Genomic ascertainment to quantify prevalence and cancer risk in adults with pathogenic and likely pathogenic germline variants in RASopathy genes.

Purpose: Genomic ascertainment of electronic health record-linked exome data in two large biobanks was used to quantify germline pathogenic/likely pathogenic (P/LP) variant prevalence, cancer prevalence, and survival in adults with non- RAS/mitogen-activated protein kinase genes (RASopathies).

Patients And Methods: Germline RASopathy variants were examined from adult participants in UK Biobank (UKBB; n=469,802), Geisinger MyCode (n=167,050) and Mount Sinai Bio (n=30,470). Variants were classified as per American College of Medical Genetics/Association for Molecular Pathology criteria and reviewed by a RASopathy variant expert.

Large-scale genome-wide association study of 398,238 women unveils seven novel loci associated with high-grade serous epithelial ovarian cancer risk.

Background: Nineteen genomic regions have been associated with high-grade serous ovarian cancer (HGSOC). We used data from the Ovarian Cancer Association Consortium (OCAC), Consortium of Investigators of Modifiers of (CIMBA), UK Biobank (UKBB), and FinnGen to identify novel HGSOC susceptibility loci and develop polygenic scores (PGS).

Methods: We analyzed >22 million variants for 398,238 women.

Specifications of the ACMG/AMP Variant Classification Guidelines for Germline Variant Curation.

Germline pathogenic variants in predispose individuals to develop a variety of benign and malignant tumors. Accurate variant curation and classification is essential for reliable diagnosis of -related tumor predisposition and identification of individuals who may benefit from surveillance. Since 2015, most labs have followed the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) sequence variant classification guidelines for germline variant curation.

Genome-first approach of the prevalence and cancer phenotypes of pathogenic or likely pathogenic germline TP53 variants.

Pathogenic or likely pathogenic (P/LP) germline TP53 variants are the primary cause of Li-Fraumeni syndrome (LFS), a hereditary cancer predisposition disorder characterized by early-onset cancers. The population prevalence of P/LP germline TP53 variants is estimated to be approximately one in every 3,500 to 20,000 individuals. However, these estimates are likely impacted by ascertainment biases and lack of clinical and genetic data to account for potential confounding factors, such as clonal hematopoiesis.

Spectrum and Excess Risk of Gastrointestinal Tumors in Li-Fraumeni Syndrome.

Li-Fraumeni syndrome (LFS), linked to heterozygous germline pathogenic/likely pathogenic variants in TP53, confers exceptionally high cancer risk, including core cancers (sarcoma, breast, adrenocortical, and brain cancer) among many other cancer types. Colorectal cancer (CRC) is most common after the core and hematologic cancers, accounting for ∼2.8% of diagnoses.

Workplace and non-workplace cannabis use and the risk of workplace injury: Findings from a longitudinal study of Canadian workers.

Objectives: Findings of previous studies examining the relationship between cannabis use and workplace injury have been conflicting, likely due to methodological shortcomings, including cross-sectional designs and exposure measures that lack consideration for timing of use. The objective was to estimate the association between workplace cannabis use (before and/or at work) and non-workplace use and the risk of workplace injury.

Methods: Canadian workers participating in a yearly longitudinal study (from 2018 to 2020) with at least two adjacent years of survey data comprised the analytic sample (n = 2745).

Workplace Supported Recovery from Substance Use Disorders: Defining the Construct, Developing a Model, and Proposing an Agenda for Future Research.

Substance use disorders (SUDs) represent a critical public and occupational health issue. Therefore, understanding the process of SUD recovery has become an issue of growing importance among substance use and recovery professionals. Nonetheless, despite the acknowledged importance of employment for SUD recovery, little conceptual or empirical work exists on how the workplace might support or undermine SUD recovery.

Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers.

The contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic BRCA1 or BRCA2 variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 BRCA1 and 10,740 BRCA2 pathogenic variant carriers. We used these results to prioritise a candidate breast cancer risk-modifier gene for laboratory analysis and biological validation.

Cannabis use and workplace cannabis availability, perceptions and policies among Canadian workers: a comparison before and after the legalisation of non-medical cannabis.

Objectives: Little data exist examining the impact of non-medical (recreational) cannabis legalisation among a working population. The objective was to compare cannabis use patterns and workplace risk perceptions, cannabis availability and workplace use policies before and almost 1 year after legalisation in Canadian workers.

