Tumor purity estimated from bulk DNA methylation can be used for adjusting beta values of individual samples to better reflect tumor biology.

Epigenetic deregulation through altered DNA methylation is a fundamental feature of tumorigenesis, but tumor data from bulk tissue samples contain different proportions of malignant and non-malignant cells that may confound the interpretation of DNA methylation values. The adjustment of DNA methylation data based on tumor purity has been proposed to render both genome-wide and gene-specific analyses more precise, but it requires sample purity estimates. Here we present PureBeta, a single-sample statistical framework that uses genome-wide DNA methylation data to first estimate sample purity and then adjust methylation values of individual CpGs to correct for sample impurity.

Tumour immune characterisation of primary triple-negative breast cancer using automated image quantification of immunohistochemistry-stained immune cells.

The tumour immune microenvironment (TIME) in breast cancer is acknowledged with an increasing role in treatment response and prognosis. With a growing number of immune markers analysed, digital image analysis may facilitate broader TIME understanding, even in single-plex IHC data. To facilitate analyses of the latter an open-source image analysis pipeline, Tissue microarray MArker Quantification (TMArQ), was developed and applied to single-plex stainings for p53, CD3, CD4, CD8, CD20, CD68, FOXP3, and PD-L1 (SP142 antibody) in a 218-patient triple negative breast cancer (TNBC) cohort with complementary pathology scorings, clinicopathological, whole genome sequencing, and RNA-sequencing data.

Molecular characteristics of lung adenocarcinoma with respect to patient age at diagnosis.

Lung cancer is primarily a disease of the elderly, with a median age at diagnosis around 70 years. In our study we sought to address the question of whether and how clinical characteristics, molecular alterations and molecular phenotypes differ between patient populations with early-stage lung adenocarcinoma (AC) with respect to age at diagnosis. Patients were stratified based on age at diagnosis into five systematic age bins (<50, 50-60, 60-70, 70-80 and ≥80 years).

Tumor purity adjusted beta values improve biological interpretability of high-dimensional DNA methylation data.

A common issue affecting DNA methylation analysis in tumor tissue is the presence of a substantial amount of non-tumor methylation signal derived from the surrounding microenvironment. Although approaches for quantifying and correcting for the infiltration component have been proposed previously, we believe these have not fully addressed the issue in a comprehensive and universally applicable way. We present a multi-population framework for adjusting DNA methylation beta values on the Illumina 450/850K platform using generic purity estimates to account for non-tumor signal.

SRIQ clustering: A fusion of Random Forest, QT clustering, and KNN concepts.

Gene expression profiling together with unsupervised analysis methods, typically clustering methods, has been used extensively in cancer research to unravel, e.g., new molecular subtypes that hold promise of disease refinement that may ultimately benefit patients.

Proteogenomics of non-small cell lung cancer reveals molecular subtypes associated with specific therapeutic targets and immune evasion mechanisms.

Despite major advancements in lung cancer treatment, long-term survival is still rare, and a deeper understanding of molecular phenotypes would allow the identification of specific cancer dependencies and immune evasion mechanisms. Here we performed in-depth mass spectrometry (MS)-based proteogenomic analysis of 141 tumors representing all major histologies of non-small cell lung cancer (NSCLC). We identified six distinct proteome subtypes with striking differences in immune cell composition and subtype-specific expression of immune checkpoints.

Comprehensive molecular comparison of BRCA1 hypermethylated and BRCA1 mutated triple negative breast cancers.

Homologous recombination deficiency (HRD) is a defining characteristic in BRCA-deficient breast tumors caused by genetic or epigenetic alterations in key pathway genes. We investigated the frequency of BRCA1 promoter hypermethylation in 237 triple-negative breast cancers (TNBCs) from a population-based study using reported whole genome and RNA sequencing data, complemented with analyses of genetic, epigenetic, transcriptomic and immune infiltration phenotypes. We demonstrate that BRCA1 promoter hypermethylation is twice as frequent as BRCA1 pathogenic variants in early-stage TNBC and that hypermethylated and mutated cases have similarly improved prognosis after adjuvant chemotherapy.

Methylation Patterns and Chromatin Accessibility in Neuroendocrine Lung Cancer.

Lung cancer is the worldwide leading cause of death from cancer. Epigenetic modifications such as methylation and changes in chromatin accessibility are major gene regulatory mechanisms involved in tumorigenesis and cellular lineage commitment. We aimed to characterize these processes in the context of neuroendocrine (NE) lung cancer.

Genetic Alterations in the Molecular Subtypes of Bladder Cancer: Illustration in the Cancer Genome Atlas Dataset.

Context: Recent whole genome mRNA expression profiling studies revealed that bladder cancers can be grouped into molecular subtypes, some of which share clinical properties and gene expression patterns with the intrinsic subtypes of breast cancer and the molecular subtypes found in other solid tumors. The molecular subtypes in other solid tumors are enriched with specific mutations and copy number aberrations that are thought to underlie their distinct progression patterns, and biological and clinical properties.

Objective: The availability of comprehensive genomic data from The Cancer Genome Atlas (TCGA) and other large projects made it possible to correlate the presence of DNA alterations with tumor molecular subtype membership.

Novel genetic loci associated with long-term deterioration in blood lipid concentrations and coronary artery disease in European adults.

