المؤلفون: Sjöström, Martin, Zhao, Shuang G, Levy, Samuel, Zhang, Meng, Ning, Yuhong, Shrestha, Raunak, Lundberg, Arian, Herberts, Cameron, Foye, Adam, Aggarwal, Rahul, Hua, Junjie T, Li, Haolong, Bergamaschi, Anna, Maurice-Dror, Corinne, Maheshwari, Ashutosh, Chen, Sujun, Ng, Sarah WS, Ye, Wenbin, Petricca, Jessica, Fraser, Michael, Chesner, Lisa, Perry, Marc D, Moreno-Rodriguez, Thaidy, Chen, William S, Alumkal, Joshi J, Chou, Jonathan, Morgans, Alicia K, Beer, Tomasz M, Thomas, George V, Gleave, Martin, Lloyd, Paul, Phillips, Tierney, McCarthy, Erin, Haffner, Michael C, Zoubeidi, Amina, Annala, Matti, Reiter, Robert E, Rettig, Matthew B, Witte, Owen N, Fong, Lawrence, Bose, Rohit, Huang, Franklin W, Luo, Jianhua, Bjartell, Anders, Lang, Joshua M, Mahajan, Nupam P, Lara, Primo N, Evans, Christopher P, Tran, Phuoc T, Posadas, Edwin M, He, Chuan, Cui, Xiao-Long, Huang, Jiaoti, Zwart, Wilbert, Gilbert, Luke A, Maher, Christopher A, Boutros, Paul C, Chi, Kim N, Ashworth, Alan, Small, Eric J, He, Housheng H, Wyatt, Alexander W, Quigley, David A, Feng, Felix Y

المصدر: Cancer Research. 82(21)

مصطلحات موضوعية: Biological Sciences, Biomedical and Clinical Sciences, Genetics, Clinical Sciences, Oncology and Carcinogenesis, Cancer, Aging, Prostate Cancer, Human Genome, Urologic Diseases, Detection, screening and diagnosis, 4.2 Evaluation of markers and technologies, 4.1 Discovery and preclinical testing of markers and technologies, Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being, Male, Humans, 5-Methylcytosine, Prostatic Neoplasms, Prostate, Biopsy, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis

الوصف: Analysis of DNA methylation is a valuable tool to understand disease progression and is increasingly being used to create diagnostic and prognostic clinical biomarkers. While conversion of cytosine to 5-methylcytosine (5mC) commonly results in transcriptional repression, further conversion to 5-hydroxymethylcytosine (5hmC) is associated with transcriptional activation. Here we perform the first study integrating whole-genome 5hmC with DNA, 5mC, and transcriptome sequencing in clinical samples of benign, localized, and advanced prostate cancer. 5hmC is shown to mark activation of cancer drivers and downstream targets. Furthermore, 5hmC sequencing revealed profoundly altered cell states throughout the disease course, characterized by increased proliferation, oncogenic signaling, dedifferentiation, and lineage plasticity to neuroendocrine and gastrointestinal lineages. Finally, 5hmC sequencing of cell-free DNA from patients with metastatic disease proved useful as a prognostic biomarker able to identify an aggressive subtype of prostate cancer using the genes TOP2A and EZH2, previously only detectable by transcriptomic analysis of solid tumor biopsies. Overall, these findings reveal that 5hmC marks epigenomic activation in prostate cancer and identify hallmarks of prostate cancer progression with potential as biomarkers of aggressive disease.SignificanceIn prostate cancer, 5-hydroxymethylcytosine delineates oncogene activation and stage-specific cell states and can be analyzed in liquid biopsies to detect cancer phenotypes. See related article by Wu and Attard, p. 3880.

الوصول الحر: https://escholarship.org/uc/item/4mx5410zTest

المؤلفون: Guler, Gulfem D, Ning, Yuhong, Coruh, Ceyda, Mognol, Giuliana P, Phillips, Tierney, Nabiyouni, Maryam, Hazen, Kyle, Scott, Aaron, Volkmuth, Wayne, Levy, Samuel

المساهمون: ClearNote Health

المصدر: Journal for ImmunoTherapy of Cancer ; volume 12, issue 1, page e008028 ; ISSN 2051-1426

