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• Decoding Human Endogenous Retrovirus Expression in Liver Metastatic Colorectal Cancers: Implications for Diagnosis and Prognosis

  The association between Human Endogenous RetroVirus (HERV) expression and cancer can be considered to both reflect the epigenetic deregulation of cancer and facilitate oncogenesis through its promoter/enhancer action on genes. More than 50% of colorectal cancers develop liver metastases and HERV has never been studied in this setting. We collected 400 RNAseq samples from more than 200 patients with primary and liver metastases from published and unpublished databases. We corroborated our findings with tandem mass spectrometry from primary colorectal cancer and single-cell RNAseq from liver metastatic colorectal cancer (lmCRC). We identified global stability in HERV expression between liver metastases and primary colorectal cancers, suggesting an early oncogenic footprint. Therefore, we proposed a list of seventeen HERV loci for lmCRC characterization with ERV-derived peptides but no expression in normal tissues. Among them, we discovered six prognostic markers after surgical resection of lmCRC. Four of them, HERVH_Xp22.32a, HERVH_20p11.23b, HERVH_13q33.3, HERVH_13q31.3, showed poor prognostic value when expressed (log-rank p-value 0.028, 0.0083, 9e-4, 0.05, respectively). HERVH_Xp22.2c (log-rank p-value 0.032) and HERVH_8q21.3b (only in multivariate models) were associated with better prognosis when expressed. These markers showed a cumulative effect on survival when expressed. Some HERVs were associated with decreased cytotoxic immune cells and most of them correlated with cell cycle pathways. Our findings provide new insights into lmCRC classification and suggest novel prognostic biomarkers and potential therapeutic targets.

  Study EGAS50000000307

• Cancer-associated fibroblasts promote drug resistance in ALK-driven lung adenocarcinoma cells by upregulating lipid biosynthesis

  Targeted therapy interventions using tyrosine kinase inhibitors (TKIs) provide encouraging treatment responses in ALK-rearranged lung adenocarcinomas, yet resistances occur almost inevitably. Apart from tumor cell-intrinsic resistance mechanisms, accumulating evidence supports a role of cancer-associated fibroblasts (CAFs) in affecting the therapeutic vulnerability of lung cancer cells. Here, we aimed to investigate underlying molecular networks shaping the therapeutic susceptibility of ALK-driven lung adenocarcinoma cells via tumor microenvironmental cues using three-dimensional (3D) spheroid co-culture settings. We show that CAFs promote therapy resistance of lung tumor cells against ALK inhibition by reducing apoptotic cell death and increasing cell proliferation. Using single-cell RNA-sequencing analysis, we show that genes involved in lipogenesis constitute the major transcriptional difference between TKI-treated homo- and heterotypic lung tumor spheroids. CAF-conditioned medium and CAF-secreted factors HGF and NRG1 were both able to promote resistance of 3D-cultured ALK-rearranged lung tumor cells via AKT signaling, which was accompanied by enhanced de novo lipogenesis and supression of lipid peroxidation. Notably, simultaneous targeting of ALK and SREBP-1 was able to overcome the established CAF-driven lipid metabolic-supportive niche of TKI-resistant lung tumor spheroids. Our findings highlight a crucial role of CAFs in mediating ALK-TKI resistance via lipid metabolic reprogramming and suggest new ways to overcome resistance towards molecular directed drugs by targeting vulnerabilities downstream of oncogenic signaling.

  Study EGAS50000000135

• Genomic landscapes of endometrioid and mucinous ovarian cancers and morphologically similar tumor types