Background: Cross-sectional genome-wide association studies have identified hundreds of loci associated with blood lipids and related cardiovascular traits, but few genetic association studies have focused on long-term changes in blood lipids.

Methods: Participants from the GLACIER Study (Nmax = 3492) were genotyped with the MetaboChip array, from which 29 387 SNPs (single nucleotide polymorphisms; replication, fine-mapping regions and wildcard SNPs for lipid traits) were extracted for association tests with 10-year change in total cholesterol (ΔTC) and triglycerides (ΔTG). Four additional prospective cohort studies (MDC, PIVUS, ULSAM, MRC Ely; Nmax = 8263 participants) were used for replication.

Comprehensive Transcriptional Analysis of Early-Stage Urothelial Carcinoma.

Non-muscle-invasive bladder cancer (NMIBC) is a heterogeneous disease with widely different outcomes. We performed a comprehensive transcriptional analysis of 460 early-stage urothelial carcinomas and showed that NMIBC can be subgrouped into three major classes with basal- and luminal-like characteristics and different clinical outcomes. Large differences in biological processes such as the cell cycle, epithelial-mesenchymal transition, and differentiation were observed.

An integrated genomics analysis of epigenetic subtypes in human breast tumors links DNA methylation patterns to chromatin states in normal mammary cells.

Background: Aberrant DNA methylation is frequently observed in breast cancer. However, the relationship between methylation patterns and the heterogeneity of breast cancer has not been comprehensively characterized.

Methods: Whole-genome DNA methylation analysis using Illumina Infinium HumanMethylation450 BeadChip arrays was performed on 188 human breast tumors.

On Molecular Classification of Bladder Cancer: Out of One, Many.

Comparative analysis showed that bladder cancer classification systems identify overlapping subtypes but at different levels. Muscle-invasive bladder cancer shows remarkable heterogeneity, and six subtypes were identified that differ in transcriptional networks, marker profiles, and expression of actionable targets.

Biological determinants of bladder cancer gene expression subtypes.

Molecular stratification of tumors by gene expression profiling has been applied to a large number of human malignancies and holds great promise for personalized treatment. Comprehensive classification schemes for urothelial carcinoma have been proposed by three separate groups but have not previously been evaluated simultaneously in independent data. Here we map the interrelations between the proposed molecular subtypes onto the intrinsic structure of a rich independent dataset and show that subtype stratification within each scheme can be explained in terms of a set of common underlying biological processes.

Molecular subtypes of urothelial carcinoma are defined by specific gene regulatory systems.

Background: Molecular stratification of bladder cancer has revealed gene signatures differentially expressed across tumor subtypes. While these signatures provide important insights into subtype biology, the transcriptional regulation that governs these signatures is not well characterized.

Methods: In this study, we use publically available ChIP-Seq data on regulatory factor binding in order to link transcription factors to gene signatures defining molecular subtypes of urothelial carcinoma.

Integrative epigenomic analysis of differential DNA methylation in urothelial carcinoma.

Background: Urothelial carcinoma of the bladder (UC) is a common malignancy. Although extensive transcriptome analysis has provided insights into the gene expression patterns of this tumor type, the mechanistic underpinnings of differential methylation remain poorly understood. Multi-level genomic data may be used to profile the regulatory potential and landscape of differential methylation in cancer and gain understanding of the processes underlying epigenetic and phenotypic characteristics of tumors.

A Molecular Pathologic Framework for Risk Stratification of Stage T1 Urothelial Carcinoma.

Background: One third of patients with stage T1 urothelial carcinoma (UC) progress to muscle-invasive disease requiring radical surgery. Thus, reliable tools are needed for risk stratification of stage T1 UC.

Objective: To investigate the extent to which stratification of stage T1 tumours into previously described molecular pathologic UC subtypes can provide improved information on tumour progression.

Genome-Wide DNA Methylation Analysis in Melanoma Reveals the Importance of CpG Methylation in MITF Regulation.

The microphthalmia-associated transcription factor (MITF) is a key regulator of melanocyte development and a lineage-specific oncogene in melanoma; a highly lethal cancer known for its unpredictable clinical course. MITF is regulated by multiple intracellular signaling pathways, although the exact mechanisms that determine MITF expression and activity remain incompletely understood. In this study, we obtained genome-wide DNA methylation profiles from 50 stage IV melanomas, normal melanocytes, keratinocytes, and dermal fibroblasts and utilized The Cancer Genome Atlas data for experimental validation.

Toward a molecular pathologic classification of urothelial carcinoma.

We recently defined molecular subtypes of urothelial carcinomas according to whole genome gene expression. Herein we describe molecular pathologic characterization of the subtypes using 20 genes and IHC of 237 tumors. In addition to differences in expression levels, the subtypes show important differences in stratification of protein expression.

Detailed Analysis of Focal Chromosome Arm 1q and 6p Amplifications in Urothelial Carcinoma Reveals Complex Genomic Events on 1q, and SOX4 as a Possible Auxiliary Target on 6p.

Background: Urothelial carcinoma shows frequent amplifications at 6p22 and 1q21-24. The main target gene at 6p22 is believed to be E2F3, frequently co-amplified with CDKAL1 and SOX4. There are however reports on 6p22 amplifications that do not include E2F3.