الوصف: Background Treatment with immune checkpoint inhibitors (ICIs) targeting programmed death-1 (PD-1) can yield durable antitumor responses, yet not all patients respond to ICIs. Current approaches to select patients who may benefit from anti-PD-1 treatment are insufficient. 5-hydroxymethylation (5hmC) analysis of plasma-derived cell-free DNA (cfDNA) presents a novel non-invasive approach for identification of therapy response biomarkers which can tackle challenges associated with tumor biopsies such as tumor heterogeneity and serial sample collection. Methods 151 blood samples were collected from 31 patients with non-small cell lung cancer (NSCLC) before therapy started and at multiple time points while on therapy. Blood samples were processed to obtain plasma-derived cfDNA, followed by enrichment of 5hmC-containing cfDNA fragments through biotinylation via a two-step chemistry and binding to streptavidin coated beads. 5hmC-enriched cfDNA and whole genome libraries were prepared in parallel and sequenced to obtain whole hydroxymethylome and whole genome plasma profiles, respectively. Results Comparison of on-treatment time point to matched pretreatment samples from same patients revealed that anti-PD-1 treatment induced distinct changes in plasma cfDNA 5hmC profiles of responding patients, as judged by Response evaluation criteria in solid tumors, relative to non-responders. In responders, 5hmC accumulated over genes involved in immune activation such as inteferon (IFN)-γ and IFN-α response, inflammatory response and tumor necrosis factor (TNF)-α signaling, whereas in non-responders 5hmC increased over epithelial to mesenchymal transition genes. Molecular response to anti-PD-1 treatment, as measured by 5hmC changes in plasma cfDNA profiles were observed early on, starting with the first cycle of treatment. Comparison of pretreatment plasma samples revealed that anti-PD-1 treatment response and resistance associated genes can be captured by 5hmC profiling of plasma-derived cfDNA. Furthermore, 5hmC profiling of ...

الإتاحة: https://doi.org/10.1136/jitc-2023-008028Test

المؤلفون: Haan, David, Bergamaschi, Anna, Friedl, Verena, Guler, Gulfem D., Ning, Yuhong, Reggiardo, Roman, Kesling, Michael, Collins, Micah, Gibb, Bill, Hazen, Kyle, Bates, Steve, Antoine, Michael, Fraire, Carolina, Lopez, Vanessa, Malta, Roger, Nabiyouni, Maryam, Nguyen, Albert, Phillips, Tierney, Riviere, Michael, Leighton, Anna, Ellison, Christopher, McCarthy, Erin, Scott, Aaron, Gigliotti, Lauren, Nilson, Eric, Sheard, Judith, Peters, Melissa, Bethel, Kelly, Chowdhury, Shimul, Volkmuth, Wayne, Levy, Samuel

المصدر: Clinical Gastroenterology and Hepatology ; volume 21, issue 7, page 1802-1809.e6 ; ISSN 1542-3565

مصطلحات موضوعية: Gastroenterology, Hepatology

الإتاحة: https://doi.org/10.1016/j.cgh.2023.03.016Test
https://api.elsevier.com/content/article/PII:S1542356523002240?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S1542356523002240?httpAccept=text/plainTest

المؤلفون: Bansal, Vikas, Gassenhuber, Johann, Phillips, Tierney, Oliveira, Glenn, Harbaugh, Rebecca, Villarasa, Nikki, Topol, Eric J, Seufferlein, Thomas, Boehm, Bernhard O

المصدر: BMC medicine. 15(1)

مصطلحات موضوعية: Humans, Diabetes Mellitus, Type 2, Prognosis, Case-Control Studies, Cohort Studies, Sequence Analysis, DNA, DNA Mutational Analysis, Phenotype, Mutation, Mutation, Missense, Adult, Female, Male, High-Throughput Nucleotide Sequencing, DNA pooling, High-throughput sequencing, MODY, Monogenic diabetes, Pathogenic variants, Targeted sequencing, Type 2 diabetes, General & Internal Medicine, Medical and Health Sciences

