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.

Increased frequency of germline pathogenic variants among individuals with dermatofibrosarcoma protuberans.

Purpose: To identify candidate susceptibility genes for dermatofibrosarcoma protuberans (DFSP).

Methods: All individuals with DFSP from the International Sarcoma Kindred Study ( = 3767 individuals with sarcoma diagnoses from Australia, Europe, New Zealand, and United States) and cohorts that were not ascertained based on sarcoma status or other phenotypes (Geisinger MyCode,  = 170,503 individuals, United States; UK Biobank,  = 469,789 individuals, United Kingdom) were evaluated for germline pathogenic or likely pathogenic (P/LP) variants in 156 cancer genes.

Results: There were 92 unrelated individuals with DFSP across the 3 cohorts.

A Genome-Wide Association Study and Rare Variant Analysis for Dupuytren Disease in a North American Population.

Purpose: Although European genome-wide association studies (GWAS) have aided in defining genetic associations in Dupuytren disease (DD), North American populations have been infrequently analyzed. Additionally, there are a paucity of rare variant analyses (RVA) for DD, which can help define both trait variability and risk for low-frequency variants. Our purpose was to perform a GWAS and RVA for DD using a North American database.

Genomic ascertainment of -related cancer predisposition.

Purpose: There is clear evidence that deleterious germline variants in increases risk for breast and prostate cancers; there is limited or conflicting evidence for other cancers. Genomic ascertainment was used to quantify cancer risk in germline pathogenic variant heterozygotes.

Patients And Methods: Germline variants were extracted from two exome-sequenced biobanks linked to the electronic health record: UK Biobank (n= 469,765) and Geisinger MyCode (n=170,503).

A genome-first approach to characterize DICER1 pathogenic variant prevalence, penetrance and cancer, thyroid, and other phenotypes in 2 population-scale cohorts.

Purpose: Population-scale, exome-sequenced cohorts with linked electronic health records (EHR) permit genome-first exploration of phenotype. Phenotype and cancer risk are well-characterized in children with a pathogenic (HGNC ID:17098) variant. Here, the prevalence, penetrance and phenotype of pathogenic germline variants in adults was investigated in two population-scale cohorts.

Most Fanconi anemia heterozygotes are not at increased cancer risk: A genome-first DiscovEHR cohort population study.

Purpose: Fanconi anemia (FA) is a bone marrow failure and cancer predisposition syndrome caused primarily by biallelic pathogenic variants in 1 of 22 genes involved in DNA interstrand cross-link repair. An enduring question concerns cancer risk of those with a single pathogenic FA gene variant. To investigate all FA genes, this study utilized the DiscovEHR cohort of 170,503 individuals with exome sequencing and electronic health data.

Intronic Germline Variants in Patients With Sertoli-Leydig Cell Tumor.

Germline pathogenic loss-of-function (pLOF) variants in are associated with a predisposition for a variety of solid neoplasms, including pleuropulmonary blastoma and Sertoli-Leydig cell tumor (SLCT). The most common pLOF variants include small insertions or deletions leading to frameshifts, and base substitutions leading to nonsense codons or altered splice sites. Larger deletions and pathogenic missense variants occur less frequently.

Development of a Polygenic Risk Score to Predict Diverticulitis.

Background: Despite its prevalence and associated morbidity, we remain limited in our ability to predict the course of a patient with diverticular disease. Although several clinical and genetic risk factors have been identified, we do not know how these factors relate to one another.

Objective: Our aim was to determine whether a polygenic risk score could improve risk prediction for diverticulitis and recurrent diverticulitis compared with a model using only clinical factors.

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.

Estimated Prevalence, Tumor Spectrum, and Neurofibromatosis Type 1-Like Phenotype of CDKN2A-Related Melanoma-Astrocytoma Syndrome.

Importance: Knowledge about the prevalence and tumor types of CDKN2A-related melanoma-astrocytoma syndrome (MAS) is limited and could improve disease recognition.

Objective: To estimate the prevalence and describe the tumor types of MAS.

Design, Setting, And Participants: This retrospective cohort study analyzed all available MAS cases from medical centers in the US (2 sites) and Europe (2 sites) and from biomedical population genomic databases (UK Biobank [United Kingdom], Geisinger MyCode [US]) between January 1, 1976, and December 31, 2020.

