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Three inherited autosomal dominant conditions--BRCA-related hereditary breast and ovarian cancer (HBOC), Lynch syndrome (LS) and familial hypercholesterolemia (FH)--have been termed the Centers for Disease Control and Prevention Tier 1 (CDCT1) genetic conditions, for which early identification and intervention have a meaningful potential for clinical actionability and a positive impact on public health.sup.1. In typical medical practice, genetic testing for these conditions is based on personal or family history, ethnic background or other demographic characteristics.sup.2. In this study of a cohort of 26,906 participants in the Healthy Nevada Project (HNP), we first evaluated whether population screening could efficiently identify carriers of these genetic conditions and, second, we evaluated the impact of genetic risk on health outcomes for these participants. We found a 1.33% combined carrier rate for pathogenic and likely pathogenic (P/LP) genetic variants for HBOC, LS and FH. Of these carriers, 21.9% of participants had clinically relevant disease, among whom 70% had been diagnosed with relevant disease before age 65. Moreover, 90% of the risk carriers had not been previously identified, and less than 19.8% of these had documentation in their medical records of inherited genetic disease risk, including family history. In a direct follow-up survey with all carriers, only 25.2% of individuals reported a family history of relevant disease. Our experience with the HNP suggests that genetic screening in patients could identify at-risk carriers, who would not be otherwise identified in routine care. Screening for a set of autosomal-dominant genetic conditions in a large, unselected cohort of individuals uncovers carriers who were missed by routine medical care, demonstrating the utility of broad genetic screening., Author(s): J. J. Grzymski [sup.1] [sup.2] , G. Elhanan [sup.2] , J. A. Morales Rosado [sup.3] [sup.4] , E. Smith [sup.2] , K. A. Schlauch [sup.2] , R. Read [sup.2] [...]

The monkey parasite Plasmodium knowlesi was discovered to be a common cause of malaria in humans in 2004, initially from investigations in the Kapit division of Sarawak state, Malaysian Borneo [...]

Sporadic reports have described cancer cases in which multiple driver mutations (MMs) occur in the same oncogene.sup.1,2. However, the overall landscape and relevance of MMs remain elusive. Here we carried out a pan-cancer analysis of 60,954 cancer samples, and identified 14 pan-cancer and 6 cancer-type-specific oncogenes in which MMs occur more frequently than expected: 9% of samples with at least one mutation in these genes harboured MMs. In various oncogenes, MMs are preferentially present in cis and show markedly different mutational patterns compared with single mutations in terms of type (missense mutations versus in-frame indels), position and amino-acid substitution, suggesting a cis-acting effect on mutational selection. MMs show an overrepresentation of functionally weak, infrequent mutations, which confer enhanced oncogenicity in combination. Cells with MMs in the PIK3CA and NOTCH1 genes exhibit stronger dependencies on the mutated genes themselves, enhanced downstream signalling activation and/or greater sensitivity to inhibitory drugs than those with single mutations. Together oncogenic MMs are a relatively common driver event, providing the underlying mechanism for clonal selection of suboptimal mutations that are individually rare but collectively account for a substantial proportion of oncogenic mutations. Analysis of genomic data from more than 60,000 cancer samples uncovers frequent multiple driver mutations in individual oncogenes, which confer enhanced oncogenicity in combination., Author(s): Yuki Saito [sup.1] [sup.2] , Junji Koya [sup.1] , Mitsugu Araki [sup.3] , Yasunori Kogure [sup.1] , Sumito Shingaki [sup.1] , Mariko Tabata [sup.1] [sup.4] , Marni B. McClure [...]

Mycobacterium tuberculosis (M. tuberculosis) has coevolved with humans for millennia and developed multiple mechanisms to evade host immunity. Restoring host immunity in order to improve outcomes and potentially shorten existing therapy will require identification of the full complement by which host immunity is inhibited. Perturbation of host DNA methylation is a mechanism induced by chronic infections such as HIV, HPV, lymphocytic choriomeningitis virus (LCMV), and schistosomiasis to evade host immunity. Here, we evaluated the DNA methylation status of patients with tuberculosis (TB) and their asymptomatic household contacts and found that the patients with TB have DNA hypermethylation of the IL-2/STAT5, TNF/NF-[kappa]B, and IFN-[gamma] signaling pathways. We performed methylation- sensitive restriction enzyme-quantitative PCR (MSRE-qPCR) and observed that multiple genes of the IL-12/IFN-[gamma] signaling pathway (IL12B, IL12RB2, TYK2, IFNGR1, JAK1, and JAK2) were hypermethylated in patients with TB. The DNA hypermethylation of these pathways was associated with decreased immune responsiveness with decreased mitogen-induced upregulation of IFN-[gamma], TNF, IL-6, CXCL9, CXCL10, and IL-1 p production. The DNA hypermethylation of the IL-12/IFN-[gamma] pathway was associated with decreased IFN-[gamma]-induced gene expression and decreased IL-12-inducible upregulation of IFN-[gamma]. This study demonstrates that immune cells from patients with TB are characterized by DNA hypermethylation of genes critical to mycobacterial immunity resulting in decreased mycobacteria-specific and nonspecific immune responsiveness., Introduction Tuberculosis (TB) continues to be a global problem, with 10 million cases and over 1 million deaths each year (1). Anti-TB therapy (ATT) requires 6 months of antibiotics, despite [...]