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• Overcoming Clinical Resistance to EZH2 Inhibition Using Rational Epigenetic Combination Therapy

  Essential epigenetic dependencies have become evident in many cancers. Based on functional antagonism between BAF/SWI/SNF and PRC2 in SMARCB1-deficient sarcomas, we and colleagues recently completed the clinical trial of the EZH2 inhibitor tazemetostat, leading to its FDA approval. However, the principles of tumor response to epigenetic therapy in general and tazemetostat in particular remain unknown. Using functional genomics of patient tumors and diverse experimental models, we defined molecular mechanisms of tazemetostat resistance. We found distinct classes of acquired mutations that converge on the RB1/E2F axis, decoupling EZH2-dependent differentiation and cell cycle control. This allows tumor cells to escape tazemetostat-induced G1 arrest despite EZH2 inhibition and suggests a general mechanism for effective EZH2 therapy. Using RNA-sequencing of patient tumor specimens, we identified specific genes as markers of a deficient RB1/E2F axis, which we propose as prospective biomarkers for therapy stratification. This offers a paradigm for rational epigenetic combination therapy suitable for immediate translation to clinical trials.This study was performed on archived tumor tissue collected as part of the above clinical trial at Memorial Sloan Kettering Cancer Center. Patient tumors were classified into "Response" or "Progression" groups based on RECIST 1.1 criteria. "Response" included tumors exhibiting a complete response, partial response, or stable disease. All other tumors were classified under the "Progression" group. Archived frozen tumor samples were weighed and up to 20-30mg were homogenized in RLT buffer, followed by extraction using the AllPrep DNA/RNA Mini Kit (QIAGEN catalog 80204) according to the manufacturer's instructions. RNA was eluted in 13 μL nuclease-free water. After RiboGreen quantification and quality control by Agilent BioAnalyzer, 1 μg of total RNA with DV200 percentages varying from 78% to 100% underwent ribosomal depletion and library preparation using the TruSeq Stranded Total RNA LT Kit (Illumina catalog RS-122-1202) according to instructions provided by the manufacturer with 8 cycles of PCR. Samples were barcoded and sequenced using NovaSeq 6000 in a PE150 mode, with the NovaSeq 6000 S4 Reagent Kit (Illumina). On average, 84 million paired reads were generated per sample and 70% of the data mapped to mRNA. For analysis, read adaptors were trimmed and quality filtered using 'trim_galore' and mapped to GRCh38/hg19 reference genome using STAR v2.7.9 with default parameters.

  Study phs003188

• Clinical outcomes in ctDNA-positive urothelial carcinoma patients treated with adjuvant immunotherapy

  Minimally invasive approaches to detect residual disease after surgery are urgently needed to select patients at highest risk for metastatic relapse for additional therapies. Circulating tumour DNA (ctDNA) holds promise as a biomarker for molecular residual disease (MRD) and relapse,1-3 but its clinical value has yet to be demonstrated in a randomised clinical trial. We evaluated outcomes in post-surgical ctDNA-positive (+) patients in a randomised phase III trial of adjuvant atezolizumab versus observation. IMvigor010 enrolled 809 patients with muscle-invasive urothelial carcinoma and did not meet its primary endpoint of disease-free survival (DFS) in the intent-to-treat population. Within the study, an exploratory planned analysis of prospectively collected plasma was performed, which tested the utility of ctDNA to identify patients who may benefit from adjuvant atezolizumab treatment. ctDNA was measured at the start of therapy (cycle 1 day 1; C1D1) and at week 6 (cycle 3 day 1; C3D1), and 581 patients were evaluable for ctDNA. The prevalence of ctDNA positivity at C1D1 was 37% (n=214), and ctDNA positivity identified patients with poor prognosis (observation arm DFS HR= 6.19 (4.29, 8.91), p<0.0001). Here we show that ctDNA(+) patients had improved DFS and overall survival (OS) with atezolizumab versus observation (DFS HR= 0.56 (0.41-0.77); p=0.0003 and OS HR= 0.58 (0.4-0.86); p=0.0063). No difference in DFS or OS between arms was noted for ctDNA-negative patients. The rate of ctDNA clearance was higher with atezolizumab (18%) versus observation (4%) (p=0.0041). Transcriptomic analysis revealed that tumours from ctDNA(+) patients had higher expression of cell cycle and keratin genes. Within the ctDNA(+) patient population in the atezolizumab arm, non-relapsing patients were further enriched in prominent immune response signatures including PD-L1, IFNG, CXCL9, and high tumour mutational burden, whereas relapse was associated with angiogenesis and fibroblast-transforming growth factor-beta signatures (F-TBRS). TCGA molecular subset analysis revealed increased efficacy of atezolizumab in patients with basal-squamous tumours, consistent with underlying tumour-immune contexture. Together these findings suggest that adjuvant atezolizumab may be associated with improved outcomes compared with observation in this high-risk ctDNA(+) population. These findings, if validated in other settings, would shift approaches to post-operative cancer care.

  Study EGAS00001004997

• This DAC is to control access to data contained within dataset EGAS00001001147, for Myeloma XI clinical trial patients.

  Dac EGAC00001000307

• Detection of ctDNA in Plasma of Patients with Clinically Localised Prostate Cancer is Associated with Rapid Disease Progression

  Dac EGAC00001001718

• Ampliseq library dataset

  This is the dataset for Ampliseq sequencing

  Dataset EGAD50000000536

• Degradation of Cyclin K/CDK12 is a druggable vulnerability of colorectal cancer (H012)

  Study EGAS00001004517

• Increased trunk fat is associated with altered gene expression in breast tissue of normal weight women

  Study EGAS00001005138

• Navarrabiomed DAC for XPAND project

  This DAC is created for the XPAND project by the Translational Bioinformatics unit.

  Dac EGAC50000000462

• DAC Fondazione Michelangelo

  This is the DAC responsible for granting access to sequencing data generated by Fondazione Michelangelo

  Dac EGAC50000000179

• Enrichment of Lung Microbiome with Supraglottic Taxa which is Associated with Increased Pulmonary Inflammation

  Background: The lung microbiome of healthy individuals frequently harbors oral organisms. Despite evidence that micro-aspiration is commonly associated with smoking-related lung diseases, the effects of lung microbiome enrichment with upper airway taxa on inflammation has not been studied. We hypothesize that the presence of oral microorganisms in the lung microbiome is associated with enhanced pulmonary inflammation. Methods: We sampled bronchoalveolar lavage (BAL) from the lower airways of 29 asymptomatic subjects (9 never-smokers, 14 former-smokers and 6 current-smokers). We quantified, amplified, and sequenced 16S rRNA genes from BAL samples by qPCR and 454 sequencing. Pulmonary inflammation was assessed by exhaled nitric oxide (eNO), BAL lymphocytes and neutrophils. Results: BAL had lower total 16S than supraglottic samples and higher than saline background. Bacterial communities in the lower airway clustered in two distinct groups that we designated as pneumotypes. The rRNA gene concentration and microbial community of the first pneumotype was similar to that of the saline background. The second pneumotype had higher rRNA gene concentration and higher relative abundance of supraglottic-characteristic taxa (SCT), such as Veillonella and Prevotella, and we called it pneumotypeSCT. Smoking had no effect on pneumotype allocation, alpha or beta diversity. PneumotypeSCT was associated with higher BAL lymphocyte-count (p = 0.007), BAL neutrophil-count (p = 0.034) and eNO (p = 0.022). Conclusion: A pneumotype with high relative abundance of supraglottic-characteristic taxa is associated with enhanced subclinical lung inflammation.

  Study phs000633