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This research was funded by the Spanish Ministry of Science and Innovation (Agencia Estatal de Investigación), and co-funded by FEDER funds a way to build Europe [Grants No. SAF2016-80888-R (LV), PID2020-112595RB-I00 (LV), and PID2019-111254RB-I00 (GC), and predoctoral fellowship “Formación de Personal Investigador” (IQ)]; Instituto de Salud Carlos III [CIBERONC CB16/12/00234, Sara Borrell Postdoctoral contract (PM)]; Government of Catalonia, Spain [PERIS MedPerCan, AGAUR 2017SGR1282, CERCA Program for institutional support]; Scientific Foundation “Asociación Española Contra el Cáncer” [AECC Investigador (MT)]; Marie Skłodowska-Curie Individual Fellowship [Organ-VIP; Grant agreement No. 897064 (NG-A)]. The Solve-RD project is funded by the European Union's Horizon 2020 research and innovation program under grant agreement No. 779257. This study was supported by the European Reference Network on Genetic Tumor Risk Syndromes (ERN GENTURIS) - Project ID No. 739547 (www.genturis.eu), and the COST action CA17118, supported by COST (European Cooperation in Science and Technology).

Background: BRAF V600E mutations are reportedly associated with sporadic microsatellite-unstable (MSI) colorectal cancer (CRC), while rarely detected in CRCs of Lynch syndrome (LS) patients. Therefore, current international diagnostic guidelines recommend somatic BRAF mutation testing in MLH1-deficient MSI CRC patients to exclude LS. As sporadic BRAF- mutant MSI CRC is a disease of the elderly, while LS-associated CRC usually occurs at younger age, we hypothesized that the efficacy of BRAF testing in LS diagnostics may be age-dependent. Methods: We systematically compared the prevalence of BRAF mutations in LS-associated CRCs and MSI CRCs from population-based cohorts in different age groups as available from published studies, databases, and population-based patient cohorts. Cost calculations and sensitivity analysis of BRAF testing for exclusion of LS was performed. Findings: Among 969 MSI CRCs from LS carriers in the literature and German HNPCC Consortium, 15 (1∙6%, 95% CI: 0∙9-2∙6%) harboured BRAF mutations. 6/7 LS patients with BRAF-mutant CRC and reported age were 60 years. In MSI CRC patients

Four and a half LIM domain protein-2 (FHL2) is a component of the focal adhesion structures and has been suggested to have an important role in cancer progression. This study analyses the role of FHL2 in peritumoural fibroblasts of sporadic and hereditary non-polyposis colorectal cancer (HNPCC). Tissue specimens of 48 sporadic and 49 hereditary colon cancers, respectively, were stained immunohistochemically for FHL2, transforming growth factor (TGF)-β1 ligand and α-SMA. Myofibroblasts at the tumour invasion front co-expressed α-SMA and FHL2. Sporadic colon cancer but not HNPCC cases showed a correlation between TGF-β1 expression of the invading tumour cells and FHL2 staining of peritumoural myofibroblasts. Overexpression of FHL2 in peritumoural myofibroblasts correlated to lymphatic metastasis in sporadic colon cancer but not in HNPCC. In cultured mouse fibroblasts, TGF-β1 treatment induced myofibroblast differentiation, stimulated FHL2 protein expression and elevated number of migratory cells in transwell motility assays, suggesting that FHL2 is regulated downstream of TGF-β. Physical contact of colon cancer cells and myofibroblasts via FHL2-positive focal adhesions was detected in human colon carcinoma tissue and in co-culture assays using sporadic as well as HNPCC-derived tumour cell lines. Our data provide strong evidence for an important role of FHL2 in the progression of colon cancers. Tumour-secreted TGF-β1 stimulates FHL2 protein expression in peritumoural fibroblasts, probably facilitating the invasion of tumour glands into the surrounding tissue by enhanced myofibroblast migration and tight connection of fibroblasts to tumour cells via focal adhesions. These findings are absent in HNPCC-associated colon cancers in vivo and may contribute to a less invasive and more protruding tumour margin of microsatellite instable carcinomas.