Evaluation of agreement between common clustering strategies for DNA methylation-based subtyping of breast tumours.

Aims: Clustering algorithms have been widely applied to tumor DNA methylation datasets to define methylation-based cancer subtypes. This study aimed to evaluate the agreement between subtypes obtained from common clustering strategies.

Materials & Methods: We used tumor DNA methylation data from 409 women with breast cancer from the Melbourne Collaborative Cohort Study (MCCS) and 781 breast tumors from The Cancer Genome Atlas (TCGA).

Detection of differentially methylated CpGs between tumour and adjacent benign cells in diagnostic prostate cancer samples.

Differentially methylated CpG sites (dmCpGs) that distinguish prostate tumour from adjacent benign tissue could aid in the diagnosis and prognosis of prostate cancer. Previously, the identification of such dmCpGs has only been undertaken in radical prostatectomy (RP) samples and not primary diagnostic tumour samples (needle biopsy or transurethral resection of the prostate). We interrogated an Australian dataset comprising 125 tumour and 43 adjacent histologically benign diagnostic tissue samples, including 41 paired samples, using the Infinium Human Methylation450 BeadChip.

Methylation scores for smoking, alcohol consumption and body mass index and risk of seven types of cancer.

Methylation marks of exposure to health risk factors may be useful markers of cancer risk as they might better capture current and past exposures than questionnaires, and reflect different individual responses to exposure. We used data from seven case-control studies nested within the Melbourne Collaborative Cohort Study of blood DNA methylation and risk of colorectal, gastric, kidney, lung, prostate and urothelial cancer, and B-cell lymphoma (N cases = 3123). Methylation scores (MS) for smoking, body mass index (BMI), and alcohol consumption were calculated based on published data as weighted averages of methylation values.

Heritable methylation marks associated with prostate cancer risk.

DNA methylation marks that are inherited from parents to offspring are known to play a role in cancer risk and could explain part of the familial risk for cancer. We therefore conducted a genome-wide search for heritable methylation marks associated with prostate cancer risk. Peripheral blood DNA methylation was measured for 133 of the 469 members of 25 multiple-case prostate cancer families, using the EPIC array.

Wildfire-related PM and DNA methylation: An Australian twin and family study.

Background: Wildfire-related fine particulate matter (PM) has many adverse health impacts, but its impacts on human epigenome are unknown. We aimed to evaluate the associations between long-term exposure to wildfire-related PM and blood DNA methylation, and whether the associations differ from those with non-wildfire-related PM.

Methods: We studied 479 Australian women comprising 132 twin pairs and 215 of their sisters.

Epigenome-wide association study of short-term temperature fluctuations based on within-sibship analyses in Australian females.

Background: Temperature fluctuations can affect human health independent of the effect of mean temperature. However, no study has evaluated whether short-term temperature fluctuations could affect DNA methylation.

Methods: Peripheral blood DNA methylation for 479 female siblings of 130 families were analysed.

Does genetic predisposition modify the effect of lifestyle-related factors on DNA methylation?

Lifestyle-related phenotypes have been shown to be heritable and associated with DNA methylation. We aimed to investigate whether genetic predisposition to tobacco smoking, alcohol consumption, and higher body mass index (BMI) moderates the effect of these phenotypes on blood DNA methylation. We calculated polygenic scores (PGS) to quantify genetic predisposition to these phenotypes using training ( = 7,431) and validation ( = 4,307) samples.

Early life affects late-life health through determining DNA methylation across the lifespan: A twin study.

Background: Previous findings for the genetic and environmental contributions to DNA methylation variation were for limited age ranges only. We investigated the lifespan contributions and their implications for human health for the first time.

Methods: 1,720 monozygotic twin (MZ) pairs and 1,107 dizygotic twin (DZ) pairs aged 0-92 years were included.

Association of Blood DNA Methylation with Cancer Risk, Cancer Survival, and Mortality.

Genetic variants in are associated with longevity. Here, we assessed whether blood DNA methylation at was associated with cancer risk, survival, and mortality. We used data from eight prospective case-control studies of breast ( = 409 cases), colorectal ( = 835), gastric ( = 170), kidney ( = 143), lung ( = 332), prostate ( = 869), and urothelial ( = 428) cancer and B-cell lymphoma ( = 438).