  While endometrioid and mucinous ovarian cancers represent nearly a quarter of ovarian cancers, their molecular characteristics and pathologic origins are poorly understood. To characterize the genomic and epigenomic alterations of these ovarian cancer subtypes and evaluate links to morphologically similar tumors from other sites, we performed sequence, copy number, mutation signature, rearrangement, and methylation analyses from tumor samples and matched normal tissues of 133 patients. These analyses included patients with ovarian endometrioid (n=44), ovarian mucinous (n=43), uterine endometrial (n=15), and gastrointestinal mucinous cancers (n=31). In addition to identifying genes previously known to be involved in these tumors, we identified alterations in RAD51C, NOTCH4, SMARCA1/4 and JAK1 in ovarian endometrioid, ESR1 in uterine endometrioid, and SMARCA4 in ovarian mucinous cancers. Whole genome sequencing revealed rearrangements involving PTEN, NF1, and NF2 in ovarian endometrioid tumors, and NF1 and MED1 in ovarian mucinous cancers. The number of alterations and affected genes in ovarian and uterine endometrioid cancers were similar as were genome-wide methylation profiles, suggesting that these tumors may have a similar tissue of origin. By contrast, methylation patterns in ovarian mucinous cancers were more similar to other gastrointestinal mucinous cancers, including mucinous cancers of the stomach, colon, and pancreas. These analyses provide insights into the genomic landscapes and origins of mucinous and endometrioid ovarian carcinomas, providing new avenues for early clinical intervention and management of patients with these cancers.

  Study EGAS50000000523

• Systematic Growth Factor Profiling Platform for 3D Tumor Models Reveals EstradiolResponsive Cellular Mechanisms of Immunotherapy Resistance

  Epithelial ovarian cancer (EOC) exhibits significant molecular heterogeneity, which is thought to be influenced by the tumor microenvironment (TME). However, the specific factors driving this heterogeneity remain poorly understood. In this study, we integrated growth factoromics and genomic data to identify TME factors contributing to EOC heterogeneity and immunosuppression. Our analysis revealed distinct subgroups of EOC samples with differential responsiveness to specific growth factors, particularly estradiol and R-spondin. Notably, samples with high responsiveness to estradiol and Wnt (C1 cluster) were enriched in the Mesenchymal (MES) molecular subtype, while samples with high responsiveness to R-spondin (C2 cluster) were associated with the Differentiated (DIF) and Immunoreactive (IMR) subtypes. We discovered that the G protein-coupled estrogen receptor (GPER), rather than the classical estrogen receptor alpha (ERα), was the key mediator of estrogen responsiveness and a determinant of molecular subtype classification. Single-cell sequencing analysis identified subsets of estrogen-responsive malignant cell (MAL.PDCD5) and cancer-associated fibroblast (FB.TNFSF10), which were associated with immunosuppressive patterns in the TCGA cohort. Importantly, the interaction between these cell populations significantly increased upon estrogen treatment, suggesting a potential mechanism by which estrogen signaling may contribute to the development of an immunosuppressive TME. Our findings highlight the critical role of estrogen signaling in shaping the molecular heterogeneity and immunosuppressive TME of EOC and provide novel insights into potential therapeutic targets for overcoming immunosuppression in this malignancy.

  Study EGAS50000000422

• CRISPR screening in human trophoblast stem cells reveals both shared and distinct aspects of human and mouse placental development

  The placenta serves as the interface between the mother and fetus, facilitating the exchange of gases and nutrients between their separate blood circulation systems. Trophoblasts in the placenta play a central role in this process. Our current understanding of mammalian trophoblast development relies largely on mouse models. However, given the diversification of mammalian placentas, findings from the mouse placenta cannot be readily extrapolated to other mammalian species, including humans. To fill this knowledge gap, we performed CRISPR knockout (KO) screening in human trophoblast stem cells (hTSCs). We targeted genes essential for mouse placental development and identified more than 100 genes as critical regulators in both human hTSCs and mouse placentas. Among them, we further characterized in detail two transcription factors, DLX3 and GCM1, and revealed their essential roles in hTSC differentiation. Moreover, a gene function-based comparison between human and mouse trophoblast subtypes suggests that their relationship may differ significantly from previous assumptions based on tissue localization or cellular function. Notably, our data reveal that hTSCs may not be analogous to mouse TSCs or the extraembryonic ectoderm (ExE) in which in vivo TSCs reside. Instead, hTSCs may be analogous to progenitor cells in the mouse ectoplacental cone and chorion. This finding is consistent with the absence of ExE-like structures during human placental development. Our data not only deepen our understanding of human trophoblast development but also facilitate cross-species comparison of mammalian placentas.

