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• Circulating cell-free DNA analyses for Patient Monitoring in Small Cell Lung Cancer

  This study consists of over 200 data files from cfDNA and germline DNA from 69 patients and 32 healthy normal volunteers discussed in this publication.

  Dataset EGAD00001007070

• untargeted whole genome sequencing - Evaluation and correction of GC biases in cell-free DNA at the fragment level

  These are aligned paired-end reads from Illumina NovaSeq 6000 whole-genome sequencing of 4 cfDNA samples extracted from blood plasma (plasma-Seq). Three samples from patients with breast cancer, prostate cancer, or colorectal cancer and one sample from a healthy individual were aligned to GRCh38 (GCA_000001405.15_GRCh38_no_alt_plus_hs38d1_analysis_set). The observed GC bias is different in each of these cfDNA samples which leads to different average GC content per sample. This bias is corrected using the GCparagon commandline tool.

  Dataset EGAD00001010100

• Clinical and biomarker dataset

  Clinical & biomarker data from IMagyn050: treatment arm, treatment approach, outcome of surgery, ECOG PS, PD-L1 status, race, age, disease stage, progression free survival (investigator assessed), overall survival, histology, tumor mutation burden and status, genomic loss of heterozygosity, microsatellite status, BRCA1/2 mutation status, tissue of origin. Mutation status based on FoundationOne NGS for the following genes is also being provided: TP53, BRCA1, CCNE1, MYC, NF1, PIK3CA, RAD21, TERC, PRKCI, KRAS, RB1, BRCA2, ARID1A, AKT2, PTEN, KDM5A, NOTCH3, FGF12, ERBB2, CDK12, EMSY, WHSC1L1, BCL2L1, CDKN2A, GNAS, ARFRP1, ZNF217, SOX2, CCND2, FGF6, FGF23, LYN, MUTYH, AURKA, FGFR1, MCL1, MLL2, MYCL1, ZNF703, BRAF, MAP2K4, CREBBP, TSC2

  Dataset EGAD00001009797

• Genome-wide cell-free DNA termini in patients with cancer

  The structure, fragmentation pattern, length and terminal sequence of cell-free DNA (cfDNA) is under the influence of nucleases present in the blood. We hypothesized that differences in the diversity of bases at the end of cfDNA fragments can be leveraged on a genome-wide scale to enhance the sensitivity for detecting the presence of tumor signals in plasma. We surveyed the cfDNA termini in 72 plasma samples from 319 patients with 18 different cancer types using low-coverage whole genome sequencing. The fragment-end sequence and diversity were altered in all cancer types in comparison to 76 healthy controls. We converted the fragment end sequences into a quantitative metric and observed that this correlates with circulating tumor DNA tumor fraction (R = 0.58, p < 0.001, Spearman). Using these metrics, we were able to classify cancer samples from control at a low tumor content (AUROC of 91% at 1% tumor fraction) and shallow sequencing coverage (mean AUROC = 0.99 at >1M fragments). Combining fragment-end sequences and diversity using machine learning, we classified cancer from healthy controls (mean AUROC = 0.99, SD = 0.01). Using unsupervised clustering we showed that early-stage lung cancer can be classified from control or later stages based on fragment-end sequences. We observed that fragment-end sequences can be used for prognostication (hazard ratio: 0.49) and residual disease detection inresectable esophageal adenocarcinoma patients, moving fragmentomics toward a greater clinical implementation.

  Study EGAS00001005738

• Genome-wide cell-free DNA termini in patients with cancer

  The structure, fragmentation pattern, length and terminal sequence of cell-free DNA (cfDNA) is under the influence of nucleases present in the blood. We hypothesized that differences in the diversity of bases at the end of cfDNA fragments can be leveraged on a genome-wide scale to enhance the sensitivity for detecting the presence of tumor signals in plasma. We surveyed the cfDNA termini in 72 plasma samples from 319 patients with 18 different cancer types using low-coverage whole genome sequencing. The fragment-end sequence and diversity were altered in all cancer types in comparison to 76 healthy controls. We converted the fragment end sequences into a quantitative metric and observed that this correlates with circulating tumor DNA tumor fraction (R = 0.58, p < 0.001, Spearman). Using these metrics, we were able to classify cancer samples from control at a low tumor content (AUROC of 91% at 1% tumor fraction) and shallow sequencing coverage (mean AUROC = 0.99 at >1M fragments). Combining fragment-end sequences and diversity using machine learning, we classified cancer from healthy controls (mean AUROC = 0.99, SD = 0.01). Using unsupervised clustering we showed that early-stage lung cancer can be classified from control or later stages based on fragment-end sequences. We observed that fragment-end sequences can be used for prognostication (hazard ratio: 0.49) and residual disease detection inresectable esophageal adenocarcinoma patients, moving fragmentomics toward a greater clinical implementation.