Repeatability of methylation measures using a QIAseq targeted methyl panel and comparison with the Illumina HumanMethylation450 assay.

Objective: In previous studies using Illumina Infinium methylation arrays, we have identified DNA methylation marks associated with cancer predisposition and progression. In the present study, we have sought to find appropriate technology to both technically validate our data and expand our understanding of DNA methylation in these genomic regions. Here, we aimed to assess the repeatability of methylation measures made using QIAseq targeted methyl panel and to compare them with those obtained from the Illumina HumanMethylation450 (HM450K) assay.

Smoking Methylation Marks for Prediction of Urothelial Cancer Risk.

Background: Self-reported information may not accurately capture smoking exposure. We aimed to evaluate whether smoking-associated DNA methylation markers improve urothelial cell carcinoma (UCC) risk prediction.

Methods: Conditional logistic regression was used to assess associations between blood-based methylation and UCC risk using two matched case-control samples: 404 pairs from the Melbourne Collaborative Cohort Study (MCCS) and 440 pairs from the Women's Health Initiative (WHI) cohort.

Surrounding Greenness and Biological Aging Based on DNA Methylation: A Twin and Family Study in Australia.

Background: High surrounding greenness has many health benefits and might contribute to slower biological aging. However, very few studies have evaluated this from the perspective of epigenetics.

Objectives: We aimed to evaluate the association between surrounding greenness and biological aging based on DNA methylation.

Ambient temperature and genome-wide DNA methylation: A twin and family study in Australia.

Little is known about the association between ambient temperature and DNA methylation, which is a potential biological process through which ambient temperature affects health. This study aimed to evaluate the association between ambient temperature and DNA methylation across human genome. We included 479 Australian women, including 132 twin pairs and 215 sisters of these twins.

Characterization of a -silenced high-grade serous ovarian cancer model during development of PARP inhibitor resistance.

Acquired PARP inhibitor (PARPi) resistance in - or -mutant ovarian cancer often results from secondary mutations that restore expression of functional protein. is a less commonly studied ovarian cancer susceptibility gene whose promoter is sometimes methylated, leading to homologous recombination (HR) deficiency and PARPi sensitivity. For this study, the PARPi-sensitive patient-derived ovarian cancer xenograft PH039, which lacks HR gene mutations but harbors promoter methylation, was selected for PARPi resistance by cyclical niraparib treatment .

DNA Methylation Signatures and the Contribution of Age-Associated Methylomic Drift to Carcinogenesis in Early-Onset Colorectal Cancer.

We investigated aberrant DNA methylation (DNAm) changes and the contribution of ageing-associated methylomic drift and age acceleration to early-onset colorectal cancer (EOCRC) carcinogenesis. Genome-wide DNAm profiling using the Infinium HM450K on 97 EOCRC tumour and 54 normal colonic mucosa samples was compared with: (1) intermediate-onset CRC (IOCRC; diagnosed between 50-70 years; 343 tumour and 35 normal); and (2) late-onset CRC (LOCRC; >70 years; 318 tumour and 40 normal). CpGs associated with age-related methylation drift were identified using a public dataset of 231 normal mucosa samples from people without CRC.

Epigenetic Drift Association with Cancer Risk and Survival, and Modification by Sex.

To investigate age- and sex-specific DNA methylation alterations related to cancer risk and survival, we used matched case-control studies of colorectal ( = 835), gastric ( = 170), kidney ( = 143), lung ( = 332), prostate ( = 869) and urothelial ( = 428) cancers, and mature B-cell lymphoma ( = 438). Linear mixed-effects models were conducted to identify age-, sex- and age-by-sex-associated methylation markers using a discovery (controls)-replication (cases) strategy. Replication was further examined using summary statistics from Generation Scotland (GS).

Residential surrounding greenness and DNA methylation: An epigenome-wide association study.

Background: DNA methylation is a potential biological mechanism through which residential greenness affects health, but little is known about its association with greenness and whether the association could be modified by genetic background. We aimed to evaluate the association between surrounding greenness and genome-wide DNA methylation and potential gene-greenness interaction effects on DNA methylation.

