Abstract
Recent studies have reported high frequencies of somatic mutations in the phosphoinositide-3-kinase, catalytic-α (PIK3CA) gene in various human solid tumors. More than 75 % of those somatic mutations are clustered in the helical (exon 9) and kinase domains (exon 20). The three hot-spot mutations, E542K, E545K, and H1047R, have been proven to elevate the lipid kinase activity of PIK3CA and activate the Akt signaling pathway. The Raf/MEK/ERK (MAPK) signal transduction is an important mediator of a number of cellular fates including growth, proliferation and survival. The BRAF gene is activated by onogenic RAS, leading to cooperative effects in cells responding to growth factor signals. The mutational status of PIK3CA, KRAS and BRAF in intraductal papillary mucinous neoplasm/ carcinoma (IPMN/IPMNC) has not been evaluated previously. To evaluate a possible role for PIK3CA, KRAS and BRAF in the tumorigenesis of IPMN and IPMNC, exons 1, 4, 5, 6, 7, 9, 12, 18, and 20 for PIK3CA, Exons 1 for KRAS, and 5, 11, and 15 for BRAF were analyzed in 36 IPMN/IPMC and two mucinous cystadenoma specimens by direct genomic DNA sequencing. We identified four missense mutations in the nine screened exons of PIK3CA within the 36 IPMN/IPMC specimens (11 %). One of the four mutations, H1047R, has been previously reported to be a »hot-spot« mutation. The remaining three mutations, T324I, W551G, and S1015F, were novel and somatic. In addition, we identified 17 (47 %) KRAS mutations in exon 1, and one missense mutation (2,7 %) in exon 15 of BRAF. These mutations also appeared to be somatic since none of these alterations was detected in the corresponding normal tissues. This is the first report of PIK3CA mutation in pancreatic cancer. In addition it appears to be the first oncogene to be mutated in IPMN/IPMC and not in conventional ductal adenocarcinoma of the pancreas. Our data provide evidence that oncogenic properties of PIK3CA and BRAF contribute to the tumorigenesis of IPMN/IPMC, but at a lower frequency than KRAS.
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© 2008 Springer Medizin Verlag Heidelberg
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Schönleben, F., Qiu, W., Hohenberger, W., Su, G.H. (2008). PIK3CA, KRAS und BRAF Mutationen in Intraduktalen Papillären Muzinösen Neoplasien/Karzinomen (IPMN/C) des Pankreas. In: Arbogast, R., Schackert, H.K., Bauer, H. (eds) Chirurgisches Forum 2008. Deutsche Gesellschaft für Chirurgie, vol 37. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-78833-1_26
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DOI: https://doi.org/10.1007/978-3-540-78833-1_26
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