  Study EGAS00001005747

• Ancestry and somatic profile predict acral melanoma origin and prognosis – WXS

  Acral melanoma, which is not ultraviolet (UV)-associated, is the most common type of melanoma in several low- and middle-income countries including Mexico. Latin American samples are significantly underrepresented in global cancer genomics studies, which directly affects patients in these regions as it is known that cancer risk and incidence may be influenced by ancestry and environmental exposures. To address this, we characterise the genome and transcriptome of 123 acral melanoma tumours from 92 Mexican patients, a population notable because of its genetic admixture. Compared with other studies of melanoma, we found fewer frequent mutations in classical driver genes such as BRAF, NRAS or NF1. While most patients had predominantly Amerindian genetic ancestry, those with higher European ancestry had increased frequency of BRAF mutations and a lower median number of structural variants. The tumours with activating BRAF mutations have a transcriptional profile more similar to cutaneous non-volar melanocytes, suggesting that acral melanomas in these patients may arise from a distinct cell of origin compared to other tumours arising in these locations. KIT mutations were found in a subset of these tumours, and quadruple wild-type samples (non BRAF/NRAS/NF1/KIT) differed from mutated samples in their structural genomic profile and overall and recurrence-free survival patterns. Transcriptional profiling defined three expression clusters; these characteristics were associated with recurrence-free and overall survival. We highlight potential novel low-frequency drivers, such as PTPRJ, NF2 and RDH5. Our study enhances knowledge of this understudied disease and underscores the importance of including samples from diverse ancestries in cancer genomics studies.

  Dataset EGAD00001015755

• WGS

  Whole Genome sequencing. 1 ug of genomic DNA from each lymph node sample was used for the construction of a TruSeq DNA PCR Free (350) library before sequencing in a Illumina HiSeq X Ten (2 × 151 bp). Mean coverage 30x.

  Dataset EGAD00001005423

• HEMa_LP

  This dataset contain WGBS sequencing result of HEMa_LP. The cells were cultured in Medium 254 supplemented with PMA-Free Human Melanocyte Growth Supplement-2 (HMGS-2) under 37°C,5% CO2.

  Dataset EGAD00001005486

• MATISSE bulk RNA-sequencing data

  Tumor availability: Bulk RNA sequencing was performed on tumor biopsies of 48 patients at baseline and 45 patients across time points (baseline n=48, week 1 n=38, week 2 n=34, week 4 n=37), including lymph node metastasis that were sequenced in addition to the primary tumor. Tumor RNA was extracted from formalin-fixed paraffin-embedded (FFPE) primary tumor and lymph node metastasis sections containing at least 10% viable tumor cells present in the sample, except for on-treatment samples with a complete pathological response in which we isolated samples with at least 10% immune-infiltration with no viable tumor cells. A pathologist (LS) scored the tumor percentage and indicated the most tumor-dense region on a hematoxylin and eosin (H&E) stain slide for subsequent RNA isolation. According to the manufacturer's protocol, five to 10 FFPE slides (10 µm) were used for RNA isolation using the AllPrep DNA/RNA FFPE isolation kit (Qiagen, 80234) and the QIAcube. Genetic Diagnostics and Sequencing Services (CeGaT) performed RNA sequencing in Germany. Data processing: Demultiplexing of the sequencing reads was performed with Illumina bcl2fastq (v2.20). Adapters of the reads (Pico v2 SMART adapter, first three nucleotides of the second sequencing read) were trimmed with Skewer (v0.2.2), without quality trimming. RNA-sequencing data was aligned to GRCh38 (Ensembl v109) using STAR (v2.7.9) in 2-pass mode with default settings. Gene counts were generated with the HTSeq (v2.0.2). FastQC (v0.12.1) and MultiQC (v1.14) were used for assessing data quality, on FASTQ files and intermediate processing steps.

