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• Low and variable tumor reactivity of the intratumoral TCR repertoire in human cancers

  Infiltration of human cancers by T cells is generally interpreted as a sign of immune recognition, and there is a growing effort to reactivate dysfunctional T cells at such tumor sites. However, these efforts only have value if the intratumoral T cell receptor (TCR) repertoire of such cells is intrinsically tumor-reactive, and this has not been established in an unbiased manner for most human cancers. To address this issue, we analyzed the intrinsic tumor-reactivity of the intratumoral TCR repertoire of CD8+ T cells in ovarian and colorectal cancer – two tumor types for which T cell infiltrates form a positive prognostic marker. Data obtained demonstrate that a capacity to recognize autologous tumor is limited to approximately 10% of intratumoral CD8+ T cells. Furthermore, in two out of four patient samples tested, no tumor-reactive TCRs were identified, despite infiltration of their tumors by T cells. These data indicate that the intrinsic capacity of intratumoral T cells to recognize adjacent tumor tissue can be rare and variable, and suggest that clinical efforts to reactivate intratumoral T cells will benefit from approaches that simultaneously increase the quality of the intratumoral TCR repertoire.

  Study EGAS00001003119

• Epigenome wide DNA methylation assay of gingivo-buccal oral squamous cell carcinoma using single base resolution high throughput array

  Gingivo-buccal oral squamous cell carcinoma (OSCC-GB) is the most common cancer among men in India and is associated with high mortality. Although OSCC-GB is known to be quite different from tongue cancer in its genomic presentation and its clinical behavior, it is treated identically as tongue cancer. Predictive markers of prognosis and therapy that are specific to OSCC-GB are, therefore, required. To achieve this, we have carried out epigenomic (n=87) profiling of paired tumor-normal tissues collected from OSCC-GB patients from India and genome-wide DNA methylation assays were performed. DNA was isolated using DNeasy Blood and Tissue Kit (Qiagen). The purity and concentration was estimated using NanoDrop 2000 (Thermo Fisher Scientific). Approximately 500 ng genomic DNA from each sample was used for sodium bisulfite conversion using the EZ DNA methylation Gold Kit (Zymo Research, USA). Genome-wide DNA methylation was assayed using iScan (Illumina), for paired tumour and adjacent normal samples of 25 patients using the Infinium Human Methylation450 BeadChip and of 62 patients using the Infinium MethylationEPIC BeadChip.

  Study EGAS00001003896

• Allele-specific expression of GATA2 due to epigenetic dysregulation in double mutated CEBPA AML

  Transcriptional deregulation is a central event in the development of acute myeloid leukemia (AML). To identify potential disturbances in gene regulation, we conducted an unbiased screen of allele-specific expression (ASE) in 209 AML cases. The gene encoding GATA binding protein 2 (GATA2) displayed ASE more often than any other myeloid or cancer-related gene. GATA2 ASE was strongly associated with CEBPA double mutations (CEBPA DM), with 95% of cases presenting GATA2 ASE. In CEBPA DM AML with GATA2 mutations, the mutated allele was preferentially expressed. We found that GATA2 ASE is a somatic event lost in complete remission, supporting the notion that it plays a role in CEBPA DM AML. Acquisition of GATA2 ASE involved silencing of one allele via promoter methylation, compensated by overactivation of the other allele, thereby preserving expression levels. Notably, promoter methylation was also lost in remission together with GATA2 ASE. In summary, we propose that GATA2 ASE is acquired by epigenetic mechanisms and is a prerequisite for the development of AML with CEBPA DM. This finding constitutes a novel example of an epigenetic hit cooperating with a genetic hit in the pathogenesis of AML.

  Study EGAS00001004684

• The Human Phenotype Project (HPP) is a large-scale deep-phenotype prospective longitudinal and ethnically diverse cohort

