Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses.

Mesenchymal tumor subpopulations secrete pro-tumorigenic cytokines and promote treatment resistance1-4. This phenomenon has been implicated in chemorefractory small cell lung cancer and resistance to targeted therapies5-8, but remains incompletely defined. Here, we identify a subclass of endogenous retroviruses (ERVs) that engages innate immune signaling in these cells. Stimulated 3 prime antisense retroviral coding sequences (SPARCS) are oriented inversely in 3' untranslated regions of specific genes enriched for regulation by STAT1 and EZH2. Derepression of these loci results in double-stranded RNA generation following IFN-γ exposure due to bi-directional transcription from the STAT1-activated gene promoter and the 5' long terminal repeat of the antisense ERV. Engagement of MAVS and STING activates downstream TBK1, IRF3, and STAT1 signaling, sustaining a positive feedback loop. SPARCS induction in human tumors is tightly associated with major histocompatibility complex class 1 expression, mesenchymal markers, and downregulation of chromatin modifying enzymes, including EZH2. Analysis of cell lines with high inducible SPARCS expression reveals strong association with an AXL/MET-positive mesenchymal cell state. While SPARCS-high tumors are immune infiltrated, they also exhibit multiple features of an immune-suppressed microenviroment. Together, these data unveil a subclass of ERVs whose derepression triggers pathologic innate immune signaling in cancer, with important implications for cancer immunotherapy

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Endoscopic surveillance with systematic random biopsy for the early diagnosis of hereditary diffuse gastric cancer: a prospective 16-year longitudinal cohort study.

BACKGROUND: Hereditary diffuse gastric cancer, generally caused by germline pathogenic variants in CDH1, presents with early-onset signet ring cell carcinoma. Prophylactic total gastrectomy is the definitive treatment. Endoscopic surveillance can inform the timing of prophylactic total gastrectomy through detection of microscopic signet ring cell carcinoma foci. However, evidence is scarce about the optimal endoscopic sampling technique and characterisation of signet ring cell carcinoma foci in hereditary diffuse gastric cancer. We aimed to formally assess the diagnostic yield of different sampling strategies and to identify criteria for the characterisation of endoscopic lesions. METHODS: For this prospective longitudinal cohort study, we included individuals aged 18 years or older at the Cambridge University Hospitals National Health Service (NHS) Foundation Trust who fulfilled testing criteria for hereditary diffuse gastric cancer between June 1, 2005, and July 31, 2021. The primary outcome was detection of intramucosal signet ring cell carcinoma foci. We assessed the detection rate and anatomical location of signet ring cell carcinoma in random biopsy samples taken according to a systematic protocol compared with biopsies targeted to endoscopic findings. Endoscopic lesions were examined with white-light and narrow band imaging with magnification to assess the likelihood of cancerous foci. FINDINGS: 145 individuals were included, of whom 68 (47%) were male and 92 (63%) carried the CDH1 pathogenic variant. 58 (40%) patients were diagnosed with invasive signet ring cell carcinoma over a median follow-up time of 51 months (IQR 18-80). The first diagnosis of signet ring cell carcinoma was most commonly made from random biopsies (29 [50%] of 58 patients), rather than targeted biopsies (15 [26%] patients). The anatomical distribution of signet ring cell carcinoma foci detected by random biopsies more accurately reflected those identified in prophylactic total gastrectomy specimens than did targeted biopsies. Omitting random biopsies in our cohort would have led to an under-diagnosis rate of 42%. Using a novel panel of endoscopic criteria, gastric lesions containing signet ring cell carcinoma were predicted with a sensitivity of 67·3% and a specificity of 90·2%. INTERPRETATION: Random biopsies enhance the early detection of signet ring cell carcinoma and are complementary to targeted biopsies in surveillance of hereditary diffuse gastric cancer. This sampling method should be the standard of care when performing all surveillance endoscopies for individuals with hereditary diffuse gastric cancer. FUNDING: UK Medical Research Council

Breath Biopsy® to Identify Exhaled Volatile Organic Compounds Biomarkers for Liver Cirrhosis Detection.

BACKGROUND AND AIMS: The prevalence of chronic liver disease in adults exceeds 30% in some countries and there is significant interest in developing tests and treatments to help control disease progression and reduce healthcare burden. Breath is a rich sampling matrix that offers non-invasive solutions suitable for early-stage detection and disease monitoring. Having previously investigated targeted analysis of a single biomarker, here we investigated a multiparametric approach to breath testing that would provide more robust and reliable results for clinical use. METHODS: To identify candidate biomarkers we compared 46 breath samples from cirrhosis patients and 42 from controls. Collection and analysis used Breath Biopsy OMNI™, maximizing signal and contrast to background to provide high confidence biomarker detection based upon gas chromatography mass spectrometry (GC-MS). Blank samples were also analyzed to provide detailed information on background volatile organic compounds (VOCs) levels. RESULTS: A set of 29 breath VOCs differed significantly between cirrhosis and controls. A classification model based on these VOCs had an area under the curve (AUC) of 0.95±0.04 in cross-validated test sets. The seven best performing VOCs were sufficient to maximize classification performance. A subset of 11 VOCs was correlated with blood metrics of liver function (bilirubin, albumin, prothrombin time) and separated patients by cirrhosis severity using principal component analysis. CONCLUSIONS: A set of seven VOCs consisting of previously reported and novel candidates show promise as a panel for liver disease detection and monitoring, showing correlation to disease severity and serum biomarkers at late stage