  Dataset EGAD50000001470

• Prospective Analysis of Genotypes in Adults Undergoing Therapy for Lung Cancer (Paclitaxel Cohort)

  Lung cancer is frequently treated with paclitaxel in combination with several other agents; however, paclitaxel treatment is often ineffective or limited by treatment-related toxicities. Heritable variants in genes associated with absorption, distribution, metabolism, and elimination may predict paclitaxel clinical outcome and toxicity. We designed a prospective multi-institutional study that recruited 546 patients receiving therapy with a 5-year follow up. All patients were genotyped using the Drug Metabolizing Enzymes and Transporters (DMET) platform, which ascertains 1931 genotypes in 235 genes. Genotypes were compared to the progression-free survival of paclitaxel therapy and clinically-significant paclitaxel toxicities. Seven genetic variants were associated with paclitaxel PFS (in ABCB11, ABCC3, ABCG1, CYP8B1, NR3C1, FMO6P, and GSTM3), whereas four genetic variants (in VKORC1, SLC22A14, GSTA2, and DCK) were associated with paclitaxel toxicities. The present SNPs have limited clinical utility but suggest that certain genes are related to important paclitaxel pathways in lung cancer.

  Study phs001660

• Genetic Study of Vascular Anomalies

  Vascular anomalies are malformations or tumors of the vasculature that can result in significant morbidity and mortality. Vascular anomalies are caused by germline or post-zygotic pathogenic variants in genes that regulate cell growth and vascular development. Complex or extensive vascular anomalies are often intractable despite interventions such as sclerotherapy, embolization, or surgery. In recent years, targeted therapy has played an increasingly crucial role in the management of these diseases. Identification of the molecular causes of vascular anomalies is essential to provide efficacious therapy; however, genetic profiling is often limited by difficulty obtaining affected tissues and limited sequencing depth. The lack of this information limits treatment options and the precision of targeted therapy, especially for primary complex lymphatic anomalies. To address these limitations, we have applied novel techniques, including analysis of unconventional samples such as endothelial cells isolated from lymphatic fluid and cell-free DNA, deep coverage exome sequencing, and unique molecular identifier ultra-deep targeted sequencing, in the molecular profiling of these diseases.

  Study phs003197

• Gene Expression between PMD and Control LCLs at Baseline, E2, and E2 Withdrawal

  In this study, lymphoblastoid cell lines (LCLs) derived from women with past perimenopausal depression (PMD) (n = 8) and asymptomatic controls (n = 9) were compared via poly(A)-selected transcriptome sequencing (RNA-seq). LCLs were cultured in three experimental conditions: at vehicle baseline (ovarian steroid-free), during estradiol (E2) treatment, and following E2-withdrawal. Transcriptomic analysis revealed significant differences in transcript expression in PMD LCLs compared to controls in all experimental conditions, and significant overlap in genes that were changed in PMD regardless of experimental condition. Among these, chemokine CXCL10 was upregulated in women with PMD, but most so after E2-WD and CYP7B1, an enzyme intrinsic to DHEA metabolism, was upregulated in PMD across experimental conditions. Finally, this in vitro model identified gene networks dysregulated in PMD which included inflammatory response, early/late E2-response, and cholesterol homeostasis. Data available will include the normalized counts for each subject in the study.

  Study phs003003

• ucfDNA workflows for molecular profiling of malignant disease

  Urinary cell-free DNA (ucfDNA) is a promising liquid biopsy analyte obtained by a non-invasive sampling method, particularly valuable in urological cancers due to the proximity of biofluids to the tumor site. However, extremely high fragmentation and low abundance of ucfDNA pose significant analytical challenges. Improper handling and storage can severely affect ucfDNA quality, necessitating optimized pre-analytical workflows for clinical applications. We evaluated multiple pre-analytical workflows, including urine stabilization approaches against unstabilized urine samples. Our results demonstrated that without stabilization, ucfDNA degraded rapidly and minimal quantities remaining after 72 hours. In contrast, urine stabilization preserved ucfDNA integrity, enabling successful downstream analyses, including digital PCR and next-generation sequencing, for mutation detection in cancer-related genes and genome wide copy number profiling. These findings underscore the critical role of stabilization for a reliable ucfDNA analysis and highlight its potential in molecular diagnostics as a complementary tool to plasma-based liquid biopsies.