Methods: We measured blood-derived DNA methylation using the HumanMethylation450 BeadChip array (Illumina) for 479 Australian women, including 66 monozygotic, 66 dizygotic twin pairs, and 215 sisters of these twins.

: Genetic Variation, Heritable Methylation and Disease Association.

is a metastable epiallele with accumulating evidence that methylation at this region is heritable, modifiable and associated with disease including risk and progression of cancer. This study investigated the influence of genetic variation and other factors such as age and adult lifestyle on blood DNA methylation in this region. We first sequenced the gene region in multiple-case breast cancer families in which methylation was identified as heritable and associated with breast cancer risk.

Association of variably methylated tumour DNA regions with overall survival for invasive lobular breast cancer.

Background: Tumour DNA methylation profiling has shown potential to refine disease subtyping and improve the diagnosis and prognosis prediction of breast cancer. However, limited data exist regarding invasive lobular breast cancer (ILBC). Here, we investigated the genome-wide variability of DNA methylation levels across ILBC tumours and assessed the association between methylation levels at the variably methylated regions and overall survival in women with ILBC.

Biological Aging Measures Based on Blood DNA Methylation and Risk of Cancer: A Prospective Study.

Background: We previously investigated the association between 5 "first-generation" measures of epigenetic aging and cancer risk in the Melbourne Collaborative Cohort Study. This study assessed cancer risk associations for 3 recently developed methylation-based biomarkers of aging: , , and predicted telomere length.

Methods: We estimated rate ratios (RRs) for the association between these 3 age-adjusted measures and risk of colorectal (N = 813), gastric (N = 165), kidney (N = 139), lung (N = 327), mature B-cell (N = 423), prostate (N = 846), and urothelial (N = 404) cancer using conditional logistic regression models.

Methylation marks of prenatal exposure to maternal smoking and risk of cancer in adulthood.

Background: Prenatal exposure to maternal smoking is detrimental to child health but its association with risk of cancer has seldom been investigated. Maternal smoking induces widespread and long-lasting DNA methylation changes, which we study here for association with risk of cancer in adulthood.

Methods: Eight prospective case-control studies nested within the Melbourne Collaborative Cohort Study were used to assess associations between maternal-smoking-associated methylation marks in blood and risk of several cancers: breast (n = 406 cases), colorectal (n = 814), gastric (n = 166), kidney (n = 139), lung (n = 327), prostate (n = 847) and urothelial (n = 404) cancer and B-cell lymphoma (n = 426).

Genetic and environmental causes of variation in epigenetic aging across the lifespan.

Background: DNA methylation-based biological age (DNAm age) is an important biomarker for adult health. Studies in specific age ranges have found widely varying results about its genetic and environmental causes of variation. However, these studies are not able to provide a comprehensive view of the causes of variation over the lifespan.

DNA Methylation in Peripheral Blood and Risk of Gastric Cancer: A Prospective Nested Case-control Study.

DNA methylation in peripheral blood is a potential biomarker of gastric cancer risk which could be used for early detection. We conducted a prospective case-control study nested within the Melbourne Collaborative Cohort Study. Genomic DNA was prepared from blood samples collected a median of 12 years before diagnosis for cases ( = 168).

Integrating DNA methylation measures to improve clinical risk assessment: are we there yet? The case of BRCA1 methylation marks to improve clinical risk assessment of breast cancer.

Current risk prediction models estimate the probability of developing breast cancer over a defined period based on information such as family history, non-genetic breast cancer risk factors, genetic information from high and moderate risk breast cancer susceptibility genes and, over the past several years, polygenic risk scores (PRS) from more than 300 common variants. The inclusion of additional data such as PRS improves risk stratification, but it is anticipated that the inclusion of epigenetic marks could further improve model performance accuracy. Here, we present the case for including information on DNA methylation marks to improve the accuracy of these risk prediction models, and consider how this approach contrasts genetic information, as identifying DNA methylation marks associated with breast cancer risk differs inherently according to the source of DNA, approaches to the measurement of DNA methylation, and the timing of measurement.