Lung diseases, such as cystic fibrosis and COPD, are characterized by mucus obstruction and chronic airway inflammation, but their mechanistic link remains poorly understood. Here, we focus on the function of the mucostatic airway microenvironment on epigenetic reprogramming of airway macrophages (AM) and resulting transcriptomic and phenotypical changes. Using a mouse model of muco-obstructive lung disease (Scnn1b-transgenic), we identify epigenetically controlled, differentially regulated pathways and transcription factors involved in inflammatory responses and macrophage polarization. Functionally, AMs from Scnn1b-transgenic mice have reduced efferocytosis and phagocytosis, and excessive inflammatory responses upon lipopolysaccharide challenge, mediated through enhanced Irf1 function and expression. Ex vivo stimulation of wild-type AMs with native mucus impairs efferocytosis and phagocytosis capacities. In addition, mucus induces gene expression changes, comparable with those observed in AMs from Scnn1b-transgenic mice. Our data show that mucostasis induces epigenetic reprogramming of AMs, leading to changes favoring tissue damage and disease progression. Targeting these altered AMs may support therapeutic approaches in patients with muco-obstructive lung diseases.

Adult "T cell" acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy that is associated with poor outcomes, requiring additional therapeutic options. The DNA methylation landscapes of adult T-ALL remain undercharacterized. Here, we systematically analyzed the DNA methylation profiles of normal thymic-sorted T cell subpopulations and 143 primary adult T-ALLs as part of the French GRAALL 2003–2005 trial. Our results indicated that T-ALL is epigenetically heterogeneous consisting of five subtypes (C₁-C₅), which were either associated with co-occurring DNA methyltransferase 3 alpha (DNMT3A)/isocitrate dehydrogenase [NADP(+)] 2 (IDH2) mutations (C₁), TAL bHLH transcription factor 1, erythroid differentiation factor (TAL1) deregulation (C₂), T cell leukemia homeobox 3 (TLX3) (C₃), TLX1/in cis-homeobox A9 (HOXA9) (C₄), or in trans-HOXA9 overexpression (C₅). Integrative analysis of DNA methylation and gene expression identified potential cluster-specific oncogenes and tumor suppressor genes. In addition to an aggressive hypomethylated subgroup (C₁), our data identified an unexpected subset of hypermethylated T-ALL (C₅) associated with poor outcome and primary therapeutic response. Using mouse xenografts, we demonstrated that hypermethylated T-ALL samples exhibited therapeutic responses to the DNA hypomethylating agent 5-azacytidine, which significantly (survival probability; P = 0.001 for C₃, 0.01 for C₄, and 0.0253 for C₅) delayed tumor progression. These findings suggest that epigenetic-based therapies may provide an alternative treatment option in hypermethylated T-ALL.

The high plasticity of lung epithelial cells, has for many years, confounded the correct identification of the cell-of-origin of lung adenocarcinoma (LUAD), one of the deadliest malignancies worldwide. Here, we employ lineage-tracing mouse models to investigate the cell of origin of Eml4-Alk LUAD, and show that Club and Alveolar type 2 (AT2) cells give rise to tumours. We focus on Club cell originated tumours and find that Club cells experience an epigenetic switch by which they lose their lineage fidelity and gain an AT2-like phenotype after oncogenic transformation. Single-cell transcriptomic analyses identified two trajectories of Club cell evolution which are similar to the ones used during lung regeneration, suggesting that lung epithelial cells leverage on their plasticity and intrinsic regeneration mechanisms to give rise to a tumour. Together, this study highlights the role of Club cells in LUAD initiation, identifies the mechanism of Club cell lineage infidelity, confirms the presence of these features in human tumours, and unveils key mechanisms conferring LUAD heterogeneity.

Background: Epigenetic disturbances are crucial in cancer initiation, potentially with pleiotropic effects, and may be influenced by the genetic background. Methods: In a subsets (ASSET) meta-analytic approach, we investigated associations of genetic variants related to epigenetic mechanisms with risks of breast, lung, colorectal, ovarian and prostate carcinomas using 51,724 cases and 52,001 controls. False discovery rate–corrected P values (q values < 0.05) were considered statistically significant. Results: Among 162,887 imputed or genotyped variants in 555 candidate genes, SNPs in eight genes were associated with risk of more than one cancer type. For example, variants in BABAM1 were confirmed as a susceptibility locus for squamous cell lung, overall breast, estrogen receptor (ER)–negative breast, and overall prostate, and overall serous ovarian cancer; the most significant variant was rs4808076 [OR = 1.14; 95% confidence interval (CI) = 1.10–1.19; q = 6.87 × 10⁻⁵]. DPF1 rs12611084 was inversely associated with ER-negative breast, endometrioid ovarian, and overall and aggressive prostate cancer risk (OR = 0.93; 95% CI = 0.91–0.96; q = 0.005). Variants in L3MBTL3 were associated with colorectal, overall breast, ER-negative breast, clear cell ovarian, and overall and aggressive prostate cancer risk (e.g., rs9388766: OR = 1.06; 95% CI = 1.03–1.08; q = 0.02). Variants in TET2 were significantly associated with overall breast, overall prostate, overall ovarian, and endometrioid ovarian cancer risk, with rs62331150 showing bidirectional effects. Analyses of subpathways did not reveal gene subsets that contributed disproportionately to susceptibility. Conclusions: Functional and correlative studies are now needed to elucidate the potential links between germline genotype, epigenetic function, and cancer etiology. Impact: This approach provides novel insight into possible pleiotropic effects of genes involved in epigenetic processes. Cancer Epidemiol Biomarkers Prev; 26(6); 816–25. ©2017 AACR.

An individual’s inherited genetic variation may contribute to the ‘angiogenic switch’, which is essential for blood supply and tumor growth of microscopic and macroscopic tumors. Polymorphisms in angiogenesis-related genes potentially predispose to colorectal cancer (CRC) or affect the survival of CRC patients. We investigated the association of 392 single nucleotide polymorphisms (SNPs) in 33 angiogenesis-related genes with CRC risk and survival of CRC patients in 1754 CRC cases and 1781 healthy controls within DACHS (Darmkrebs: Chancen der Verhütung durch Screening), a German population-based case-control study. Odds ratios and 95% confidence intervals (CI) were estimated from unconditional logistic regression to test for genetic associations with CRC risk. The Cox proportional hazard model was used to estimate hazard ratios (HR) and 95% CIs for survival. Multiple testing was adjusted for by a false discovery rate. No variant was associated with CRC risk. Variants in EFNB2, MMP2 and JAG1 were significantly associated with overall survival. The association of the EFNB2 tagging SNP rs9520090 (p < 0.0001) was confirmed in two validation datasets (p-values: 0.01 and 0.05). The associations of the tagging SNPs rs6040062 in JAG1 (p-value 0.0003) and rs2241145 in MMP2 (p-value 0.0005) showed the same direction of association with overall survival in the first and second validation sets, respectively, although they did not reach significance (p-values: 0.09 and 0.25, respectively). EFNB2, MMP2 and JAG1 are known for their functional role in angiogenesis and the present study points to novel evidence for the impact of angiogenesis-related genetic variants on the CRC outcome.