  Study EGAS50000001093

• A comprehensive assessment of somatic mutation detection in cancer using whole genome sequencing

  As whole genome sequencing for cancer genome analysis becomes a clinical tool, a full understanding of the variables affecting sequencing analysis output is required. Using tumor-normal sample pairs from two different types of cancer, chronic lymphocytic leukemia and medulloblastoma, we conducted a benchmarking exercise within the context of the International Cancer Genome Consortium. We compare sequencing methods, analysis pipelines, and even validation methods. Here we show that using PCR-free methods and increasing sequencing depth to ~100x showed benefits, as long as the tumor:control coverage ratio remains balanced. We observe widely varying mutation call rates and low concordance among analysis pipelines, reflecting the artifact-prone nature of the raw data and lack of standards for dealing with the artifacts. However, armed with the benchmark mutation set we have created, we show that many issues are in fact easy to remedy and have an immediate positive impact on mutation detection accuracy.

  Study EGAS00001001539

• Immune-awakening revealed by peripheral T cell dynamics after one cycle of immunotherapy

  BACKGROUND: Our understanding of T cell evolution under checkpoint inhibitors (CPI) is still incomplete, restraining the achievement of full benefit from CPI.OBJECTIVES: We studied peripheral T cell turnover and evolution and their prognostic value after 3weeks on treatment with CPI (one cycle) analysing T cell receptor-β (TCR) sequences in plasma cell-free DNA (cfDNA) and PBMC, and performing a phenotypic analysis of peripheral T cell subsets.RESULTS: Peripheral T cell turnover and TCR repertoire dynamics correlated with response. Additionally, the cfDNA TCR repertoire reorganisation fingerprint correlated with the expansion of an immune-effector subset of peripheral T cells that predicted treatment response and identified the patients with longer overall survival.CONCLUSIONS: Here we show that prognostic changes in peripheral T cells occur within 3 weeks of commencing CPI treatment. This dynamic immune-awakening informs on the immune-system reorganization can be monitored using minimally invasive liquid biopsies.

  Study EGAS00001004043

• A Machine Learning Tool Integrating Circulating Cell-Free DNA Methylation with Clinical Variables for Non-Invasive Diagnosis of Liver Graft Pathology

  Liver Transplant Recipients (LTRs) with elevated liver enzymes can develop graft injury due to various etiologies, such as T-cell mediated rejection (TCMR) and NASH (NASH-LT). While liver biopsy is the gold standard method for diagnosis of graft pathology, it is invasive and is associated with risks. The goal of our study was to develop a Machine Learning (ML) tool integrating clinical variables with methylation patterns on circulating DNA in plasma as a non-invasive diagnostic tool of graft injury. We generated methylation profiles of circulating DNA in a pilot study of 43 LTRs (11 NASH-LT, 19 TCMR, and 13 Control-LT), and developed an L2 multinomial logistic regression ML approach across 101 bootstrapped models to distinguish between the graft conditions. NASH was associated with distinctive methylation patterns on genes involved in fatty acid metabolism, while methylation of platelet-derived growth factors was identified in patients with TCMR. Our ML model achieved a mean multi-classification accuracy of 0.91, with mean specificity and sensitivity of 0.94 and 0.91, respectively. The model was found to be particularly adept at detecting TCMR and Control-LT, with true positive rates (TPRs) of 95% and 90%, and areas under the curve (AUROC) of 0.992 and 0.985, respectively. For NASH-LT, the models achieved a performance with a TPR of 82% and an AUROC of 0.991. These preliminary results suggest that our newly developed ML tool, leveraging cell-free DNA methylation and clinical variables, is a promising non-invasive classifier of graft pathology.

