Mutations of PIK3CA in gastric adenocarcinoma.
BACKGROUND
Activation of the phosphatidylinositol 3-kinase (PI3K) through mutational inactivation of PTEN tumour suppressor gene is common in diverse cancer types, but rarely reported in gastric cancer. Recently, mutations in PIK3CA, which encodes the p110alpha catalytic subunit of PI3K, have been identified in various human cancers, including 3 of 12 gastric cancers. Eighty percent of these reported mutations clustered within 2 regions involving the helical and kinase domains. In vitro study on one of the "hot-spot" mutants has demonstrated it as an activating mutation.


METHODS
Based on these data, we initiated PIK3CA mutation screening in 94 human gastric cancers by direct sequencing of the gene regions in which 80% of all the known PIK3CA mutations were found. We also examined PIK3CA expression level by extracting data from the previous large-scale gene expression profiling study. Using Significance Analysis of Microarrays (SAM), we further searched for genes that show correlating expression with PIK3CA.


RESULTS
We have identified PIK3CA mutations in 4 cases (4.3%), all involving the previously reported hotspots. Among these 4 cases, 3 tumours demonstrated microsatellite instability and 2 tumours harboured concurrent KRAS mutation. Data extracted from microarray studies showed an increased expression of PIK3CA in gastric cancers when compared with the non-neoplastic gastric mucosae (p < 0.001). SAM further identified 2910 genes whose expression levels were positively associated with that of PIK3CA.


CONCLUSIONS
Our data suggested that activation of the PI3K signalling pathway in gastric cancer may be achieved through up-regulation or mutation of PIK3CA, in which the latter may be a consequence of mismatch repair deficiency.
Li
Vivian Sze Wing
VS
Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Hong Kong. vswli@hkucc.hku.hk
Wong
Chi Wai
CW
Chan
Tsun Leung
TL
Chan
Agnes Sze Wah
AS
Zhao
Wei
W
Chu
Kent-Man
KM
So
Samuel
S
Chen
Xin
X
Yuen
Siu Tsan
ST
Leung
Suet Yi
SY
D000230:Adenocarcinoma / Q000235:genetics*; D058534:Class I Phosphatidylinositol 3-Kinases; D006801:Humans; D018895:Microsatellite Repeats; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D013274:Stomach Neoplasms / Q000235:genetics*
D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human