• Asian Pacific Journal of Cancer Prevention
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• v.16 no.11
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• pp.4759-4768
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• 2015

Background: Several studies have investigated predictive and prognostic biomarkers for patients treated with anti-epidermal growth factor receptor (EGFR) agents in lung cancer. However, the conclusion is controversial. Materials and Methods: A meta-analysis was conducted to evaluate the associations of mutant K-ras, PIK3CA and PTEN deficiency with the efficacy of anti-EGFR agents in lung cancer. The primary endpoint was objective response rate (ORR). The secondary endpoints were overall survival (OS) and progression-free survival (PFS). Results: A total of 61 studies were included in the final meta-analysis. The result showed that K-ras mutation was a good predictor for ORR (RR=0.42, 95%CI, 0.33-0.55, p=0.000) and an effective prognostic marker for OS (HR=1.37, 95%CI, 1.15-1.65, p=0.001) and PFS (HR=1.33, 95%CI, 1.05-1.69, p=0.019). However, PTEN deficiency or PIK3CA mutation did not show any significance predictive value for ORR (PTEN, RR=0.82, 95%CI, 0.56-1.19, p=0.286; PIK3CA, RR=1.08, 95%CI, 0.17-6.66, P=0.938). And PTEN deficiency or expression of PIK3CA did not show significance prognostic value for OS (PTEN, HR=0.88, 95%CI, 0.31-2.46,P=0.805; PIK3CA, HR=0.79, 95%CI: 0.23-2.68, P=0.706). Conclusions: Our meta-analysis showed that K-ras mutation may be an effective predictor in lung cancer patients treated with anti-EGFR agents. Whereas, the predictive and prognostic value of PTEN deficiency and PIK3CA mutation need to be further investigated.

• Journal of Breast Cancer
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• v.21 no.4
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• pp.382-390
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• 2018

Purpose: PIK3CA mutation is considered to be a possible cause for resistance to neoadjuvant chemotherapy (NAC) in human epidermal growth factor receptor 2 (HER2)-positive breast cancer. We investigated the association between PIK3CA mutations and the outcome of NAC in HER2-positive breast cancers. Methods: A total of 100 HER2-positive breast cancer patients who had undergone NAC and surgery between 2004 and 2016 were examined. Mutation status was sequentially assessed in pre-NAC, post-NAC, and recurrent specimens taken from these patients. Results: PIK3CA mutations were identified in the sequential specimens of 17 patients (17.0%). These 17 patients experienced shorter disease-free survival (DFS) than the rest of the patients (58.3 months vs. 119.3 months, p=0.020); however, there was no significant difference in pathologic complete response (pCR) and overall survival (OS) (pCR, 17.6% vs. 33.7%, p=0.191; OS, 84.5 months vs. 118.0 months, p=0.984). While there was no difference in pCR between the wild-type and mutant PIK3CA groups in pre-NAC specimens (25.0% vs. 31.8%, p=0.199), PIK3CA mutations correlated with lower pCR in postNAC specimens (0.0% vs. 24.3%, p<0.001). Multivariate analysis revealed significantly worse DFS in the mutant PIK3CA group than in the wild-type group (hazard ratio, 3.540; 95% confidence interval, 1.001-12.589; p=0.050). Moreover, the DFS curves of the change of PIK3CA mutation status in sequential specimens were significantly different (p=0.016). Conclusion: PIK3CA mutation in HER2-positive breast cancer was correlated with a lower pCR rate and shorter DFS. These results suggest that PIK3CA mutation is a prognostic marker for NAC in HER2-positive breast cancer, especially in post-NAC specimens.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.21
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• pp.9327-9333
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• 2014