  Study EGAS00001007171

• POPRES: Population Reference Sample

  POPRES version 1 and 2 Technological and scientific advances, stemming in large part from the Human Genome and HapMap projects, have made large-scale, genome-wide investigations feasible and cost-effective. These advances have the potential to dramatically impact drug discovery and development by identifying genetic factors that contribute to variation in disease risk as well as drug pharmacokinetics, treatment efficacy, and adverse drug reactions. In spite of the technological advancements, successful application in biomedical research would be limited without access to suitable sample collections. To facilitate exploratory genetic research, we have assembled a DNA resource from a large number of subjects participating in multiple studies throughout the world. This resource was initially genotyped using the Affymetrix 500K SNP panel. This project includes nearly 6,000 subjects of African American, East Asian, South Asian, Mexican, and European origin. POPRES version 3 The discovery and development of novel drugs is challenging and with high attrition rates. Selection of the right target and optimal indications for novel therapeutics represent key decision points in this process, and are often hampered by our limited understanding of the biology of the target in humans. Building a robust body of knowledge of variation within drug target genes has in several cases increased the probability of success for novel therapeutics. Our knowledge of variation within drug target genes and their influence on traits of medical interest is still very limited. In an effort to fill this gap, we resequenced the exons of 202 known or suspected drug target genes in over 16,000 well-phenotyped individuals. A total of 863,883 bases were targeted, including 351 kb of coding and 323 kb of untranslated exon regions. The sequenced subjects included 3,381 from two studies that were part of the Population Reference Sample (POPRES) project: CoLaus (N = 2,059) and LOLIPOP (N = 1,322). Genotyping data generated through the targeted next generation sequencing is available through the dbGaP.

  Study phs000145

• The circulating cell-free DNA landscape in sepsis is dominated by impaired liver clearance

  Circulating cell-free DNA (cfDNA) is a promising molecular biomarker. However, its utility in severe infection remains poorly understood. Here, we isolated cfDNA from sepsis patients and controls, demonstrating a 41-fold increase in the amount of cfDNA in circulation during disease. We used sequencing to reconstruct cfDNA methylomes, fragmentation profiles, and nucleosome footprints across 58 samples. We observed no difference in cfDNA composition between patients and controls, challenging the idea that cfDNA increases due to higher immune cell death during sepsis. Instead, we suggest that liver dysfunction prevents efficient clearance of cfDNA during disease. This was supported by fragmentation and end-motif patterns, both of which showed evidence of cfDNA being exposed to circulating nucleases for a prolonged period, proportionally to the extent of liver dysfunction. Variation in cfDNA of megakaryocyte-erythroid progenitor origin was also a significant contributor in sepsis, increasing over time. Moreover, we showed that cfDNA retains nucleosome footprints with cell type-specific gene activity information. We developed a novel approach to study nucleosome phasing that successfully recovers tissue-specific signatures. By combining this with single-cell data, we demonstrated that sepsis patients with liver dysfunction have higher amounts of cfDNA derived from Kupffer cells and the liver parenchyma. In conclusion, we present the first high-throughput multi-modal study of cfDNA during sepsis, which will serve as a reference point for future studies on the role of this biomarker in critical illness.

  Study EGAS50000001033

• Structural Alterations Driving Castration-Resistant Prostate Cancer Revealed by Linked-Read Genome Sequencing

  Adapted from manuscript in review: Nearly all prostate cancer deaths are from metastatic castration-resistant prostate cancer (mCRPC) but there have been few whole genome sequencing (WGS) studies of this disease state. We performed linked-read WGS on 23 mCRPC biopsy specimens and analyzed cell-free DNA sequencing data from 86 patients with mCRPC. In addition to frequent rearrangements affecting known prostate cancer genes, we observed complex rearrangements of the AR locus in most cases. These include highly recurrent tandem duplications involving an upstream enhancer of AR. A subset of cases also displayed a genome-wide tandem duplicator phenotype associated with CDK12 inactivation. Our findings highlight the complex genomic structure of mCRPC nominate new alterations that may inform prostate cancer treatment, and suggest that additional recurrent events in the noncoding mCRPC genome remain to be discovered.

