Combined loss of CDH1 and downstream regulatory sequences drive early-onset diffuse gastric cancer and increase penetrance of hereditary diffuse gastric cancer.

BACKGROUND: Germline CDH1 pathogenic or likely pathogenic variants cause hereditary diffuse gastric cancer (HDGC). Once a genetic cause is identified, stomachs' and breasts' surveillance and/or prophylactic surgery is offered to asymptomatic CDH1 carriers, which is life-saving. Herein, we characterized an inherited mechanism responsible for extremely early-onset gastric cancer and atypical HDGC high penetrance. METHODS: Whole-exome sequencing (WES) re-analysis was performed in an unsolved HDGC family. Accessible chromatin and CDH1 promoter interactors were evaluated in normal stomach by ATAC-seq and 4C-seq, and functional analysis was performed using CRISPR-Cas9, RNA-seq and pathway analysis. RESULTS: We identified a germline heterozygous 23 Kb CDH1-TANGO6 deletion in a family with eight diffuse gastric cancers, six before age 30. Atypical HDGC high penetrance and young cancer-onset argued towards a role for the deleted region downstream of CDH1, which we proved to present accessible chromatin, and CDH1 promoter interactors in normal stomach. CRISPR-Cas9 edited cells mimicking the CDH1-TANGO6 deletion display the strongest CDH1 mRNA downregulation, more impacted adhesion-associated, type-I interferon immune-associated and oncogenic signalling pathways, compared to wild-type or CDH1-deleted cells. This finding solved an 18-year family odyssey and engaged carrier family members in a cancer prevention pathway of care. CONCLUSION: In this work, we demonstrated that regulatory elements lying down-stream of CDH1 are part of a chromatin network that control CDH1 expression and influence cell transcriptome and associated signalling pathways, likely explaining high disease penetrance and very young cancer-onset. This study highlights the importance of incorporating scientific-technological updates and clinical guidelines in routine diagnosis, given their impact in timely genetic diagnosis and disease prevention.

Wild meat trade over the last 45 years in the Peruvian Amazon.

The trade in wild meat is an important economic component of rural people's livelihoods, but it has been perceived to be among the main causes of the decline of wildlife species. Recently, the COVID-19 pandemic has brought to light an additional concern of wildlife markets as a major human-health challenge. We analyzed data from the largest longitudinal monitoring (1973-2018) of the most important urban wild-meat markets in Iquitos, Peru, to examine the trends in and impacts of these markets on people's livelihoods. Over the last 45 years, wild meat sales increased at a rate of 6.4 t/year (SD 2.17), paralleling urban population growth. Wild meat sales were highest in 2018 (442 t), contributing US$2.6 million (0.76%) to the regional gross domestic product. Five species of ungulates and rodents accounted for 88.5% of the amount of biomass traded. Vulnerable and Endangered species represented 7.0% and 0.4% of individuals sold, respectively. Despite growth in sales, the contribution of wild meat to overall urban diet was constant: 1-2%/year of total meat consumed. This result was due to greater availability and higher consumption of cheaper meats (e.g., in 2018, poultry was 45.8% cheaper and was the most consumed meat) coupled with the lack of economic incentives to harvest wild meat species in rural areas. Most wild meat was sold salted or smoked, reducing the likelihood of foodborne diseases. Community-based wildlife management plans and the continued trade bans on primates and threatened taxa may avoid biodiversity loss. Considering the recent COVID-19 pandemic, future management plans should include potential viral hosts and regulation and enforcement of hygiene practices in wild-meat markets.

Comercio de Carne de Monte en los Últimos 45 Años en la Amazonia Peruana Resumen El comercio de carne de monte es un componente económico importante del sustento de habitantes de zonas rurales, pero se ha percibido como una de las principales causas de la declinación de especies de vida silvestre. Recientemente, la pandemia de COVID-19 ha traído a la luz una preocupación adicional de los mercados de vida silvestre como un reto importante para la salud humana. Analizamos datos del monitoreo longitudinal más extenso (1973-2018) de los mercados urbanos de carne de monte más importantes en Iquitos, Perú, para examinar las tendencias y los impactos de estos mercados sobre el sustento de los habitantes. Las ventas de carne de monte incrementaron en los últimos 45 años a una tasa de 6.4 t/año (DS 2.17), en paralelo con el crecimiento de la población. Las ventas de carne de monte fueron más altas en 2018 (442 t), aportando U.S. $2.6 millones (0.76%) al producto interno bruto de la región. Cinco especies de ungulados y roedores comprendieron el 88.5% de la biomasa comercializada. Especies vulnerables y en peligro representaron 7.0% y 0.4% de los individuos vendidos, respectivamente. A pesar del incremento de las ventas, la contribución de la carne de monte al total de la dieta urbana fue constante: 1-2%/año del total de carne consumida. Este resultado se debió a una mayor disponibilidad y consumo de carnes más baratas (e. g., en 2018 la carne de pollo fue 45.8% más barata y fue la más consumida) aparejado con la falta de incentivos económicos para cosechar carne de especies silvestres en áreas rurales. La mayor parte de la carne de monte se vendía salada o ahumada, reduciendo con ello la probabilidad de enfermedades transmitidas por alimentos. Los planes de manejo de vida silvestre basados en comunidades y la prohibición continua del comercio de primates y taxa amenazados pueden evitar la pérdida de biodiversidad. Considerando la reciente pandemia de COVID-19, los planes de manejo futuros deben incluir potenciales huéspedes virales y la regulación y aplicación de prácticas de higiene en los mercados de carne de especies silvestres.