  The Human Phenotype Project (HPP) is a large-scale deep-phenotype prospective longitudinal and ethnically diverse cohort and biobank that we established. To date, approximately 28,000 participants have enrolled in the study, with over 13,000 having completed their initial visit. The project is aimed at identifying novel molecular signatures with diagnostic, prognostic and therapeutic value, and at developing AI-based predictive models for disease onset and progression. A unique feature of the HPP is its deep and longitudinal profiling that includes medical history, lifestyle and nutritional habits, vital signs, anthropometrics, blood tests, continuous glucose and sleep monitoring, imaging modalities and molecular profiling of the transcriptome, genetics, gut, vaginal and oral microbiome, metabolome and immune system. For several of these modalities, the HPP is the first or largest cohort of its kind. Our analyses of this data provide novel insights into the variation of phenotypes with age and ethnicity, highlighting the importance of having ethnically diverse cohorts and the need for establishing age-dependent norms. We demonstrate how the HPP can be used to unravel personalized molecular signatures of disease by comparison to patient-specific and disease-specific matched healthy controls. Leveraging the extensive dietary and lifestyle HPP data, we systematically identify associations between lifestyle factors and health outcomes. Finally, we present a multi-modal foundation AI model that is trained using self-supervised learning on diet and CGM data and outperforms existing methods in predicting future onset of disease. We extend this AI framework to integrate all data modalities of each subject as a continuous sequence of diverse medical events, creating a digital twin that can simulate interventions and predict health trajectories and outcomes.

  Study EGAS00001008040

• A common single nucleotide variant in T is strongly associated with chordoma

  Chordoma is a rare malignant bone tumor that expresses the transcription factor T. We conducted an association study of 40 patients with chordoma and 358 ancestry-matched, unaffected individuals with replication in an independent cohort. Whole-exome and Sanger sequencing of T exons reveals a strong risk association ( allelic odds ratio (OR) = 4.9, P = 3.3x10-11, CI= 2.9-8.1) with the common (minor allelic frequency >5%) non-synonymous SNP rs2305089 in chordoma, which is exceptional in cancer genetics.

  Dataset EGAD00001000226

• Genomic characterization of co-existing biliary tract intraepithelial neoplasia and carcinoma lesions reveals distinct evolutionary paths of gallbladder cancer

  Gallbladder carcinoma is the most common cancer of the biliary tract with dismal survival largely due to delayed diagnosis. Biliary tract intraepithelial neoplasia (BilIN) is the common benign tumor that is suspected to be precancerous lesions. However, the genetic and evolutionary relationships between BilIN and carcinoma remain unclear. Here we performed whole-exome sequencing of coexisting low-grade BilIN (adenoma), high-grade BilIN, and carcinoma lesions, and normal tissues from the same patients.

  Dataset EGAD00001007792

• Genetic Studies of Chronic Kidney Disease (CKD)

  The Genetic Studies of Chronic Kidney Disease (CKD) is an ongoing genetic research and biobanking protocol which aims to elucidate the genetic basis CKD. The study recruits patients seen at the Columbia University Medical Center (CUMC) Nephrology Division for the evaluation and care of CKD. All patients clinically diagnosed with CKD are eligible to participate; there are no inclusion or exclusion criteria related to age, sex/gender, and/or race/ethnicity. In addition to office visits, patients are recruited in contexts including perinatal care and nonprofit events for patients with various forms of CKD; recruitment tools include bilingual informational brochures, flyers, and consent forms. All individuals provide informed consent; for minors, signature of the parent/guardian is required. Consent includes: use of biosamples given for genetic studies, and the request to be re-contacted if medically actionable genetic findings are identified. In the case of the latter, such research-level findings are first validated in a clinically certified (CLIA) laboratory environment, using a second sample given by the individual at the time of re-contact; following CLIA validation, the individual is once again re-contacted, and, assuming he or she still desires return of these results, they can then be returned. Following the above consent process to participate in the study, individuals provide a single biosample (generally, a venous blood sample), from which DNA is extracted using standard protocols and used for genetic studies, such as exome sequencing. Basic clinical and demographic data, including sex/gender, age, and race/ethnicity are also collected. All data collected is stored in a secure computerized database, with patient samples anonymized using numerical identifiers; the relation of this identifier to patients' names is kept in a locked computer file in a centralized database. Electronic data complies with all HIPAA and other privacy and security regulations, and resides on a firewall server maintained by the CUMC IT department.

  Study phs001828

• Multicenter International Lymphangioleiomyomatosis Efficacy of Sirolimus Trial (The MILES Trial)

