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

BACKGROUND: 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. METHODS: We complemented a new conventional PC GWAS (1D) with genome spatial autocorrelation analysis (2D) permitting to prioritize low frequency variants not detected by GWAS. These were further expanded via Hi-C map (3D) interactions 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. RESULTS: We identified several new variants located in genes for which there is experimental evidence of their implication in the biology and function of pancreatic acinar cells. Among them is a novel independent variant in NR5A2 (rs3790840) with a meta-analysis p value = 5.91E-06 in 1D approach and a Local Moran's Index (LMI) = 7.76 in 2D approach. We also identified a multi-hit region in CASC8-a lncRNA associated with pancreatic carcinogenesis-with a lowest p value = 6.91E-05. Importantly, two new PC loci were identified both by 2D and 3D approaches: SIAH3 (LMI = 18.24), CTRB2/BCAR1 (LMI = 6.03), in addition to a chromatin interacting region in XBP1-a major regulator of the ER stress and unfolded protein responses in acinar cells-identified by 3D; all of them with a strong in silico functional support. CONCLUSIONS: 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.

Qualitative Assessment of the Symptoms and Impact of Pancreatic Exocrine Insufficiency (PEI) to Inform the Development of a Patient-Reported Outcome (PRO) Instrument.

BACKGROUND: Pancreatic exocrine insufficiency (PEI) affects patients with chronic pancreatitis (CP) and cystic fibrosis (CF) who produce insufficient digestive pancreatic enzymes. Common symptoms include steatorrhoea, diarrhea, and abdominal pain. OBJECTIVE: The objective of the study was to develop and test the content validity of a patient-reported outcome (PRO) instrument assessing PEI symptoms and their impact on health-related quality of life. METHODS: Instrument development was supported by a literature review, expert physician interviews (n = 10: Germany 4, UK 3, France 3), and exploratory, qualitative, concept-elicitation interviews with patients with CF and CP with PEI (n = 61: UK 29, Germany 18, France 14) and expert physicians (n = 10). Cognitive debriefing of the draft instrument was then performed with patients with PEI (n = 37: UK 24, Germany 8, France 5), and feasibility was assessed with physicians (n = 3). For all interviews, verbatim transcripts were qualitatively analysed using thematic analysis methods and Atlas.ti computerized qualitative software. All themes were data driven rather than a priori. RESULTS: Patient interviews elicited symptoms and impacts not reported in the literature. Six symptom concepts emerged: pain, bloating, bowel symptoms, nausea/vomiting, eating problems, and tiredness/fatigue. Six impact domains were also identified. A 45-item instrument was developed in English, French, and German for testing in cognitive debriefing patient interviews. Following cognitive debriefing, 18 items were deleted. CONCLUSION: Rigorous qualitative patient research and expert clinical input supported development of a PEI-specific PRO with the potential to aid management and monitoring of unmet needs among patients with PEI. The next step is to perform psychometric evaluation of the resulting instrument.