Genetic and environmental factors predict multivariate trajectories of maternal distress after birth

Background: Maternal distress influences her own wellbeing and shapes her offspring’s psychosocial adjustment and neurodevelopment across childhood. The aim of this study was to analyze multivariate trajectories of maternal postpartum distress using a latent class modeling approach and to find genetic and psychosocial factors that predict membership within a given group (latent class). Methods: Maternal self-reports of depressive symptoms, parenting stress, general stress, and marital stress were measured at regular intervals during the first six years postpartum in 261 mothers participating in the Maternal Adversity, Vulnerability and Neurodevelopment Study. Genetic risk was determined by calculating a polygenic risk score for Major Depressive Disorder (MDD-PRS). Additionally, we assessed maternal history of early life adversity (mELA), educational level, and prenatal symptoms of depression as psychosocial risk factors. Using Latent Gold® Software, we identified latent classes of mothers based on their 1) average levels of distress and 2) change in distress over time. Results: We identified four latent classes based on average levels of distress and found that class membership probability was influenced by an interaction between MDD-PRS and prenatal depressive symptoms (WaldInteraction(3)=13.19, p=0.004; WaldMDD-PRS(3)=6.02, p=0.11; WaldDepression(3)=41.96; p<0.001), mELA (Wald(3)=8.64, p=0.035), and educational level (Wald(3)=11.61, p=0.009). Furthermore, we found five classes of mothers with distinct across- time trajectories, which were associated with mELA (Wald(3)=12.67, p=0.013). Conclusions: Our findings might become relevant in the clinical setting, e.g. for identifying pregnant women at risk for distress in the postpartum based on her prenatal symptoms of depression and genetic risk, mELA, and educational level

Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses.

Mesenchymal tumor subpopulations secrete pro-tumorigenic cytokines and promote treatment resistance1-4. This phenomenon has been implicated in chemorefractory small cell lung cancer and resistance to targeted therapies5-8, but remains incompletely defined. Here, we identify a subclass of endogenous retroviruses (ERVs) that engages innate immune signaling in these cells. Stimulated 3 prime antisense retroviral coding sequences (SPARCS) are oriented inversely in 3' untranslated regions of specific genes enriched for regulation by STAT1 and EZH2. Derepression of these loci results in double-stranded RNA generation following IFN-γ exposure due to bi-directional transcription from the STAT1-activated gene promoter and the 5' long terminal repeat of the antisense ERV. Engagement of MAVS and STING activates downstream TBK1, IRF3, and STAT1 signaling, sustaining a positive feedback loop. SPARCS induction in human tumors is tightly associated with major histocompatibility complex class 1 expression, mesenchymal markers, and downregulation of chromatin modifying enzymes, including EZH2. Analysis of cell lines with high inducible SPARCS expression reveals strong association with an AXL/MET-positive mesenchymal cell state. While SPARCS-high tumors are immune infiltrated, they also exhibit multiple features of an immune-suppressed microenviroment. Together, these data unveil a subclass of ERVs whose derepression triggers pathologic innate immune signaling in cancer, with important implications for cancer immunotherapy

Ordering of mutations in preinvasive disease stages of esophageal carcinogenesis

Cancer genome sequencing studies have identified numerous driver genes, but the relative timing of mutations in carcinogenesis remains unclear. The gradual progression from premalignant Barrett's esophagus to esophageal adenocarcinoma (EAC) provides an ideal model to study the ordering of somatic mutations. We identified recurrently mutated genes and assessed clonal structure using whole-genome sequencing and amplicon resequencing of 112 EACs. We next screened a cohort of 109 biopsies from 2 key transition points in the development of malignancy: benign metaplastic never-dysplastic Barrett's esophagus (NDBE; n = 66) and high-grade dysplasia (HGD; n = 43). Unexpectedly, the majority of recurrently mutated genes in EAC were also mutated in NDBE. Only TP53 and SMAD4 mutations occurred in a stage-specific manner, confined to HGD and EAC, respectively. Finally, we applied this knowledge to identify high-risk Barrett's esophagus in a new non-endoscopic test. In conclusion, mutations in EAC driver genes generally occur exceptionally early in disease development with profound implications for diagnostic and therapeutic strategies