Methods: Two overlapping cross-sectional samples of Canadian workers were surveyed 4 months before legalisation (time 1 (T1), n=2011) and 9-11 months after legalisation (time 2 (T2), n=4032), gathering information on cannabis use (overall and workplace use), workers' perceptions regarding risks of workplace use, availability of cannabis at work and awareness of workplace substance use policies.

Association Study between Polymorphisms in DNA Methylation-Related Genes and Testicular Germ Cell Tumor Risk.

Background: Testicular germ cell tumors (TGCT), histologically classified as seminomas and nonseminomas, are believed to arise from primordial gonocytes, with the maturation process blocked when they are subjected to DNA methylation reprogramming. SNPs in DNA methylation machinery and folate-dependent one-carbon metabolism genes have been postulated to influence the proper establishment of DNA methylation.

Methods: In this pathway-focused investigation, we evaluated the association between 273 selected tag SNPs from 28 DNA methylation-related genes and TGCT risk.

Cancer Risks Associated With and Pathogenic Variants.

Purpose: To provide precise age-specific risk estimates of cancers other than female breast and ovarian cancers associated with pathogenic variants (PVs) in and for effective cancer risk management.

Methods: We used data from 3,184 and 2,157 families in the Consortium of Investigators of Modifiers of to estimate age-specific relative (RR) and absolute risks for 22 first primary cancer types adjusting for family ascertainment.

Results: PVs were associated with risks of male breast (RR = 4.

Quantification of Discordant Variant Interpretations in a Large Family-Based Study of Li-Fraumeni Syndrome.

Purpose: The use of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology guidelines has improved germline variant classification concordance, but discrepancies persist, sometimes directly affecting medical management. We evaluated variant discordance between and within families with germline variants in the National Cancer Institute's Li-Fraumeni syndrome longitudinal cohort study.

Materials And Methods: Germline genetic testing results were obtained from 421 individuals in 140 families.

Frequency of Pathogenic Germline Variants in Cancer-Susceptibility Genes in the Childhood Cancer Survivor Study.

Background: Pediatric cancers are the leading cause of death by disease in children despite improved survival rates overall. The contribution of germline genetic susceptibility to pediatric cancer survivors has not been extensively characterized. We assessed the frequency of pathogenic or likely pathogenic (P/LP) variants in 5451 long-term pediatric cancer survivors from the Childhood Cancer Survivor Study.

Germline variants in hereditary breast cancer genes are associated with early age at diagnosis and family history in Guatemalan breast cancer.

Purpose: Mutations in hereditary breast cancer genes play an important role in the risk for cancer.

Methods: Cancer susceptibility genes were sequenced in 664 unselected breast cancer cases from Guatemala. Variants were annotated with ClinVar and VarSome.

Specifications of the ACMG/AMP variant interpretation guidelines for germline TP53 variants.

Germline pathogenic variants in TP53 are associated with Li-Fraumeni syndrome, a cancer predisposition disorder inherited in an autosomal dominant pattern associated with a high risk of malignancy, including early-onset breast cancers, sarcomas, adrenocortical carcinomas, and brain tumors. Intense cancer surveillance for individuals with TP53 germline pathogenic variants is associated with reduced cancer-related mortality. Accurate and consistent classification of germline variants across clinical and research laboratories is important to ensure appropriate cancer surveillance recommendations.

Subsequent Neoplasm Risk Associated With Rare Variants in DNA Damage Response and Clinical Radiation Sensitivity Syndrome Genes in the Childhood Cancer Survivor Study.

Purpose: Radiotherapy for childhood cancer is associated with elevated subsequent neoplasm (SN) risk, but the contribution of rare variants in DNA damage response and radiation sensitivity genes to SN risk is unknown.

Patients And Methods: We conducted whole-exome sequencing in a cohort of childhood cancer survivors originally diagnosed during 1970 to 1986 (mean follow-up, 32.7 years), with reconstruction of doses to body regions from radiotherapy records.

The Role of Past and Current Medical Use on Nonmedical Use of Prescription Drugs among College Students: Exploring Same-Drug and Cross-Drug Class Associations.

: Understanding the role that medical use of prescription drugs plays in nonmedical use of prescription drugs can inform prevention efforts. In order to understand fully the potential risk that medical use of prescription drugs conveys for nonmedical use of prescription drugs, the current study explored (a) the simultaneous associations between the medical use of several classes of prescription drugs with current nonmedical use of the same and other prescription drug classes, and (b) whether the associations depended upon past or current medical use. : Data came from a cross-sectional survey of 1686 college students, which assessed past and current medical use and current nonmedical use of stimulants, sedatives/anxiolytics, and opioid analgesics.