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Germline and somatic TP53 variants play a crucial role during tumorigenesis. However, genetic variations that solely affect the alternatively spliced p53 isoforms, p53β and p53γ, are not fully considered in the molecular diagnosis of Li-Fraumeni syndrome and cancer. In our search for additional cancer predisposing variants, we identify a heterozygous stop-lost variant affecting the p53β isoforms (p.*342Serext*17) in four families suspected of an autosomal dominant cancer syndrome with colorectal, breast and papillary thyroid cancers. The stop-lost variant leads to the 17 amino-acid extension of the p53β isoforms, which increases oligomerization to canonical p53α and dysregulates the expression of p53's transcriptional targets. Our study reveals the capacity of p53β mutants to influence p53 signalling and contribute to the susceptibility of different cancer types. These findings underscore the significance of p53 isoforms and the necessity of comprehensive investigation into the entire TP53 gene in understanding cancer predisposition., (© 2024. The Author(s).)

Two independent exome sequencing initiatives aimed to identify new genes involved in the predisposition to nonpolyposis colorectal cancer led to the identification of heterozygous loss-of-function variants in NPAT, a gene that encodes a cyclin E/CDK2 effector required for S phase entry and a coactivator of histone transcription, in two families with multiple members affected with colorectal cancer. Enrichment of loss-of-function and predicted deleterious NPAT variants was identified in familial/early-onset colorectal cancer patients compared to non-cancer gnomAD individuals, further supporting the association with the disease. Previous studies in Drosophila models showed that NPAT abrogation results in chromosomal instability, increase of double strand breaks, and induction of tumour formation. In line with these results, colorectal cancers with NPAT somatic variants and no DNA repair defects have significantly higher aneuploidy levels than NPAT-wildtype colorectal cancers. In conclusion, our findings suggest that constitutional inactivating NPAT variants predispose to mismatch repair-proficient nonpolyposis colorectal cancer., (© 2024. The Author(s), under exclusive licence to European Society of Human Genetics.)

Background: In the twenty-first century, the success story of the Post-World-War-II World has been called into question by climate change and other challenges. De-growth or zero economic growth are discussed as possible solutions for mitigating climate change. The traditional economic growth model is increasingly challenged by the demand for sustained economic growth expressed in United Nations Sustainable Development Goal 8 "sustained economic growth" (UN-SDG 8) and supported by the European Green Deal. The aim of this paper is to contribute to the general understanding of characteristics, effects and challenges of new economic growth ideas as well as their interlinkages with the food-energy-water (FEW) nexus., Methods: To address these challenges, a stylized dynamic General Equilibrium Model (GEM) was developed, which consists of two countries: an emerging, developing European country A and a developed European country B. Country A is assumed to grow, while country B shrinks. The model is based on artificial data sets. This approach was chosen to prevent the blurring of counterfactual comparison by country-specific effects of economic turbulences such as the Lehman crash or the economic break-in during the Covid-19 pandemic., Results: The gross output of the emerging European country increases, whereas the output of the developed European country decreases according to the different growth strategies. The analysis reveals that a constantly widening gap between the emerging and the developed country is created. It can further be shown how this influences the relevant economic indicators (CO 2 emissions, household budget, trade balance, utility and social welfare)., Conclusions: The analysis of the two-country stylized GE model makes distortions visible: insignificant gaps in the values and development of analyzed economic indicators become prevalent. The welfare gap affects the core of the traditional socio-economic system, because the development of the utility of the households is central for the stability of political processes. A sufficiency and subsistence sector may be an option to even out the welfare losses from the de-growth strategy of the traditional economic system to avoid that the de-growth gaps are perceived by the community as welfare losses which can endanger the realization of UN-SDG 8., Competing Interests: Competing interestsWe do not have competing interests., (© The Author(s) 2022.)