A Genome-First Approach to Estimate Prevalence of Germline Pathogenic Variants and Risk of Pancreatic Cancer in Select Cancer Susceptibility Genes.

Patients with germline pathogenic variants (GPV) in cancer predisposition genes are at increased risk of pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer. The genes most frequently found to harbor GPV in unselected PDAC cases are , , , , and . However, GPV prevalence and gene-specific associations have not been extensively studied in the general population.

Association of varicose veins with rare protein-truncating variants in PIEZO1 identified by exome sequencing of a large clinical population.

Objective: The present study sought to determine whether protein-truncating variants (PTVs) in PIEZO1 and CASZ1 genes, previously shown to be associated with varicose veins, were associated with an altered risk of varicose veins.

Methods: An exome sequence database of 131,918 participants from the Geisinger MyCode Community Health Initiative was used to identify individuals with genetic variants in the PIEZO1 or CASZ1 gene. Clinical phenotypes, including varicose vein diagnoses, were determined by analysis of the electronic health record data.

A Genome-First Approach to Characterize DICER1 Pathogenic Variant Prevalence, Penetrance, and Phenotype.

Importance: Genetic disorders are historically defined through phenotype-first approaches. However, risk estimates derived from phenotype-linked ascertainment may overestimate severity and penetrance. Pathogenic variants in DICER1 are associated with increased risks of rare and common neoplasms and thyroid disease in adults and children.

Dose-dependent effect of aerobic exercise on inflammatory biomarkers in a randomized controlled trial of women at high risk of breast cancer.

Background: Increased levels of inflammation are associated with many diseases, including cancer. Physical activity can lower breast cancer risk as well as levels of inflammation. The Women In Steady Exercise Research (WISER) Sister trial was a randomized controlled trial that investigated the effects of a dosed, moderate to vigorous, aerobic exercise intervention on levels of inflammation in premenopausal women who were at high risk of developing breast cancer.

Schweinfurthin natural products induce regression of murine melanoma and pair with anti-PD-1 therapy to facilitate durable tumor immunity.

Metastatic melanoma is a significant clinical problem with a 5-year survival rate of only 15-20%. Recent approval of new immunotherapies and targeted inhibitors have provided much needed options for these patients, in some cases promoting dramatic disease regressions. In particular, antibody-based therapies that block the PD-1/PD-L1 checkpoint inhibitory pathway have achieved an increased overall response rate in metastatic melanoma, yet durable response rates are reported only around 15%.

Durable complete responses off all treatment in patients with metastatic malignant melanoma after sequential immunotherapy followed by a finite course of BRAF inhibitor therapy.

We report 3 cases of durable complete response (CR) in patients with BRAF-mutated metastatic melanoma who were initially treated unsuccessfully with sequential immunotherapies (high dose interleukin 2 followed by ipilimumab with or without concurrent radiation therapy). After progression during or post immunotherapy, these patients were given BRAF inhibitor therapy and developed rapid CRs. Based on the concomitant presence of autoimmune manifestations (including vitiligo and hypophysitis), we postulated that there was a synergistic effect between the prior immune therapy and the BRAF targeting agents.

Randomized controlled trial of oral glutathione supplementation on body stores of glutathione.

Purpose: Glutathione (GSH), the most abundant endogenous antioxidant, is a critical regulator of oxidative stress and immune function. While oral GSH has been shown to be bioavailable in laboratory animal models, its efficacy in humans has not been established. Our objective was to determine the long-term effectiveness of oral GSH supplementation on body stores of GSH in healthy adults.

Why Do CD8+ T Cells become Indifferent to Tumors: A Dynamic Modeling Approach.

CD8+ T cells have the potential to influence the outcome of cancer pathogenesis, including complete tumor eradication or selection of malignant tumor escape variants. The Simian virus 40 large T-antigen (Tag) oncoprotein promotes tumor formation in Tag-transgenic mice and also provides multiple target determinants (sites) for responding CD8+ T cells in C57BL/6 (H-2(b)) mice. To understand the in vivo quantitative dynamics of CD8+ T cells after encountering Tag, we constructed a dynamic model from in vivo-generated data to simulate the interactions between Tag-expressing cells and CD8+ T cells in distinct scenarios including immunization of wild-type C57BL/6 mice and of Tag-transgenic mice that develop various tumors.