Sherlock-Genome: an R Shiny application for genomic analysis and visualization.

Motivation: Next-generation sequencing technologies, such as whole genome sequencing (WGS), have become prominent in cancer genomics. However, managing, visualizing, and integratively analyzing WGS results across various bioinformatic pipelines remains challenging, particularly for non-bioinformaticians, hindering the usability of WGS data for biological discovery.

Results: We developed Sherlock-Genome, an R Shiny app for data harmonization, visualization, and integrative analysis of WGS-based cancer genomics studies.

Mapping chromatin interactions at melanoma susceptibility loci and cell-type specific dataset integration uncovers distant gene targets of -regulation.

Genome-wide association studies (GWAS) of melanoma risk have identified 68 independent signals at 54 loci. For most loci, specific functional variants and their respective target genes remain to be established. Capture-HiC is an assay that links fine-mapped risk variants to candidate target genes by comprehensively mapping cell-type specific chromatin interactions.

Socioeconomic status, smoking, and lung cancer: mediation and bias analysis in the SYNERGY study.

Background: Increased lung-cancer risks for low socioeconomic status (SES) groups are only partially attributable to smoking habits. Little effort has been made to investigate the persistent risks related to low SES by quantification of potential biases.

Methods: Based on 12 case-control studies, including 18 centers of the international SYNERGY project (16,550 cases, 20,147 controls), we estimated controlled direct effects (CDE) of SES on lung cancer via multiple logistic regression, adjusted for age, study center, and smoking habits, and stratified by sex.

The mutagenic forces shaping the genomic landscape of lung cancer in never smokers.

Lung cancer in never smokers (LCINS) accounts for up to 25% of all lung cancers and has been associated with exposure to secondhand tobacco smoke and air pollution in observational studies. Here, we evaluate the mutagenic exposures in LCINS by examining deep whole-genome sequencing data from a large international cohort of 871 treatment-naïve LCINS recruited from 28 geographical locations within the Sherlock- study. mutations were 3.

APOBEC shapes tumor evolution and age at onset of lung cancer in smokers.

APOBEC enzymes are part of the innate immunity and are responsible for restricting viruses and retroelements by deaminating cytosine residues. Most solid tumors harbor different levels of somatic mutations attributed to the off-target activities of APOBEC3A (A3A) and/or APOBEC3B (A3B). However, how APOBEC3A/B enzymes shape the tumor evolution in the presence of exogenous mutagenic processes is largely unknown.

mSigSDK - private, at scale, computation of mutation signatures.

In our previous work, we demonstrated that it is feasible to perform analysis on mutation signature data without the need for downloads or installations and analyze individual patient data at scale without compromising privacy. Building on this foundation, we developed an in-browser Software Development Kit (a JavaScript SDK), mSigSDK, to facilitate the orchestration of distributed data processing workflows and graphic visualization of mutational signature analysis results. We strictly adhered to modern web computing standards, particularly the modularization standards set by the ECMAScript ES6 framework (JavaScript modules).

Impact of individual level uncertainty of lung cancer polygenic risk score (PRS) on risk stratification.

Background: Although polygenic risk score (PRS) has emerged as a promising tool for predicting cancer risk from genome-wide association studies (GWAS), the individual-level accuracy of lung cancer PRS and the extent to which its impact on subsequent clinical applications remains largely unexplored.

Methods: Lung cancer PRSs and confidence/credible interval (CI) were constructed using two statistical approaches for each individual: (1) the weighted sum of 16 GWAS-derived significant SNP loci and the CI through the bootstrapping method (PRS-16-CV) and (2) LDpred2 and the CI through posteriors sampling (PRS-Bayes), among 17,166 lung cancer cases and 12,894 controls with European ancestry from the International Lung Cancer Consortium. Individuals were classified into different genetic risk subgroups based on the relationship between their own PRS mean/PRS CI and the population level threshold.

Lung Cancer Risks Associated with Occupational Exposure to Pairs of Five Lung Carcinogens: Results from a Pooled Analysis of Case-Control Studies (SYNERGY).

Background: While much research has been done to identify individual workplace lung carcinogens, little is known about joint effects on risk when workers are exposed to multiple agents.

