Frequent alterations of the PI3K/AKT/mTOR pathways in hereditary nonpolyposis colorectal cancer |
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Authors: | Anna Isinger Ekstrand Mats J?nsson Annika Lindblom ?ke Borg and Mef Nilbert |
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Institution: | (1) Department of Oncology, Institute of Clinical Sciences, Lund University, 221 85 Lund, Sweden;(2) Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden;(3) Clinical Research Centre, Hvidovre Hospital, Copenhagen University, Copenhagen, Denmark |
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Abstract: | The phosphatidylinositol 3-kinases-AKT-mammalian target of rapamycin pathway (PI3K/AKT/mTOR) is central in colorectal tumors.
Data on its role in hereditary cancers are, however, scarce and we therefore characterized mutations in PIK3CA and KRAS, and expression of PIK3CA, phosphorylated AKT, and PTEN in colorectal cancers linked to hereditary nonpolyposis colorectal
cancer (HNPCC). Sequencing was used to identify mutations in PIK3CA, a real-time PCR-based method to identify KRAS mutations, and immunohistochemical staining was used to evaluate the expression of PIK3CA, phosphorylated AKT and PTEN in
58 HNPCC-associated colorectal cancers. Derangements of at least one of the PI3K/AKT/mTOR components analyzed were found in
51/58 (88%) tumors. Mutations in PIK3CA and KRAS were identified in 14 and 31% of the tumors respectively. Overexpression of PIK3CA and phosphorylated AKT occurred in 59
and 75% and were strongly associated (P = 0.005). Reduced/lost PTEN expression was found in 63% of the tumors. Though HNPCC-associated colorectal cancers show simple
genetic profiles with few chromosomal alterations, we demonstrate frequent and repeated targeting of the PI3K/AKT/mTOR pathway,
which suggests that therapeutic strategies directed at this pathway are likely to be beneficial also in HNPCC. |
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