Mutation of the PIK3CA gene as a prognostic factor in patients with colorectal cancer

Abstract

Abstract. Colorectal cancer (CRC) is one of the most common cancers worldwide, with ~700,000 mortalities occurring due to CRC in 2012. The treatment options are effective in a small percentage of patients, and it is important to identify specific biomarkers in order to determine patients for whom the available therapies will be beneficial. It has been hypothesised that the PIK3CA gene mutation may affect the response to therapy of patients with metastatic CRC. In the present study, primary tumour specimens were collected from 156 patients with CRC who were treated in the Military Institute of Medicine in Warsaw (Warsaw, Poland). Codons 12 and 13 of exon 1 of KRAS, exons 11 and 15 of BRAF and exons 9 and 20 of PIK3CA were analysed for mutation using direct sequencing. The prognostic value of each mutation and the clinical and pathological variables of these tumours were estimated. The results revealed that PIK3CA mutations were present in 15 patients (9.6%), of whom seven (46.7%) possessed mutations in codon 9 and eight (53.3%) possessed mutations in codon 20. Mutation in the PIK3CA gene was detected in six patients with KRAS gene mutations, which accounted for 40% of PIK3CA-mutated tumours, and in one patient with BRAF mutations, which accounted for 6.6% of PIK3CA-mutated tumours. No significant differences were identified between the overall survival (OS) rates of patients with PIK3CA mutations (median OS, 56.7 months) and those with wild-type PIK3CA genes (median OS, 47.6 months) (P=0.1270). Univariate analysis identified that the following prognostic factors affected the OS rate in the current patient cohort: Gender, female patients survived for 57.5 months compared with 39.3 months for male patients (P=0.0111); and lymph node involvement grade, as survival of patients without lymph node metastases was 61.4 months compared with 45.4 months in patients presenting with metastases (P= 0.0122). The findings of the present analysis indicate that PIK3CA mutation status is not a prognostic factor in CRC patients. In addition, no statistically significant association exists between tumours with PIK3CA mutations and clinical or pathological factors.

Prevalence and coexistence of KRAS, BRAF, PIK3CA, NRAS, TP53, and APC mutations in Indian colorectal cancer patients: Next-generation sequencing–based cohort study

“…16 This PIK3CA mutation rate is comparable to the mutation rates observed in Italy, France, Japan, and Australia (14%-17.8%), lower than the mutation rates in south Italy (28%) and higher than the mutation rates observed in Singapore, France, China, Poland, Switzerland, and past Indian study (2.2%-10.1%). 14,17,39,41,[45][46][47] PIK3CA mutations were higher in male patients (22.1%) than female patients (6.8%). Previous studies have either reported more PIK3CA mutations in females 41 or a even distribution between males and females.…”

“…16 The PIK3CA mutation frequency at exon 9 (6.25%) and exon 20 (4.5%) is comparable to the Poland study (4.5% and 5.1%, respectively). 47…”

New paradigms in clonal evolution: punctuated equilibrium in cancer

“…Though certain mutagenic processes have been reported as clock‐like , the consistency of these signals throughout tumour evolution remains unknown; (ii) certain mutations have profound effects on cell phenotype, meaning that mutations do not cause step‐wise changes in phenotype. For example, the loss of APC induces colon adenomatous growth – a radical phenotypic change – while other mutations have roles in progression ; and (iii) punctuated mutational mechanisms (such as those associated with CIN) are extremely common in cancer, but have an as yet undefined role in transformation, and additionally have complex phenotypic effects . The relationship of mutation rates and phenotypic change, and in turn the evolutionary tempo, is therefore multifaceted and cannot be simplified by using genetic data exclusively.…”

Identification of different mutational profiles in cancers arising in specific colon segments by next generation sequencing

“…Most variants with confirmed oncogenic potential occurred in the helical domain encoded by exon 9 (E542K, E545A, E545G and E545K). Importantly, these variants have been recurrently reported in colon cancer [ 29 , 30 ] (see mutation mapper plots in Supplementary Figures 10-11 . Five different variants (G12V, G12D, G12S, G13D, A146V) were identified in KRAS (10/37 patients), all of which were present in the COSMIC database.…”