Breast cancer is the second most common cancer and second leading cause of cancer deaths in women. Phosphatidylinositol-3-kinase (PI3K)/AKT pathway mutations are associated with cancer and phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) gene mutations have been observed in 25-45% of breast cancer samples. Insulin growth factor binding protein-5 (IGFBP-5) can show different effects on apoptosis, cell motility and survival in breast cancer. We here aimed to determine the association between PIK3CA gene mutations and IGFBP-5 expressions for the first time in breast cancer patients. Frozen tumor samples from 101 Turkish breast cancer patients were analyzed with high resolution melting (HRM) for PIK3CA mutations (exon 9 and exon 20) and 37 HRM positive tumor samples were analyzed by DNA sequencing, mutations being found in 31. PIK3CA exon 9 mutations (Q546R, E542Q, E545K, E542K and E545D) were found in 10 tumor samples, exon 20 mutations (H1047L, H1047R, T1025T and G1049R) in 21, where only 1 tumor sample had two exon 20 mutations (T1025T and H1047R). Moreover, we detected one sample with both exon 9 (E542Q) and exon 20 (H1047R) mutations. 35% of the tumor samples with high IGFBP-5 mRNA expression and 29.4% of the tumor samples with low IGFBP-5 mRNA expression had PIK3CA mutations (p=0.9924). This is the first study of PIK3CA mutation screening results in Turkish breast cancer population using HRM analysis. This approach appears to be a very effective and reliable screening method for the PIK3CA exon 9 and 20 mutation detection. Further analysis with a greater number of samples is needed to clarify association between PIK3CA gene mutations and IGFBP-5 mRNA expression, and also clinical outcome in breast cancer patients.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.11
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• pp.5599-5603
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• 2012

Background: The epidermal growth factor receptor (EGFR) is a potential therapeutic target for breast cancer treatment; however, its use does not lead to a marked clinical response. Studies of non-small cell lung cancer and colorectal cancer showed that mutations of genes in the PIK3CA/AKT and RAS/RAF/MEK pathways, two major signalling cascades downstream of EGFR, might predict resistance to EGFR-targeted agents. Therefore, we examined the frequencies of mutations in these key EGFR pathway genes in Chinese breast cancer patients. Methods: We used a high-throughput mass-spectrometric based cancer gene mutation profiling platform to detect 22 mutations of the PIK3CA, AKT1, BRAF, EGFR, HRAS, and KRAS genes in 120 Chinese women with breast cancer. Results: Thirteen mutations were detected in 12 (10%) of the samples, all of which were invasive ductal carcinomas (two stage I, six stage II, three stage III, and one stage IV). These included one mutation (0.83%) in the EGFR gene (rs121913445-rs121913432), three (2.50%) in the KRAS gene (rs121913530, rs112445441), and nine (7.50%) in the PIK3CA gene (rs121913273, rs104886003, and rs121913279). No mutations were found in the AKT1, BRAF, and HRAS genes. Six (27.27%) of the 22 genotyping assays called mutations in at least one sample and three (50%) of the six assays queried were found to be mutated more than once. Conclusions: Mutations in the EGFR pathway occurred in a small fraction of Chinese breast cancers. However, therapeutics targeting these potential predictive markers should be investigated in depth, especially in Oriental populations.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.4
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• pp.1771-1774
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• 2014

The rhabdomyosarcoma (RMS) is the most common type of soft tissue tumor in children and adolescents; yet only a few screens for oncogenic mutations have been conducted for RMS. To identify novel mutations and potential therapeutic targets, we conducted a high-throughput Sequenom mass spectrometry-based analysis of 238 known mutations in 19 oncogenes in 17 primary formalin-fixed paraffin-embedded RMS tissue samples and two RMS cell lines. Mutations were detected in 31.6% (6 of 19) of the RMS specimens. Specifically, mutations in the NRAS gene were found in 27.3% (3 of 11) of embryonal RMS cases, while mutations in NRAS, HRAS, and PIK3CA genes were identified in 37.5% (3 of 8) of alveolar RMS (ARMS) cases; moreover, PIK3CA mutations were found in 25% (2 of 8) of ARMS specimens. The results demonstrate that tumor profiling in archival tissue samples is a useful tool for identifying diagnostic markers and potential therapeutic targets and suggests that these HRAS/ PIK3CA mutations play a critical role in the genesis of RMS.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.9
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• pp.5067-5072
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• 2013

