Costello, E. | Search bioRxiv

bioRxiv2021

Sub-communities of the vaginal ecosystem in pregnant and non-pregnant women.

Diverse and non-Lactobacillus-dominated vaginal microbial communities are associated with adverse health outcomes such as preterm birth and the acquisition of sexually transmitted infections. Despite the importance of recognizing and understanding the key risk-associated features of these communities, their heterogeneous structure and properties remain ill-defined. Clustering approaches are commonly used to characterize vaginal communities, but they lack sensitivity and robustness in resolving substructures and revealing transitions between potential sub-communities. Here, we address this need with an approach based on mixed membership topic models, using longitudinal data from cohorts of pregnant and non-pregnant study participants. We identify several non-Lactobacillus-dominated sub-communities common to both cohorts and independent of reproductive status. In non-pregnant individuals, we find that the menstrual cycle modulates transitions between and within sub-communities. In addition, a specific non-Lactobacillus-dominated sub-community, which was associated with preterm delivery in pregnant participants, was also more common during menses, a time of elevated vaginal inflammation in non-pregnant participants. Overall, our analyses based on mixed membership models reveal substructures of vaginal ecosystems which may have important clinical and biological associations.

microbiology↗

bioRxiv2021

GATA4 and GATA6 loss-of-expression is associated with extinction of the classical programme and poor outcome in pancreatic ductal adenocarcinoma

ObjectiveGATA6 is a master regulator of pancreatic differentiation and a key regulator of the classical phenotype in pancreatic ductal adenocarcinoma (PDAC). Low GATA6 expression is associated with poor patient outcome. GATA4 is the second most expressed GATA factor in the pancreas. The aim was to assess whether, and how, GATA4 contributes to PDAC phenotype and to analyze the association of expression with clinical outcome. DesignWe analyzed PDAC transcriptomic data, stratifying cases according to GATA4 and GATA6 expression, and identified differentially expressed genes and pathways. A multicenter TMA study to assess GATA4 and GATA6 expression in PDAC samples (n=745) from patients undergoing tumour resection was performed using immunohistochemistry with antibodies of validated specificity. GATA4 and GATA6 levels were dichotomized into high/low categorical variables; association with outcome was assessed using univariable and multivariable Cox regression models. ResultsSubtype classification using transcriptomic data revealed that GATA4 mRNA is enriched in classical, compared to basal-like tumours. We classified samples in 4 groups as high/low for GATA4 and GATA6. Reduced expression of GATA4 did not have a major transcriptional impact. However, concomitant low expression of GATA4 enhanced the transcriptomic effects of GATA6 low expression. Reduced expression of both proteins in tumours was associated with the worst patient survival. GATA4 and GATA6 expression significantly decreased in metastases and negatively correlated with basal markers. ConclusionsOur analyses uncover a cooperative interaction between GATA4 and GATA6 to maintain the classical PDAC phenotype and provide compelling clinical rationale for assessing their expression as biomarkers of poor prognosis. SUMMARY BOXO_ST_ABSWhat is already known about this subject?C_ST_ABS- Patients with classical-type PDAC have a better outcome - Retrospective analyses suggest that classical-type PDAC is more sensitive to 5-FU-based chemotherapy - GATA6 is a surrogate biomarker of classical tumours and its expression is associated with better survival - GATA4 and GATA6 have overlapping and unique functions during pancreatic and gastrointestinal development What are the new findings?- Tumours displaying only low GATA4 expression have a transcriptomic profile similar to those with preserved expression of both transcription factors - Combined low expression of GATA4 and GATA6 has the highest transcriptomic impact - In a large multicenter tissue microarray study, patients with tumours showing low expression of both GATA4 and GATA6 have the worst overall survival - Low expression of GATA4 and GATA6 is an independent predictor of survival in patients with resectable PDAC - GATA4 levels are down-regulated in liver metastases and are negatively correlated with basal markers such as KRT5/6, KRT14, and TP63 How might it impact on clinical practice in the foreseeable future?- The combined assessment of GATA4 and GATA6 expression may improve prognostic stratification of patients with PDAC - Prospective studies should confirm whether GATA4 and GATA6 expression is also predictive of response to chemotherapy in PDAC patients

cancer biology↗

bioRxiv2020

A multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer

Pancreatic cancer (PC) is a complex disease in which both non-genetic and genetic factors interplay. To-date, 40 GWAS hits have been associated with PC risk in individuals of European descent, explaining 4.1% of the phenotypic variance. Here, we complemented a classical new PC GWAS (1D) with spatial autocorrelation analysis (2D) and Hi-C maps (3D) to gain additional insight into the inherited basis of PC. In-silico functional analysis of public genomic information allowed prioritization of potentially relevant candidate variants. We replicated 17/40 previous PC-GWAS hits and identified novel variants with potential biological functions. The spatial autocorrelation approach prioritized low MAF variants not detected by GWAS. These were further expanded via 3D interactions to 54 target regions with high functional relevance. This multi-step strategy, combined with an in-depth in-silico functional analysis, offers a comprehensive approach to advance the study of PC genetic susceptibility and could be applied to other diseases.

genetics↗