELIAL NEOPLASIA: A SYSTEMATIC REVIEW AND META-ANALYSIS, Publisher: BMJ PUBLISHING GROUP, Pages: A84-A86, ISSN: 1048-891X
Oltra SS, Pena-Chilet M, Flower K, et al., 2019, Acceleration in the DNA methylation age in breast cancer tumours from very young women, SCIENTIFIC REPORTS, Vol: 9, ISSN: 2045-2322
Li A, Geyer FC, Blecua P, et al., 2019, Homologous recombination DNA repair defects in PALB2-associated breast cancers, npj Breast Cancer, Vol: 5, Pages: 1-14, ISSN: 2374-4677
Mono-allelic germline pathogenic variants in the Partner And Localizer of BRCA2 (PALB2) gene predispose to a high-risk of breast cancer development, consistent with the role of PALB2 in homologous recombination (HR) DNA repair. Here, we sought to define the repertoire of somatic genetic alterations in PALB2-associated breast cancers (BCs), and whether PALB2-associated BCs display bi-allelic inactivation of PALB2 and/or genomic features of HR-deficiency (HRD). Twenty-four breast cancer patients with pathogenic PALB2 germline mutations were analyzed by whole-exome sequencing (WES, n = 16) or targeted capture massively parallel sequencing (410 cancer genes, n = 8). Somatic genetic alterations, loss of heterozygosity (LOH) of the PALB2 wild-type allele, large-scale state transitions (LSTs) and mutational signatures were defined. PALB2-associated BCs were found to be heterogeneous at the genetic level, with PIK3CA (29%), PALB2 (21%), TP53 (21%), and NOTCH3 (17%) being the genes most frequently affected by somatic mutations. Bi-allelic PALB2 inactivation was found in 16 of the 24 cases (67%), either through LOH (n = 11) or second somatic mutations (n = 5) of the wild-type allele. High LST scores were found in all 12 PALB2-associated BCs with bi-allelic PALB2 inactivation sequenced by WES, of which eight displayed the HRD-related mutational signature 3. In addition, bi-allelic inactivation of PALB2 was significantly associated with high LST scores. Our findings suggest that the identification of bi-allelic PALB2 inactivation in PALB2-associated BCs is required for the personalization of HR-directed therapies, such as platinum salts and/or PARP inhibitors, as the vast majority of PALB2-associated BCs without PALB2 bi-allelic inactivation lack genomic features of HRD.
Beetch M, Lubecka K, Shen K, et al., 2019, Stilbenoid-Mediated Epigenetic Activation of Semaphorin 3A in Breast Cancer Cells Involves Changes in Dynamic Interactions of DNA with DNMT3A and NF1C Transcription Factor., Mol Nutr Food Res, Pages: e1801386-e1801386
SCOPE: Loci-specific increase in DNA methylation occurs in cancer and may underlie gene silencing. It is investigated whether dietary stilbenoids, resveratrol, and pterostilbene exert time-dependent effects on DNA methylation patterns and specifically methylation-silenced tumor suppressor genes in breast cancer cells. METHODS AND RESULTS: Following genome-wide DNA methylation analysis with Illumina-450K, changes characteristic of early and late response to stilbenoids are identified. Interestingly, often the same genes but at different CpG loci, the same gene families, or the same functional gene categories are affected. CpG loci that lose methylation in exposed cells correspond to genes functionally associated with cancer suppression. There is a group of genes, including SEMA3A, at which the magnitude of hypomethylation in response to stilbenoids rises with increasing invasive potential of cancer cells. Decreased DNA methylation at SEMA3A promoter and concomitant gene upregulation coincide with increased occupancy of active histone marks. Open chromatin upon exposure to stilbenoids may be linked to decreased DNMT3A binding followed by increased NF1C transcription factor occupancy. Sequestration of DNMT3A is possibly a result of stilbenoid-mediated increase in SALL3 expression, which was previously shown to bind and inhibit DNMT3A activity. CONCLUSIONS: The findings define mechanistic players in stilbenoid-mediated epigenetic reactivation of genes suppressing cancer.
