Phosphatidylinositol‐3‐kinase pathway aberrations in gastric and colorectal cancer: Meta‐analysis, co‐occurrence and ethnic variation

Abstract

Inhibition of the phosphatidylinositol-3-kinase (PI3K) signaling pathway is a cancer treatment strategy that has entered into clinical trials. We performed a meta-analysis on the frequency of prominent genetic (PIK3CA mutation, PIK3CA amplification and PTEN deletion) and protein expression (high PI3K, PTEN loss and high pAkt) aberrations in the PI3K pathway in gastric cancer (GC) and colorectal cancer (CRC). We also performed laboratory analysis to investigate the co-occurrence of these aberrations. The meta-analysis indicated that East Asian and Caucasian GC patients differ significantly for the frequencies of PIK3CA Exon 9 and 20 mutations (7% vs. 15%, respectively), PTEN deletion (21% vs. 4%) and PTEN loss (47% vs. 78%), while CRC patients differed for PTEN loss (57% vs. 26%). High study heterogeneity (I(2) > 80) was observed for all aberrations except PIK3CA mutations. Laboratory analysis of tumors from East Asian patients revealed significant differences between GC (n = 79) and CRC (n = 116) for the frequencies of PIK3CA amplification (46% vs. 4%) and PTEN loss (54% vs. 78%). The incidence of GC cases with 0, 1, 2 and 3 concurrent aberrations was 14%, 52%, 27% and 8%, respectively, while for CRC it was 10%, 60%, 25% and 4%, respectively. Our study consolidates knowledge on the frequency, co-occurrence and clinical relevance of PI3K pathway aberrations in GC and CRC. Up to 86% of GC and 90% of CRC have at least one aberration in the PI3K pathway, and there are significant differences in the frequencies of these aberrations according to cancer type and ethnicity.

Causes and consequences of microsatellite instability in gastric carcinogenesis

“…Our group also evaluated PIK3CA mutations in a series of MSI GC samples and identified PIK3CA mutations in about 14% of the samples [65] . More recently, a meta-analysis evaluating PI3K aberrations identified PIK3CA mutations in 7%-15% and PIK3CA amplification in 46% of the GC [88] . PIK3CA was also evaluated by Shi et al [86] reporting that 67% of GC had amplification of the gene.…”

Novel targets in the treatment of advanced gastric cancer: a perspective review

“…In previous series the prevalence of this mutation has been reported to range between 5% and 16% [Barbi et al 2010] and to be more frequent in white patients compared with Asian patients (15% versus 7%) [Chong et al 2014]. In the TCGA report, 80% of EBV tumours and 42% of MSI tumours harboured a mutation in PIK3CA (although more commonly in the exon 20 kinase domain in non-EBV type tumours), thus supporting the rationale of pursuing the inhibition of this pathway in clinical trials.…”

Assessment of the In Vivo Activity of PI3K and MEK Inhibitors in Genetically Defined Models of Colorectal Cancer

“…In addition, sequencing analysis reveals that mutations in adenomatous polyposis coli (APC), KRAS, and PI3K are the most frequently observed genetic events in human colorectal cancer (17). Loss of the tumorsuppressor protein PTEN has been shown to occur in 12% to 80% of human colorectal cancer cases (18)(19)(20). Moreover, PTEN loss is associated with poor prognosis and predicts nonresponse to anti-EGFR agents currently available for KRAS wild-type colorectal cancer patients (21,22).…”