الوصف: BackgroundDiagnosis of monogenic as well as atypical forms of diabetes mellitus has important clinical implications for their specific diagnosis, prognosis, and targeted treatment. Single gene mutations that affect beta-cell function represent 1-2% of all cases of diabetes. However, phenotypic heterogeneity and lack of family history of diabetes can limit the diagnosis of monogenic forms of diabetes. Next-generation sequencing technologies provide an excellent opportunity to screen large numbers of individuals with a diagnosis of diabetes for mutations in disease-associated genes.MethodsWe utilized a targeted sequencing approach using the Illumina HiSeq to perform a case-control sequencing study of 22 monogenic diabetes genes in 4016 individuals with type 2 diabetes (including 1346 individuals diagnosed before the age of 40 years) and 2872 controls. We analyzed protein-coding variants identified from the sequence data and compared the frequencies of pathogenic variants (protein-truncating variants and missense variants) between the cases and controls.ResultsA total of 40 individuals with diabetes (1.8% of early onset sub-group and 0.6% of adult onset sub-group) were carriers of known pathogenic missense variants in the GCK, HNF1A, HNF4A, ABCC8, and INS genes. In addition, heterozygous protein truncating mutations were detected in the GCK, HNF1A, and HNF1B genes in seven individuals with diabetes. Rare missense mutations in the GCK gene were significantly over-represented in individuals with diabetes (0.5% carrier frequency) compared to controls (0.035%). One individual with early onset diabetes was homozygous for a rare pathogenic missense variant in the WFS1 gene but did not have the additional phenotypes associated with Wolfram syndrome.ConclusionTargeted sequencing of genes linked with monogenic diabetes can identify disease-relevant mutations in individuals diagnosed with type 2 diabetes not suspected of having monogenic forms of the disease. Our data suggests that GCK-MODY frequently masquerades as classical type 2 diabetes. The results confirm that MODY is under-diagnosed, particularly in individuals presenting with early onset diabetes and clinically labeled as type 2 diabetes; thus, sequencing of all monogenic diabetes genes should be routinely considered in such individuals. Genetic information can provide a specific diagnosis, inform disease prognosis and may help to better stratify treatment plans.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/3xq3598fTest

المؤلفون: Jones, Marilyn C, Topol, Sarah E, Rueda, Manuel, Oliveira, Glenn, Phillips, Tierney, Spencer, Emily G, Torkamani, Ali

المصدر: Genetics in Medicine. 19(10)

مصطلحات موضوعية: Biological Sciences, Genetics, Pediatric, Congenital Structural Anomalies, Brain Disorders, Rare Diseases, 2.1 Biological and endogenous factors, Aetiology, Congenital, Adaptor Proteins, Signal Transducing, Adolescent, Adult, Aged, Female, Humans, Kidney, LIM-Homeodomain Proteins, Male, Mutation, Nail-Patella Syndrome, Patella, Pedigree, Phenotype, Repressor Proteins, Transcription Factors, Fong disease, HOOD syndrome, nail dysplasia, Nail-Patella syndrome, Turner-Kieser syndrome, Clinical Sciences, Genetics & Heredity

الوصف: PurposeNail-Patella syndrome is a dominantly inherited genetic disorder characterized by abnormalities of the nails, knees, elbows, and pelvis. Nail abnormalities are the most constant feature of Nail-Patella syndrome. Pathogenic mutations in a single gene, LMX1B, a mesenchymal determinant of dorsal-ventral patterning, explain approximately 95% of Nail-Patella syndrome cases. However, 5% of cases remain unexplained.MethodsHere, we present exome sequencing and analysis of four generations of a family with a dominantly inherited Nail-Patella-like disorder (nail dysplasia with some features of Nail-Patella syndrome) who tested negative for LMX1B mutation.ResultsWe identify a loss-of-function mutation in WIF1 (NM_007191 p.W15*), which is involved in mesoderm segmentation, as the suspected cause of the Nail-Patella-like disorder observed in this family.ConclusionsMutation of WIF1 is a potential novel cause of a Nail-Patella-like disorder. Testing of additional patients negative for LMX1B mutation is needed to confirm this finding and further clarify the phenotype.Genet Med advance online publication 06 April 2017.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/51p2p5z4Test

المؤلفون: Guler, Gulfem D., Ning, Yuhong, Ku, Chin-Jen, Phillips, Tierney, McCarthy, Erin, Ellison, Christopher K., Bergamaschi, Anna, Collin, Francois, Lloyd, Paul, Scott, Aaron, Antoine, Michael, Wang, Wendy, Chau, Kim, Ashworth, Alan, Quake, Stephen R., Levy, Samuel

المصدر: Nature Communications ; volume 11, issue 1 ; ISSN 2041-1723

مصطلحات موضوعية: General Physics and Astronomy, General Biochemistry, Genetics and Molecular Biology, General Chemistry, Multidisciplinary