Background: The phosphatidylinositol 3-kinase (PI3K) pathway plays a significant role in apoptosis, cellular proliferation and motility. The aim of the present study was to analyze mutations and gene expression profiles of the PI3KCA gene to determine any role in breast carcinomas. Materials and Methods: We analyzed 38 breast cancers for mutations in the two PIK3CA hotspots in exons 9 and 20 by direct sequencing of DNA obtained from biopsy samples. We have also analyzed expression of the PI3KCA gene in 38 breast carcinoma tumor and corresponding control tissue samples at the mRNA level by RT-PCR. The Fisher's exact test ($2{\times}2$ only) was performed using MedCalc software for to examine associations with mRNA levels. Results: In the present study a total of 13 cases demonstrated somatic mutations. In 9/13 cases 1633 G>A (E545K) were found in exon 9, whereas in exon 20, 4/13 cases had 3140A>G mutation. Our combined analysis showed PI3KCA mutations present in 34% of human breast cancer patients. In our study, we have also clearly found significantly higher expression in breast cancer tissues in comparison with control tissues (p=0.001). Conclusions: PIK3CA mutation is an emerging tumor marker that, in the future, might be used in the process of choosing a treatment. The detection of PI3KCA mutation might have important clinical implications for diagnosis, progression and therapy.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.5
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• pp.2743-2746
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• 2013

Background: Dilantin sodium (phenytoin) is an antiepileptic drug, which is routinely used to control generalized tonic clonic seizure and partial seizure episodes. A few case reports of oral squamous cell carcinomas arising from regions of phenytoin induced gingival overgrowth (GO), and overexpression of mitogenic factors and p53 have presented this condition as a pathology with potential to transform into malignancy. We recently investigated the genetic status of p53 and H-ras, which are known to be frequently mutated in Indian oral carcinomas in GO tissues and found them to only contain wild type sequences, which suggested a non-neoplastic nature of phenytoin induced GO. However, besides p53 and H-ras, other oncogenes and tumor suppressors such as PIK3CA, p14ARF, p16INK4a and $p21^{Waf1/Cip1}$, are frequently altered in oral squamous cell carcinoma, and hence are required to be analyzed in phenytoin induced GO tissues to be affirmative of its non-neoplastic nature. Methods: 100ng of chromosomal DNA isolated from twenty gingival overgrowth tissues were amplified with primers for exons 9 and 20 of PIK3CA, exons $1{\alpha}$, $1{\beta}$ and 2 of p16INK4a and p14ARF, and exon 2 of $p21^{Waf1/Cip1}$, in independent reactions. PCR amplicons were subsequently gel purified and eluted products were sequenced. Results: Sequencing analysis of the twenty samples of phenytoin induced gingival growth showed no mutations in the analyzed exons of PIK3CA, p14ARF, p16INK4a and $p21^{Waf1/Cip1}$. Conclusion: The present data indicate that the mutational alterations of genes, PIK3CA, p14ARF, p16INK4a and $p21^{Waf1/Cip1}$ that are frequently mutated in oral squamous cell carcinomas are rare in phenytoin induced gingival growth. Thus the findings provide further evidence that phenytoin induced gingival overgrowth as a non-neoplastic lesion, which may be considered as clinically significant given the fact that the epileptic patients are routinely administered with phenytoin for the rest of their lives to control seizure episodes.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.2
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• pp.539-543
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• 2016