Bodelon C, Ambatipudi S, Dugué P-A, et al., 2019, Blood DNA methylation and breast cancer risk: a meta-analysis of four prospective cohort studies, Breast Cancer Research, Vol: 21, ISSN: 1465-5411
BACKGROUND: Environmental and genetic factors play an important role in the etiology of breast cancer. Several small blood-based DNA methylation studies have reported risk associations with methylation at individual CpGs and average methylation levels; however, these findings require validation in larger prospective cohort studies. To investigate the role of blood DNA methylation on breast cancer risk, we conducted a meta-analysis of four prospective cohort studies, including a total of 1663 incident cases and 1885 controls, the largest study of blood DNA methylation and breast cancer risk to date. METHODS: We assessed associations with methylation at 365,145 CpGs present in the HumanMethylation450 (HM450K) Beadchip, after excluding CpGs that did not pass quality controls in all studies. Each of the four cohorts estimated odds ratios (ORs) and 95% confidence intervals (CI) for the association between each individual CpG and breast cancer risk. In addition, each study assessed the association between average methylation measures and breast cancer risk, adjusted and unadjusted for cell-type composition. Study-specific ORs were combined using fixed-effect meta-analysis with inverse variance weights. Stratified analyses were conducted by age at diagnosis (< 50, ≥ 50), estrogen receptor (ER) status (+/-), and time since blood collection (< 5, 5-10, > 10 years). The false discovery rate (q value) was used to account for multiple testing. RESULTS: The average age at blood draw ranged from 52.2 to 62.2 years across the four cohorts. Median follow-up time ranged from 6.6 to 8.4 years. The methylation measured at individual CpGs was not associated with breast cancer risk (q value > 0.59). In addition, higher average methylation level was not associated with risk of breast cancer (OR = 0.94, 95% CI = 0.85, 1.05; P = 0.26; P for study heterogeneity = 0.86
Johansson A, Palli D, Masala G, et al., 2019, Epigenome-wide association study for lifetime estrogen exposure identifies an epigenetic signature associated with breast cancer risk, Clinical Epigenetics, Vol: 11, ISSN: 1868-7083
BackgroundIt is well established that estrogens and other hormonal factors influence breast cancer susceptibility. We hypothesized that a woman’s total lifetime estrogen exposure accumulates changes in DNA methylation, detectable in the blood, which could be used in risk assessment for breast cancer.MethodsAn estimated lifetime estrogen exposure (ELEE) model was defined using epidemiological data from EPIC-Italy (n = 31,864). An epigenome-wide association study (EWAS) of ELEE was performed using existing Illumina HumanMethylation450K Beadchip (HM450K) methylation data obtained from EPIC-Italy blood DNA samples (n = 216). A methylation index (MI) of ELEE based on 31 CpG sites was developed using HM450K data from EPIC-Italy and the Generations Study and evaluated for association with breast cancer risk in an independent dataset from the Generations Study (n = 440 incident breast cancer cases matched to 440 healthy controls) using targeted bisulfite sequencing. Lastly, a meta-analysis was conducted including three additional cohorts, consisting of 1187 case-control pairs.ResultsWe observed an estimated 5% increase in breast cancer risk per 1-year longer ELEE (OR = 1.05, 95% CI 1.04–1.07, P = 3 × 10−12) in EPIC-Italy. The EWAS identified 694 CpG sites associated with ELEE (FDR Q < 0.05). We report a DNA methylation index (MI) associated with breast cancer risk that is validated in the Generations Study targeted bisulfite sequencing data (ORQ4_vs_Q1 = 1.77, 95% CI 1.07–2.93, P = 0.027) and in the meta-analysis (ORQ4_vs_Q1 = 1.43, 95% CI 1.05–2.00, P = 0.024); however, the correlation between the MI and ELEE was not validated across study cohorts.ConclusionWe have identified a blood DNA methylation signature associated with breast cancer risk in this study. Further investigation is required to confirm the inte