Objectives: We investigated the pairwise joint effects of occupational exposures to asbestos, respirable crystalline silica, metals (i.e.

Prevalent occupational exposures and risk of lung cancer among women: Results from the application of the Canadian Job-Exposure Matrix (CANJEM) to a combined set of ten case-control studies.

Background: Worldwide, lung cancer is the second leading cause of cancer death in women. The present study explored associations between occupational exposures that are prevalent among women, and lung cancer.

Methods: Data from 10 case-control studies of lung cancer from Europe, Canada, and New Zealand conducted between 1988 and 2008 were combined.

Lung Cancer in Ever- and Never-Smokers: Findings from Multi-Population GWAS Studies.

Background: Clinical, molecular, and genetic epidemiology studies displayed remarkable differences between ever- and never-smoking lung cancer.

Methods: We conducted a stratified multi-population (European, East Asian, and African descent) association study on 44,823 ever-smokers and 20,074 never-smokers to identify novel variants that were missed in the non-stratified analysis. Functional analysis including expression quantitative trait loci (eQTL) colocalization and DNA damage assays, and annotation studies were conducted to evaluate the functional roles of the variants.

CYP2A6 Activity and Cigarette Consumption Interact in Smoking-Related Lung Cancer Susceptibility.

Unlabelled: Cigarette smoke, containing both nicotine and carcinogens, causes lung cancer. However, not all smokers develop lung cancer, highlighting the importance of the interaction between host susceptibility and environmental exposure in tumorigenesis. Here, we aimed to delineate the interaction between metabolizing ability of tobacco carcinogens and smoking intensity in mediating genetic susceptibility to smoking-related lung tumorigenesis.

Identification of genetically predicted DNA methylation markers associated with non-small cell lung cancer risk among 34,964 cases and 448,579 controls.

Background: Although the associations between genetic variations and lung cancer risk have been explored, the epigenetic consequences of DNA methylation in lung cancer development are largely unknown. Here, the genetically predicted DNA methylation markers associated with non-small cell lung cancer (NSCLC) risk by a two-stage case-control design were investigated.

Methods: The genetic prediction models for methylation levels based on genetic and methylation data of 1595 subjects from the Framingham Heart Study were established.

Molecular Profile of Subungual Melanoma: A MelaNostrum Consortium Study of 68 Cases Reporting BRAF, NRAS, KIT, and TERT Promoter Status.

Background: Subungual melanoma (SM) is an unusual type of melanocytic tumor affecting the nail apparatus. The mutational prevalence of the most prominently mutated genes in melanoma has been reported in small cohorts of SM, with unclear conclusions on whether SM is different from the rest of melanomas arising in acral locations or not. Hence, the molecular profile of a large series of SM is yet to be described.

Occupational Benzene Exposure and Lung Cancer Risk: A Pooled Analysis of 14 Case-Control Studies.

Benzene has been classified as carcinogenic to humans, but there is limited evidence linking benzene exposure to lung cancer. We aimed to examine the relationship between occupational benzene exposure and lung cancer. Subjects from 14 case-control studies across Europe and Canada were pooled.

Context-aware single-cell multiome approach identified cell-type specific lung cancer susceptibility genes.

Genome-wide association studies (GWAS) identified over fifty loci associated with lung cancer risk. However, the genetic mechanisms and target genes underlying these loci are largely unknown, as most risk-associated-variants might regulate gene expression in a context-specific manner. Here, we generated a barcode-shared transcriptome and chromatin accessibility map of 117,911 human lung cells from age/sex-matched ever- and never-smokers to profile context-specific gene regulation.

Uncovering the complex relationship between balding, testosterone and skin cancers in men.

Male-pattern baldness (MPB) is related to dysregulation of androgens such as testosterone. A previously observed relationship between MPB and skin cancer may be due to greater exposure to ultraviolet radiation or indicate a role for androgenic pathways in the pathogenesis of skin cancers. We dissected this relationship via Mendelian randomization (MR) analyses, using genetic data from recent male-only meta-analyses of cutaneous melanoma (12,232 cases; 20,566 controls) and keratinocyte cancers (KCs) (up to 17,512 cases; >100,000 controls), followed by stratified MR analysis by body-sites.