Background: It is well known that peritoneal carcinomatosis (PC) from colorectal cancer (CRC) is associated with a poor prognosis. However, data on the prognostic significance of modern chemotherapy containing bevacizumab, cetuximab or panitumumab are not available. Materials and Methods: This retrospective review concerned 526 patients with metastatic CRC who were classified into two groups according to the presence or absence of PC, and were treated with systemic chemotherapy, with or without bevacizumab or anti-EGFR antibodies. The genetic background, in particular KRAS, BRAF, and PIK3CA gene mutations, and overall survival (OS) were compared between the two groups. Results: The median OS values were 23.3 and 29.1 months for PC and non-PC patients, respectively (hazard ratio [HR]=1.20; p=0.17). Among all patients, tumor location, number of metastatic sites and BRAF mutation status were significant prognostic factors, whereas the presence of PC was not. In the PC group, chemotherapy with bevacizumab resulted in a significantly longer OS than forchemotherapy without bevacizumab (HR=0.38, p<0.01), but this was not the case in the non-PC group (HR=0.80, p=0.10). Furthermore, the incidence of the BRAF V600E mutation was significantly higher in PC than in non-PC patients (27.7% versus 7.3%, p<0.01). BRAF mutations displayed a strong correlation with shorter OS in non-PC (HR=2.26), but not PC patients (HR=1.04). Conclusions: Systemic chemotherapy, especially when combined with bevacizumab, improved survival in patients with PC from CRC as well as non-PC patients. While BRAF mutation demonstrated a high frequency in PC patients, but it was not associated with prognosis.

• Korean Journal of Clinical Laboratory Science
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• v.55 no.2
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• pp.93-104
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• 2023

This study aimed to identify new markers that cause lung adenocarcinoma by analyzing mutation hotspots for the top five genes with high mutation frequency in lung adenocarcinoma in Koreans by next generation sequencing (NGS) analysis. The association between TP53 mutation types and patterns with smoking, a major cause of lung cancer, was examined. The clinicopathological characteristics of lung adenocarcinoma patients with TP53 P72R SNPs were analyzed. In Korean lung adenocarcinoma cases, regardless of the smoking status, the TP53 P72R SNP was the most frequently occurring mutational hotspot, in which the nucleotide base was transversed from C to G, and the amino acid was substituted from proline to arginine at codon 72 of TP53. An analysis of the clinicopathological characteristics of lung adenocarcinoma cases with TP53 P72R SNP revealed no significant correlation with the patient's age, gender, smoking status, and tumor differentiation, but a significant correlation with low stage (P-value =0.026). This study confirmed an increase in TP53 rather than EGFR, which was reported as the most frequent mutations in lung adenocarcinoma in Koreans through NGS. Among them, TP53 P72R SNP is the most frequent regardless of smoking status.

• Journal of Gastric Cancer
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• v.20 no.1
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• pp.29-40
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• 2020

Purpose: Gastrointestinal stromal tumors (GISTs) frequently harbor activating gene mutations in either KIT or platelet-derived growth factor receptor A (PDGFRA) and are highly responsive to several selective tyrosine kinase inhibitors. In this study, a targeted next-generation sequencing (NGS) assay with an Oncomine Focus Assay (OFA) panel was used for the genetic characterization of molecular targets in 30 Korean patients with GIST. Materials and Methods: Using the OFA that enables rapid and simultaneous detection of hotspots, single nucleotide variants (SNVs), insertion and deletions (Indels), copy number variants (CNVs), and gene fusions across 52 genes relevant to solid tumors, targeted NGS was performed using genomic DNA extracted from formalin-fixed and paraffin-embedded samples of 30 GISTs. Results: Forty-three hotspot/other likely pathogenic variants (33 SNVs, 8 Indels, and 2 amplifications) in 16 genes were identified in 26 of the 30 GISTs. KIT variants were most frequent (44%, 19/43), followed by 6 variants in PIK3CA, 3 in PDGFRA, 2 each in JAK1 and EGFR, and 1 each in AKT1, ALK, CCND1, CTNNB1, FGFR3, FGFR4, GNA11, GNAQ, JAK3, MET, and SMO. Based on the mutation types, majority of the variants carried missense mutations (60%, 26/43), followed by 8 frameshifts, 6 nonsense, 1 stop-loss, and 2 amplifications. Conclusions: Our study confirmed the advantage of using targeted NGS with a cancer gene panel to efficiently identify mutations associated with GISTs. These findings may provide a molecular genetic basis for developing new drugs targeting these gene mutations for GIST therapy.