PIK3CAandTP53mutations predict overall survival of stage II/III colorectal cancer patients

Abstract

AIMTo investigate the predictive value of PIK3CA and TP53 mutation status in colorectal cancer (CRC) patients treated with 5-fluorouracil-based chemotherapy.METHODSIn this study, a total of 315 patients with histologically proven CRC were enrolled from Yangpu Hospital affiliated to Shanghai Tongji University between 2007 and 2011. Of these patients, 241 with stage II/III CRC received 5-fluorouracil-based adjuvant chemotherapy. Formalin-fixed paraffin-embedded lesion samples of the patients with curatively resected CRC were collected. Next-generation sequencing was performed to identify somatic gene mutations. The correlation of PIK3CA and TP53 mutation status with overall survival (OS) was analyzed using a Cox proportional hazard model and the Kaplan-Meier method.RESULTSAmong the 241 patients with stage II/III in this cohort, the PIK3CA and/or TP53 mutation was detected in 177 patients, among which 54 patients had PIK3CA and TP53 double mutations. The PIK3CA or TP53 mutation was not significantly correlated with OS in univariate and multivariate analyses. Compared with patients without PIK3CA and TP53 mutations, those with double PIK3CA-TP53 mutations showed a significantly worse survival (univariate HR = 2.21; 95%CI: 1.15-4.24; multivariate HR = 2.02; 95%CI: 1.04-3.91). The PIK3CA mutation located in the kinase domain showed a trend toward a shorter OS compared with wild-type tumors (multivariate HR = 1.56; 95%CI: 1.00-2.44; P = 0.052). The Kaplan-Meier curve showed that patients harboring the PIK3CA mutation located in the kinase domain had a worse clinical outcome than those with wild-type status (Log-rank P = 0.041)CONCLUSIONDouble mutation of PIK3CA and TP53 is correlated with a shorter OS in stage II/III CRC patients treated with 5-fluorouracil-based therapy.

Human colon cancer cells highly express myoferlin to maintain a fit mitochondrial network and escape p53-driven apoptosis

“…Tumour-suppressor TP53 is the second most frequent mutated gene in colon cancer. TP53 mutations were occasionally described as being associated with low overall survival 44,45 . In our study, TCGA-COAD data did not associate TP53 mutation status to the patient survival confirming previously reported observation 46 .…”

New Challenges in Tumor Mutation Heterogeneity in Advanced Ovarian Cancer by a Targeted Next-Generation Sequencing (NGS) Approach

“…The application of modern sequencing technologies is leading to a rethinking of the concept of occurrence of lonely driver mutations as stand-alone factors [43]. In the last few years, a tumor genetic signature defined by two or more concurrently mutated genes was correlated with worse patient prognosis and response to treatment in different types of tumors [44,45,46,47,48,49]. These studies highlighted how concomitant mutations can occur within the same tumor, and their interaction may influence sensitivity to anticancer drugs and the final response to chemotherapy, as well as survival.…”

“…In patients with different types of advanced cancers, including ovarian, the simultaneous presence of mutations in PIK3CA (especially p.H1047R) and KRAS in codons 12 or 13, has been associated with resistance to therapy with PIK3CA/AKT/mTOR inhibitors, although data were not completely confirmed in multivariate models [44]. In other recent studies performed on patients with stage II-III colorectal cancer [45] and early breast cancer [49] who received 5-fluorouracil-based and anthracycline-taxanes adjuvant chemotherapy respectively, concomitant presence of PIK3CA - TP53 mutations was a significantly poor predictive factor for OS [45] and DFS [49], also in adjusted analyses. Notably, the most frequent combinations detected in these patients included PIK3CA (p.Met1004Ile)/ TP53 (p.R248Q) and PIK3CA (p.H1047R)/ TP53 (p.R273H) [44].…”

Genomic Alterations and Their Implications on Survival in Nonmetastatic Colorectal Cancer: Status Quo and Future Perspectives

“…PIK3CA mutation prevalence is higher in right-sided, KRAS-mutated, and MSI CRC [121]. In a retrospective study, Jian and colleagues showed that simultaneous mutations in PIK3CA and TP53 are associated with poor survival in patients with stage III CRC compared to patients with wild type tumors [66]. However, single mutations in the PIK3CA gene did not affect outcome [122].…”