  Study JGAS000659

• Tumor-reactive heterotypic CD8 T cell clusters from clinical samples

  Emerging evidence suggests a correlation between CD8+ T cell-tumor cell proximity and anti-tumor immune response. However, it remains unknown whether these cells exist as functional clusters that can be isolated from clinical samples. By conventional and imaging flow cytometry, we show here that from 21/21 human melanoma metastases, we could isolate heterotypic clusters, comprising CD8+ T cells interacting with one or more tumor cells and/or antigen-presenting cells (APCs). Single-cell RNA-sequencing revealed that T cells from clusters were enriched for gene signatures associated with tumor reactivity and exhaustion. Clustered T cells exhibited increased TCR clonality indicative of expansion, while TCR-matched T cells showed more exhaustion and co-modulation when conjugated to APCs than to tumor cells. T cells that were expanded from clusters ex vivo exerted on average 9-fold increased killing activity towards autologous melanomas, which was accompanied by enhanced cytokine production. Upon adoptive cell transfer into mice, T cells from clusters showed improved patient-derived melanoma control, which was associated with increased T cell infiltration and activation. Together, these results demonstrate that tumor-reactive CD8+ T cells are enriched in functional clusters with tumor cells and/or APCs and that they can be isolated and expanded from clinical samples. Typically excluded by single cell gating in flow cytometry, these distinct heterotypic T cell clusters serve as a valuable source to decipher functional tumor-immune cell interactions, while they may also be therapeutically explored.

  Study EGAS50000000785

• Pseudodiastrophic dysplasia expands the known phenotypic spectrum of defects in proteoglycan biosynthesis

  Pseudodiastrophic dysplasia (PDD) is a severe skeletal dysplasia associated with prenatal manifestation and early lethality. Clinically, PDD is classified as a ‘dysplasia with multiple joint dislocations’ however, the molecular aetiology of the disorder is currently unknown. In order to identify the genetic defects underlying PDD, we performed whole exome sequencing (WES) on 3 patients from 2 unrelated families, clinically diagnosed with PDD. WES resulted in the identification of bi-allelic variants in the established skeletal dysplasia genes, B3GAT3 (Family 1) and CANT1 (Family 2). Mutations in these genes have previously been reported to cause ‘multiple joint dislocations, short stature, and craniofacial dysmorphism with or without congenital heart defects’ (B3GAT3) and Desbuquois dysplasia 1 (CANT1); disorders in the same nosological group as PDD. Follow-up of the B3GAT3 variants demonstrated significantly reduced B3GAT3/GlcAT-I expression. Downstream in vitro functional analysis revealed abolished biosynthesis of glycosaminoglycan side chains on proteoglycans. Functional evaluation of the CANT1 variant showed impaired nucleotidase activity, which results in inhibition of glycosaminoglycan synthesis through accumulation of uridine diphosphate. For the families described in this study, the PDD phenotype was caused by mutations in the known skeletal dysplasia genes B3GAT3 and CANT1, demonstrating the advantage of genomic analyses in delineating the molecular diagnosis of skeletal dysplasias. This finding expands the phenotypic spectrum of B3GAT3- and CANT1- related skeletal dysplasias to include PDD, and highlights the significant phenotypic overlap of conditions within the proteoglycan biosynthesis pathway.

  Study EGAS00001004145

• Illumina HumanCoreExome genotyping data from the TEENAGE (TEENs of Attica: Genes and Environment) study.