  Lymphangioleiomyomatosis (LAM) is an uncommon, progressive, cystic lung disease that predominantly affects young women. It is believed to be caused by defects within cellular pathways that regulate nutrient uptake, cell size, cell migration, and cell proliferation. The disease is caused by mutations in tuberous sclerosis complex (TSC) genes. Individuals with Lymphangioleiomyomatosis (LAM) often experience pneumothorax and chylothorax, as well progressive loss of lung function. Lymphangioleiomyomatosis (LAM) is frequently fatal and existing therapies for the disease have not proven effective. Lung transplantation can be considered as a last option, but alternative treatments are needed. Sirolimus is an immunosuppressive drug that is often used in people who have had kidney transplants. It directly affects the genetic pathway that causes Lymphangioleiomyomatosis (LAM). This study will evaluate the safety and effectiveness of sirolimus in stabilizing or improving lung function in people with Lymphangioleiomyomatosis (LAM). Individuals interested in participating in this 2-year, double-blind study will first report to the study sites for pulmonary function testing to determine their eligibility for participation. Participants deemed eligible will be randomly assigned to receive either sirolimus or placebo for 1 year. Sirolimus or placebo will be administered in 2 tablet doses (2 mg for sirolimus) for the duration of the study. Study visits will occur at baseline, Week 3, every 3 months for 12 months, and Months 18 and 24. Study visits will include a physical exam, questionnaires, a pregnancy test, blood and urine collection, and functional lung tests. A 6-minute walk test will occur at most study visits; a chest x-ray will be taken at baseline and Month 24; and a volumetric computed tomography scan will occur at baseline Month 12, and Month 24. Adverse events, medication side effects, and lung function will be assessed at each visit.

  Study phs000605

• Center for Education and Drug Abuse Research (CEDAR)

  Under its programmatic name, the Center for Education and Drug Abuse research (CEDAR), this Center of Excellence project was completed in 2015. The CEDAR sample consists of 775 nuclear families comprising an adult male (proband), his spouse/mate, and their biological child who is 10-12 years of age at recruitment. This child is designated as index child (IC), and is followed through age 30. Minimal exclusionary criteria were applied to maximize the sample's representativeness. Follow-up evaluations on ICs were conducted at ages 14, 16, 19, 22, 25, 27 and 30. Interim questionnaires were mailed annually beginning at age 20. CEDAR utilizes the family/high-risk paradigm. The offspring thus comprise high average risk (HAR) and low average risk (LAR) groups, constituting the majority of the CEDAR children sample: 250 HAR males, 100 HAR females, 250 LAR males and 94 LAR females. The remainder of the IC sample, 50 males and 31 females, are the offspring of fathers who have a lifetime non-SUD psychiatric dis-order. The follow-up rate from baseline to the final assessment is ~65%. The cohort of children is 76% White and 22% Black. The representation of females among ICs is lower than males, due to the later start of recruit-ment (2nd funding cycle; the study originally focused on males). The CEDAR genetic study has been augmented by the inclusion of its sample into the whole-genome genotyping effort conducted under the Genes, Environment and Development Initiative (GEDI). DNA from the blood samples of target children (index cases) and their siblings submitted to the NIDA Genetics Depository a Rutgers University was obtained and genotyped on Illumina Human660W-Quad Beadchips, with a high average genotyping rate of 99.8%. The sample comprised 158 females and 271 males (37 and 63 %), ~70:30 European- and African- American, with approximately 1:1 ratio of children of affected fathers and normal controls.

  Study phs001649

• NEI CIDR Methylation Profiling of Primary Open Angle Glaucoma in GLAUGEN Samples

  This is a case-control study of Primary Open Angle Glaucoma (POAG). POAG is a progressive optic neuropathy that eventually leads to blindness. More than 30 million people worldwide have Primary Open Angle Glaucoma (POAG), of which greater than 3 million are blind. Gene expression changes in the retina have been observed for POAG. Several recent studies, including the GLAUGEN (Glaucoma Gene Environment) initiative have used GWAS to identify correlative regions of the genome. Despite this, the genetic basis of Glaucoma is not well understood. Epigenetic variation may account for low heritability and environmental effects on human disease. Despite the significant advances being made in understanding the role of epigenetics in gene regulation in other fields, little is known about the relationship between DNA methylation patterns, retinal gene expression, and retinal disease. The goal of this study is to identify differentially methylated regions in the peripheral blood of patients with POAG. The case identification is as per the GLAUGEN description: Cases and controls were recruited from ophthalmology clinics and were examined by ophthalmologists. For cases the clinical exam included intraocular pressure measurements, optic nerve assessment and visual field evaluation. Controls had no family history of glaucoma, normal intraocular pressure and normal optic nerves. POAG and control samples come from Massachusetts Eye and Ear Infirmary (MEEI). These samples were collected and genotyped as part of the GLAUGEN study. From the MEEI, 50 patients were selected from POAG pedigrees, to include all the probands genotyped by CIDR and are currently undergoing exome sequencing, and to include additional genotyped probands who belong to pedigrees of sufficient size and structure that parent of origin effects could be evaluated. Additional individual-level phenotype and genotype data may be obtained through the authorized access portal of phs000308 (Geneva - Glaugen GWAS Study).

  Study phs000461