الوصف: Pancreatic cancer is often detected late, when curative therapies are no longer possible. Here, we present non-invasive detection of pancreatic ductal adenocarcinoma (PDAC) by 5-hydroxymethylcytosine (5hmC) changes in circulating cell free DNA from a PDAC cohort ( n = 64) in comparison with a non-cancer cohort ( n = 243). Differential hydroxymethylation is found in thousands of genes, most significantly in genes related to pancreas development or function ( GATA4 , GATA6 , PROX1 , ONECUT1 , MEIS2 ), and cancer pathogenesis ( YAP1 , TEAD1 , PROX1 , IGF1 ). cfDNA hydroxymethylome in PDAC cohort is differentially enriched for genes that are commonly de-regulated in PDAC tumors upon activation of KRAS and inactivation of TP53 . Regularized regression models built using 5hmC densities in genes perform with AUC of 0.92 (discovery dataset, n = 79) and 0.92–0.94 (two independent test sets, n = 228). Furthermore, tissue-derived 5hmC features can be used to classify PDAC cfDNA (AUC = 0.88). These findings suggest that 5hmC changes enable classification of PDAC even during early stage disease.

الإتاحة: https://doi.org/10.1038/s41467-020-18965-wTest
https://www.nature.com/articles/s41467-020-18965-w.pdfTest
https://www.nature.com/articles/s41467-020-18965-wTest

المؤلفون: Guler, Gulfem, Ning, Yuhong, Haan, David, Kesling, Michael, Coruh, Ceyda, Mognol, Giuliana, Phillips, Tierney, Hazen, Kyle, Volkmuth, Wayne, Levy, Samuel

المصدر: Regular and Young Investigator Award Abstracts

الإتاحة: https://doi.org/10.1136/jitc-2022-sitc2022.0007Test

المؤلفون: Bansal, Vikas, Gassenhuber, Johann, Phillips, Tierney, Oliveira, Glenn, Harbaugh, Rebecca, Villarasa, Nikki, Topol, Eric J., Seufferlein, Thomas, Boehm, Bernhard Otto

المساهمون: Lee Kong Chian School of Medicine (LKCMedicine)

مصطلحات موضوعية: High-throughput Sequencing, Monogenic Diabetes

الوصف: Diagnosis of monogenic as well as atypical forms of diabetes mellitus has important clinical implications for their specific diagnosis, prognosis, and targeted treatment. Single gene mutations that affect beta-cell function represent 1–2% of all cases of diabetes. However, phenotypic heterogeneity and lack of family history of diabetes can limit the diagnosis of monogenic forms of diabetes. Next-generation sequencing technologies provide an excellent opportunity to screen large numbers of individuals with a diagnosis of diabetes for mutations in disease-associated genes. ; MOE (Min. of Education, S’pore) ; Published version

وصف الملف: 14 p.; application/pdf

العلاقة: BMC Medicine; Bansal, V., Gassenhuber, J., Phillips, T., Oliveira, G., Harbaugh, R., Villarasa, N., et al. (2017). Spectrum of mutations in monogenic diabetes genes identified from high-throughput DNA sequencing of 6888 individuals. BMC Medicine, 15(1), 213-.; https://hdl.handle.net/10356/85852Test; http://hdl.handle.net/10220/45279Test

الإتاحة: https://doi.org/10.1186/s12916-017-0977-3Test
https://hdl.handle.net/10356/85852Test
http://hdl.handle.net/10220/45279Test

المؤلفون: Rueda, Manuel, Wagner, Jennifer L., Phillips, Tierney C., Topol, Sarah E., Muse, Evan D., Lucas, Jonathan R., Wagner, Glenn N., Topol, Eric J., Torkamani, Ali

المصدر: Frontiers in Cardiovascular Medicine ; volume 4 ; ISSN 2297-055X

مصطلحات موضوعية: Cardiology and Cardiovascular Medicine

الإتاحة: https://doi.org/10.3389/fcvm.2017.00090Test

المؤلفون: Rueda, Manuel, Wagner, Jennifer L., Phillips, Tierney C., Topol, Sarah E., Muse, Evan D., Lucas, Jonathan R., Wagner, Glenn N., Topol, Eric J., Torkamani, Ali

المساهمون: National Institutes of Health

المصدر: Frontiers in Cardiovascular Medicine ; volume 4 ; ISSN 2297-055X

مصطلحات موضوعية: Cardiology and Cardiovascular Medicine

الإتاحة: https://doi.org/10.3389/fcvm.2017.00072Test