  Study phs001577

• RNA sequencing of surgically removed lung adenocarcinoma afterwards treated with immune checkpoint inhibitors

  Patients with lung adenocarcinoma (LUAD) from The Cancer Genome Atlas (TCGA) database were enrolled in the training cohort to establish a prognostic signature based on the expression of tumor-specific amino acid metabolism related genes. The established signature was further investigated against an original cohort, KCC-ICI, of chemotherapy combined with immune checkpoint inhibitors. The signature consisting of nine genes, KYNU, PSPH, PPAT, MIF, GCLC, ACAD8, TYRP1, ALDH2, and HDC, could effectively stratify the OS in LUAD patients. The KCC-ICI cohort confirmed the predictive ability of the established signature in the clinical response to immune checkpoint blockade therapy, which correlated with the infiltration of immune cells (e.g., T lymphocytes and nature killer cells). We discovered that the high signature risk score patients showed a significantly lower concentration of plasma-free ??-aminobutyric acid (AABA).

  Study JGAS000675

• Whole Genome Bisulfite Sequencing of Circulating Cell-Free (CCF) DNA and its Cellular Contributors

  Background: Circulating cell free (ccf) fetal DNA has enabled non-invasive prenatal fetal aneuploidy testing without direct discrimination of the genetically distinct maternal and fetal DNA. Current testing may be improved by specifically enriching the sample material for fetal DNA. DNA methylation may allow for such a separation of DNA and thus support additional clinical opportunities; however, this depends on knowledge of the methylomes of ccf DNA and its cellular contributors. Results: Whole genome bisulfite sequencing was performed on a set of unmatched samples including ccf DNA from 8 non-pregnant (NP) and 7 pregnant female donors and genomic DNA from 7 buffy coat and 5 placenta samples. We found CpG cytosines within longer fragments were more likely to be methylated, linking DNA methylation and fragment size in ccf DNA. Comparison of the methylomes of placenta and NP ccf DNA revealed many of the 51,259 identified differentially methylated regions (DMRs) were located in domains exhibiting consistent placenta hypomethylation across millions of consecutive bases, regions we termed placenta hypomethylated domains. DMRs identified when comparing placenta to NP ccf DNA were recapitulated in pregnant ccf DNA, confirming the ability to detect differential methylation in ccf DNA mixtures. Conclusions: We generated methylome maps for four sample types at single base resolution, identified a link between DNA methylation and fragment length in ccf DNA, identified DMRs between sample groups, and uncovered the presence of megabase-size placenta hypomethylated domains. Furthermore, we anticipate these results to provide a foundation to which future studies using discriminatory DNA methylation may be compared.

  Study phs000846

• Control iPSC lines with clinically annotated genetic variants for versatile multi-lineage differentiation

  Induced Pluripotent Stem Cells (iPSC) derived from healthy individuals are important controls for disease modeling studies. To create a resource of genetically annotated iPSC, we reprogrammed footprint-free lines from four volunteers in the Personal Genome Project Canada (PGPC). Multilineage directed differentiation efficiently produced functional cortical neurons, cardiomyocytes and hepatocytes. Pilot users further demonstrated line versatility by generating kidney organoids, T-cells and sensory neurons. A frameshift knockout was introduced into MYBPC3 and these cardiomyocytes exhibited a hypertrophic phenotype as expected. WGS annotation of PGPC lines revealed on average 20 coding variants. Importantly, nearly all annotated PGPC and HipSci lines harboured at least one pre-existing or acquired variant with cardiac, neurological or other disease associations. Overall, PGPC lines were efficiently differentiated by multiple users into cell types found in six tissues for disease modelling, and clinical annotation highlighted variant-preferred lines for use as unaffected controls in specific disease settings.

  Study EGAS00001003684

• ENCORAFENIB COMBINED WITH BINIMETINIB FOR BRAFV600E-MUTATED RELAPSED/REFRACTORY MULTIPLE MYELOMA: THE PHASE II GMMG-BIRMA TRIAL (Hipo_K08K)

  Activating BRAF mutations are rare events in multiple myeloma but have been shown to be promising therapeutic targets in small case studies. This multicenter phase II trial assessed the efficacy and safety of the BRAF/MEK inhibitors, encorafenib and binimetinib, in patients with relapsed/refractory multiple myeloma (RRMM) carrying an activating BRAFV600E mutation. Twelve RRMM patients with a median of five prior lines of therapy were enrolled. The study met its primary endpoint with 10 patients achieving at least a partial response according to IMWG criteria (overall response rate 83.3%). Responses occurred rapidly within the first cycle and deepened over time. The median progression-free survival (PFS) was 5.6 months and overall survival was 55% at 24 months. Genomic profiling revealed RAS mutations and structural variants involving the BRAF locus to be drivers of resistance to BRAF/MEK inhibition in RRMM. This trial demonstrates the value of translationally driven clinical trials in selected patient populations.