  The TEENAGE study is a cross-sectional study comprising healthy Greek adolescents. The study was conducted according to the guidelines specified in the Declaration of Helsinki and all procedures involving human subjects were approved by the Institutional Review Board of Harokopio University and the Greek Ministry of Education, Lifelong Learning and Religious Affairs. The TEENAGE study target population comprised adolescent students aged 13 to 15 years attending the first three classes of public secondary schools located in the wider Athens area of Attica. The regions across Attica from which students were recruited were physically similar and all urban in nature. Sampling of regions and schools selected to participate was random. Students were enrolled from the wider urban region to ensure that they were coming from families with varying educational background and socio-economic status. Moreover, in order to exclude any vast economic disparities, all participating schools were exclusively public schools, which are free of charge. A total of twenty-four schools participated in the study out of 285 junior secondary public schools in Attica. Anthropometric, medical and dietary information was obtained. DNA samples were genotyped using Illumina HumanCoreExome BeadChips (Illumina, San Diego, CA, USA) at the Wellcome Trust Sanger Institute, Hinxton, UK. Genotypes were called using GenCall (Illumina Genome Studio) followed by zCall and quality control (QC) was performed in two stages (pre- and post-zCall).

  Study EGAS00001001001

• Bioinformatic Methods and Bridging of Assay Results for Reliable Tumor Mutational Burden Assessment in Non-Small Cell Lung Cancer

  Tumor mutational burden (TMB) has emerged as a predictive biomarker of response to immune checkpoint inhibitors. Standardization of TMB measurement is essential for implementing diagnostic tools to guide treatment. Here we evaluate bioinformatic TMB analysis by whole exome sequencing (WES) in formalin-fixed, paraffin-embedded samples. In CheckMate 026, TMB was retrospectively assessed in 312 patients with non-small cell lung cancer (58% of the intent-to-treat population) who received first-line nivolumab treatment or chemotherapy. We examined the sensitivity of TMB assessment to bioinformatic filtering methods and assessed concordance between TMB data derived by WES and the FoundationOne CDx™ assay. TMB scores comprising synonymous, indel, frameshift, and nonsense mutations (all mutations) were 3.1-fold higher than data including missense mutations only, but values were highly correlated (Spearman’s r = 0.99). Scores from CheckMate 026 samples including missense mutations only were similar to those generated from data in The Cancer Genome Atlas, but those including all mutations were generally higher. Using databases for germline subtraction (instead of matched controls) showed a trend for race-dependent increases in TMB scores. Parameter variation can therefore impact TMB calculations, highlighting the need for standardization. Encouragingly, WES and FoundationOne CDx outputs were highly correlated (Spearman’s r = 0.90) and differences could be accounted for by empirical calibration, suggesting that reliable TMB assessment across assays, platforms and centers is achievable.

  Study EGAS00001003661

• Transcriptomic profiles of chronic lymphocytic leukemia before and after frontline therapy: 5-year results from the randomized CLL14 study

  CLL14 (NCT02242942) is a multinational, open-label Phase III study designed to compare venetoclax-obinutuzumab (Ven-Obi) versus chlorambucil-obinutuzumab (Clb-Obi) in previously untreated patients with CLL and co-existing conditions. Between Aug 7, 2015, and Aug 4, 2016, 432 patients were enrolled and randomly assigned to receive either venetoclax plus obinutuzumab (Ven-Obi, n=216) or chlorambucil plus obinutuzumab (Clb-Obi, n=216). In both study arms, patients received fixed-duration treatment of overall 12 cycles, each cycle 28 days long, and entered subsequent post-treatment surveillance. Peripheral blood samples were collected before the start of therapy, as well as every 3-6 months during and after therapy, including at the time of disease progression. The primary endpoint of the study was progression-free survival, secondary endpoints included overall response rate, minimal residual disease response, and overall survival. The primary read-out was conducted after a median follow-up of 28.1 months, when the primary endpoint was met with 30 primary end-point events (disease progression or death) in the Ven-Obi arm and 77 in the Clb-Obi arm (hazard ratio, 0.35; 95% confidence interval [CI], 0.23 to 0.53;P<0.001). Follow-up is ongoing until 9 years after the last patient enrollment. In an exploratory analysis, bulk RNAseq was conducted with CD19-enriched blood from patients before start of therapy (418 patients) and at first relapse (44 patients).

  Study EGAS00001006596