Flanagan JM, Skrobanski H, Shi X, et al., 2019, Self-care behaviors of ovarian cancer patients before their diagnosis: Proof-of-concept study, JMIR CANCER, Vol: 5, ISSN: 2369-1999
Background: Longer patient intervals can lead to more late-stage cancer diagnoses and higher mortality rates. Individuals may delay presenting to primary care with red flag symptoms and instead turn to the internet to seek information, purchase over-the-counter medication, and change their diet or exercise habits. With advancements in machine learning, there is the potential to explore this complex relationship between a patient’s symptom appraisal and their first consultation at primary care through linkage of existing datasets (eg, health, commercial, and online).Objective: Here, we aimed to explore feasibility and acceptability of symptom appraisal using commercial- and health-data linkages for cancer symptom surveillance.Methods: A proof-of-concept study was developed to assess the general public’s acceptability of commercial- and health-data linkages for cancer symptom surveillance using a qualitative focus group study. We also investigated self-care behaviors of ovarian cancer patients using high-street retailer data, pre- and postdiagnosis.Results: Using a high-street retailer’s data, 1118 purchases—from April 2013 to July 2017—by 11 ovarian cancer patients and one healthy individual were analyzed. There was a unique presence of purchases for pain and indigestion medication prior to cancer diagnosis, which could signal disease in a larger sample. Qualitative findings suggest that the public are willing to consent to commercial- and health-data linkages as long as their data are safeguarded and users of this data are transparent about their purposes.Conclusions: Cancer symptom surveillance using commercial data is feasible and was found to be acceptable. To test efficacy of cancer surveillance using commercial data, larger studies are needed with links to individual electronic health records.
Mavaddat N, Michailidou K, Dennis J, et al., 2019, Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes., American journal of human genetics, Vol: 104, Pages: 21-34, ISSN: 0002-9297
Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57-1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628-0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.
Oltra SS, Pena-Chilet M, Vidal-Tomas V, et al., 2018, Methylation deregulation of miRNA promoters identifies miR124-2 as a survival biomarker in Breast Cancer in very young women, Scientific Reports, Vol: 8, ISSN: 2045-2322
MiRNAs are part of the epigenetic machinery, and are also epigenetically modified by DNA methylation. MiRNAs regulate expression of different genes, so any alteration in their methylation status may affect their expression. We aimed to identify methylation differences in miRNA encoding genes in breast cancer affecting women under 35 years old (BCVY), in order to identify potential biomarkers in these patients. In Illumina Infinium MethylationEPIC BeadChip samples (metEPICVal), we analysed the methylation of 9,961 CpG site regulators of miRNA-encoding genes present in the array. We identified 193 differentially methylated CpG sites in BCVY (p-value < 0.05 and methylation differences ±0.1) that regulated 83 unique miRNA encoding genes. We validated 10 CpG sites using two independent datasets based on Infinium Human Methylation 450k array. We tested gene expression of miRNAs with differential methylation in BCVY in a meta-analysis using The Cancer Genome Atlas (TCGA), Clariom D and Affymetrix datasets. Five miRNAs (miR-9, miR-124-2, miR-184, miR-551b and miR-196a-1) were differently expressed (FDR p-value < 0.01). Finally, only miR-124-2 shows a significantly different gene expression by quantitative real-time PCR. MiR-124-hypomethylation presents significantly better survival rates for older patients as opposed to the worse prognosis observed in BCVY, identifying it as a potential specific survival biomarker in BCVY.
