KRAS, BRAF and PIK3CA Mutations and the Loss of PTEN Expression in Chinese Patients with Colorectal Cancer

Chen Mao,Junhua Zhou,Jinling Tang,Qing Chen,Zuyao Yang,Xinyin Wu,Yafang Huang,Hong Shen,Chad Creighton

doi:10.1371/journal.pone.0036653

Chen Mao, Junhua Zhou + Show 7 more

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https://doi.org/10.1371/journal.pone.0036653

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Abstract

BackgroundTo investigate the frequency and relationship of the KRAS, BRAF and PIK3CA mutations and the loss of PTEN expression in Chinese patients with colorectal cancer (CRC).Methodology/Principal FindingsGenomic DNA was extracted from the formalin-fixed paraffin-embedded (FFPE) tissues of 69 patients with histologically confirmed CRC. Automated sequencing analysis was conducted to detect mutations in the KRAS (codons 12, 13, and 14), BRAF (codon 600) and PIK3CA (codons 542, 545 and 1047). PTEN protein expression was evaluated by immunohistochemistry on 3 mm FFPE tissue sections. Statistical analysis was carried out using SPSS 16.0 software. The frequency of KRAS, BRAF and PIK3CA mutations and loss of PTEN expression was 43.9% (25/57), 25.4% (15/59), 8.2% (5/61) and 47.8% (33/69), respectively. The most frequent mutation in KRAS, BRAF and PIK3CA was V14G (26.7% of all mutations), V600E (40.0% of all mutations) and V600L (40.0% of all mutations), and H1047L (80.0% of all mutations), respectivly. Six KRAS mutatant patients (24.0%) harbored BRAF mutations. BRAF and PIK3CA mutations were mutually exclusive. No significant correlation was observed between the four biomarkers and patients' characteristics.Conclusions/Significance BRAF mutation rate is much higher in this study than in other studies, and overlap a lot with KRAS mutations. Besides, the specific types of KRAS and PIK3CA mutations in Chinese patients could be quite different from that of patients in other countries. Further studies are warranted to examine their impact on prognosis and response to targeted treatment.

Highlights

Two monoclonal antibodies (MoAb) targeted at epidermal growth factor receptor (EGFR), the chimeric IgG1 MoAb cetuximab and the fully humanized IgG2 panitumumab, have proven to be effective in combination with chemotherapy or as single agent for treatment of metastatic colorectal cancer [1,2,3]
In order to facilitate selection of metastatic colorectal cancer (mCRC) patients who may benefit from anti-EGFR MoAbs treatments, there is a clear need for identifying predictive biomarkers that indicate likelihood of response amongst potential recipients
We investigated the status of KRAS, BRAF, PI3KCA mutation and PTEN expression in primary tumor from 69 Chinese mCRC patients, to clarify the rate of mutations and to detect the correlation between mutations and clinicopathological factors

Summary

Introduction

Two monoclonal antibodies (MoAb) targeted at epidermal growth factor receptor (EGFR), the chimeric IgG1 MoAb cetuximab and the fully humanized IgG2 panitumumab, have proven to be effective in combination with chemotherapy or as single agent for treatment of metastatic colorectal cancer (mCRC) [1,2,3]. In order to facilitate selection of mCRC patients who may benefit from anti-EGFR MoAbs treatments, there is a clear need for identifying predictive biomarkers that indicate likelihood of response amongst potential recipients. It has been reported that oncogenic activations of intracellular signaling pathways downstream of EGFR, including the RASRAF-MAPK and PI3K-PTEN-AKT signaling pathways, are important mechanisms for generating resistance to anti-EGFR MoAbs. In the RAS-RAF-MAPK pathway, active mutations of KRAS or BRAF are not uncommon, as such mutations are present in 35.0–45.0% and in 4.0–15.0% of mCRC patients respectively [7]. In the PI3K-PTEN-AKT pathway, mutations of PI3KCA or loss of PTEN expression are observed in 10.0–18.0% and 19.0– 42.0% of mCRC patients respectively [7]. To investigate the frequency and relationship of the KRAS, BRAF and PIK3CA mutations and the loss of PTEN expression in Chinese patients with colorectal cancer (CRC)

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