  Study EGAS00001005973

• Detection and characterization of lung cancer using cell-free DNA fragmentomes

  Lung cancer remains the leading cause of cancer death world-wide, largely due to its late diagnosis. Non-invasive approaches for assessment of cell-free DNA (cfDNA) provide an opportunity for detection and intervention that may have broader accessibility than current imaging approaches. Using a machine learning model for detecting tumor-derived cfDNA through genome-wide analyses of cfDNA fragmentation, we examined a prospective study of 365 individuals at risk for lung cancer (Lung Cancer Diagnostic Study, LUCAS), including 129 individuals ultimately diagnosed with lung cancer and 236 individuals determined to not have lung cancer. We externally validated the cancer detection model using an independent cohort of 385 non-cancer individuals and 46 predominantly early stage lung cancer patients. Combining fragmentation features with clinical risk factors and CEA levels followed by CT imaging detected 94% of patients with cancer across stages and subtypes, including 91% of stage I/II and 96% of stage III/IV, at 80% specificity. Genome-wide fragmentation profiles across ~13,000 ASCL1 transcription factor binding sites could be used to distinguish individuals with small cell lung cancer (SCLC) from those with non-small cell lung cancer (NSCLC) with high accuracy (AUC=0.98). Among individuals with lung cancer, a higher cfDNA fragmentation score was associated with tumor size and invasion, and represented an independent prognostic indicator of survival. These studies provide a facile approach for non-invasive detection of lung cancer and clinical management of this disease.

  Study EGAS00001005340

• Lactobacillus rhamnosus GG ATCC (LGG) as an immune adjuvant for influenza vaccination in the elderly

  Double blind Randomized Controlled trial to evaluate the safety of Lactobacillus rhamnosus GG ATCC 53103 (LGG) vs placebo in elderly receiving Trivalent Inactivated Influenza Vaccine (TIV) (study 1) or Double blind Randomized Controlled trial to evaluate the safety of Lactobacillus rhamnosus GG ATCC 53103 (LGG) vs. placebo in elderly subjects receiving Live Attenuated Influenza vaccine (LAIV) (study 2). Healthy elderly volunteers, ages 65-80 were enrolled as outpatients in two clinical studies in which they received the TIV vaccine (study 1, n=28) or the LAIV vaccine (study 2, n=30). In each of the 2 studies, subjects were randomized to receive either LGG capsules containing 1 x 1010 CFU, twice daily for 28 days, or matching placebo capsules twice daily for the same period of time. The study subjects completed a daily diary, telephone calls, and study visits at the Massachusetts General Hospital Clinical Research Centers at baseline, days 21, 28 and 56 and month 5 for the TIV study and baseline, days 21, 28, and 56 for the LAIV study. During each visit, the subject diary, interim history, potential adverse effects and concomitant medications were reviewed and vital signs and a physical examination were performed. Routine blood tests were obtained to monitor for safety during visits and nasopharyngeal and stool samples were collected for microbiome analysis. Volunteers in both studies who were interested in participating in the effect of LGG probiotic on the Human whole Blood Transcriptome substudy also had blood drawn for DNA and RNA extraction, after signing the substudy consent form. The main objectives of the TIV and LAIV studies were to assess the safety and tolerability of 2 x 1010 CFU LGG administered orally to elderly subjects for 28 days after administration of TIV (study 1) or LAIV (study 2). Secondary objectives were to evaluate the richness and microbial diversity in nasopharyngeal and stool specimens using pyrosequencing, and to compare cytokine production in response to bacterial stimulation by following the kinetics of mRNA expression of pro and anti-inflammatory genes and different signaling pathways, in relation to changes in stool Bifidobacterium and Lactobacillus spp. The studies were reviewed and approved by the Partners Human Research Committee (TIV study IRB # 2010p001694 and LAIV study IRB # 2011p002849) and were registered at ClinicalTrials.gov (NCT01368029 and NCT01545349, respectively).

  Study phs000981