Frequent alterations of the PI3K/AKT/mTOR pathways in hereditary nonpolyposis colorectal cancer.
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.
Ekstrand
Anna Isinger
AI
Department of Oncology, Institute of Clinical Sciences, Lund University, 221 85 Lund, Sweden. Anna.Ekstrand@med.lu.se
Jönsson
Mats
M
Lindblom
Annika
A
Borg
Ake
A
Nilbert
Mef
M
D000328:Adult; D000368:Aged; D058534:Class I Phosphatidylinositol 3-Kinases; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D053858:Metabolic Networks and Pathways / Q000235:genetics / Q000502:physiology; D008875:Middle Aged; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics*; D058570:TOR Serine-Threonine Kinases
D058534:Class I Phosphatidylinositol 3-Kinases; D047908:Intracellular Signaling Peptides and Proteins; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C484760:PIK3CA protein, human; C494929:PTEN protein, human