Lubecka K, Flower K, Beetch M, et al., 2018, Loci-specific differences in blood DNA methylation in HBV-negative populations at risk for hepatocellular carcinoma development, Epigenetics, Vol: 13, Pages: 605-626, ISSN: 1559-2294
Late onset of clinical symptoms in hepatocellular carcinoma (HCC) results in late diagnosis and poor disease outcome. Approximately 85% of individuals with HCC have underlying liver cirrhosis. However, not all cirrhotic patients develop cancer. Reliable tools that would distinguish cirrhotic patients who will develop cancer from those who will not are urgently needed. We used the Illumina HumanMethylation450 BeadChip microarray to test whether white blood cell DNA, an easily accessible source of DNA, exhibits site-specific changes in DNA methylation in blood of diagnosed HCC patients (post-diagnostic, 24 cases, 24 controls) and in prospectively collected blood specimens of HCC patients who were cancer-free at blood collection (pre-diagnostic, 21 cases, 21 controls). Out of 22 differentially methylated loci selected for validation by pyrosequencing, 19 loci with neighbouring CpG sites (probes) were confirmed in the pre-diagnostic study group and subjected to verification in a prospective cirrhotic cohort (13 cases, 23 controls). We established for the first time 9 probes that could distinguish HBV-negative cirrhotic patients who subsequently developed HCC from those who stayed cancer-free. These probes were identified within regulatory regions of BARD1, MAGEB3, BRUNOL5, FXYD6, TET1, TSPAN5, DPPA5, KIAA1210, and LSP1. Methylation levels within DPPA5, KIAA1210, and LSP1 were higher in prospective samples from HCC cases versus cirrhotic controls. The remaining probes were hypomethylated in cases compared with controls. Using blood as a minimally invasive material and pyrosequencing as a straightforward quantitative method, the established probes have potential to be developed into a routine clinical test after validation in larger cohorts.
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
Johansson A, Palli D, Masala G, et al., 2018, DNA methylation index of lifetime estrogen exposure in breast cancer, Annual Meeting of the American-Association-for-Cancer-Research (AACR), Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Galea F, White PA, Arlt VM, et al., 2018, The epigenetic effects of benzo[a]pyrene exposure, Annual Meeting of the American-Association-for-Cancer-Research (AACR), Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Bodelon C, Ambatipudi S, Dugue P-A, et al., 2018, Genome-wide blood DNA methylation and breast cancer risk: A meta-analysis of four prospective studies, Annual Meeting of the American-Association-for-Cancer-Research (AACR), Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Tyndall C, Lam C, Gunter M, et al., 2018, Metformin's potential as a breast cancer preventative agent by altering epigenetic patterns, Annual Meeting of the American-Association-for-Cancer-Research (AACR), Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
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.
Perry MM, Lavender P, Scott Kuo C-H, et al., 2018, DNA methylation modules in airway smooth muscle are associated with asthma severity, European Respiratory Journal, Vol: 51, ISSN: 0903-1936
Abnormal DNA methylation patterns distinguish airway smooth muscle cell function in asthma and asthma severity.
Johansson A, Flanagan JM, 2017, Epigenome-wide association studies for breast cancer risk and risk factors, Trends in cancer research, Vol: 12, Pages: 19-28, ISSN: 0973-1040
There have been six epigenome-wide association studies (EWAS) for breast cancer risk using blood DNA from prospective cohorts published thus far, and the only consistent finding is a global loss of methylation observed in breast cancer cases compared with controls, with no individual CpG sites passing validation across studies. In contrast, a more successful approach has been the identification of EWAS signatures of cancer risk factors such as smoking, body mass index, age and alcohol use with numerous validated CpG sites. These signatures may be used as a molecular test to quantify cancer risk associated with these factors. It is clear from the larger EWAS of risk exposures that similar-sized large collaborative studies may be needed to robustly identify DNA methylation signatures of breast cancer risk.
Sanchis S, Chilet MP, Martinez M, et al., 2017, Epigenomic landscape of breast cancer in very young women, 42nd Annual Meeting of the European-Society-of-Medical-Oncology (ESMO), Publisher: OXFORD UNIV PRESS, ISSN: 0923-7534
Lubecka K, Beetch M, Qiu J, et al., 2017, Loci-specific differences in blood DNA methylation for early detection of hepatocellular carcinoma, Annual Meeting of the American-Association-for-Cancer-Research (AACR), Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
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