Search

Colorectal cancer (CRC) is well characterized in terms of genetic mutations and the mechanisms by which they contribute to carcinogenesis. Mutations in APC, TP53, and KRAS are common in CRC, indicating key roles for these genes in tumor development and progression. However, for certain tumors with low frequencies of these mutations that are defined by tumor location and molecular phenotypes, a carcinogenic mechanism dependent on BRAF mutations has been proposed. We here analyzed targeted sequence data linked to clinical information for CRC, focusing on tumors with a high tumor mutation burden (TMB) in order to identify the characteristics of associated mutations, their relations to clinical features, and the mechanisms of carcinogenesis in tumors lacking the major driver oncogenes. Analysis of overall mutation frequencies confirmed that APC, TP53, and KRAS mutations were the most prevalent in our cohort. Compared with other tumors, TMB-high tumors were more frequent on the right side of the colon, had lower KRAS and higher BRAF mutation frequencies as well as a higher microsatellite instability (MSI) score, and showed a greater contribution of a mutational signature associated with MSI. Ranking of variant allele frequencies to identify genes that play a role early in carcinogenesis suggested that mutations in genes related to the DNA damage response (such as ATM and POLE) and to MSI (such as MSH2 and MSH6) may precede BRAF mutations associated with activation of the serrated pathway in TMB-high tumors. Our results thus indicate that TMB-high tumors suggest that mutations of genes related to mismatch repair and the DNA damage response may contribute to activation of the serrated pathway in CRC., (© 2025 The Author(s). Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Effective therapies have yet to be established for pancreatic ductal adenocarcinomas (PDAC) even though it is the most aggressive cancer. In the present study, PDAC was analyzed using novel rat mAbs against membrane proteins in conjunction with flow cytometry and immunohistochemistry. Human epidermal growth receptor (HER)1-4, mesenchymal to epithelial transition factor (MET), sphingosine-1-phospahate receptor 1 (S1PR1), l-type amino acid transporter 1 (LAT1), system x - c transporter (xCT), alanine-serine-cysteine transporter (ASCT2), cationic amino acid transporter 1 (CAT1) and variant CD44 (CD44v) were expressed at high frequencies in both in vitro and in vivo PDAC. Internalization of membrane proteins by mAbs and growth inhibition by toxin-linked mAbs were demonstrated in many PDAC cell lines, and mAbs against S1PR1, ASCT2, HER3 and CD44v inhibited the growth of xenografted MIA PaCa-2 PDAC cells. Furthermore, CD44v-high PDAC showed high mRNA expression of HER1-3, MET and CD44v, and was correlated with poor prognosis. Taken together, our results suggest that CD44v, S1PR1, HER3, MET and the above-mentioned cancer-associated amino acid transporters might be promising targets for the diagnosis and treatment of PDAC., (© 2025 The Author(s). FEBS Open Bio published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)