Prognostic value of KRAS/TP53/PIK3CA in non‑small cell lung cancer
- Authors:
- Published online on: February 4, 2019 https://doi.org/10.3892/ol.2019.10012
- Pages: 3233-3240
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Copyright: © Zhao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Lung cancer has a high mortality rate of ~27% and is becoming more prevalent in younger populations (1). Despite progress in the diagnosis and treatment of lung cancer, the 5-year survival rate is only 16% (2). Individualized therapy is a promising treatment strategy for non-small cell lung cancer (3). Mutations in epidermal growth factor receptor (EGFR) drive the development of lung adenocarcinoma and have altered the traditional treatment approaches. Next-generation sequencing revealed that patients with wild-type EGFR or ALK could present concurrent oncogenic mutations in KRAS proto-oncogene GTPase (KRAS) (4), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA) (5) and tumor protein p53 (TP53) (6). These mutations may result in differential clinical features, treatment outcomes and survival prognoses. The association between KRAS, PIK3CA and TP53 mutations, clinical features, and the prognosis of patients with NSCLC is unclear. The present study retrospectively analyzed 89 cases of NSCLC patients with KRAS, PIK3CA and TP53 mutations to elucidate the association between gene mutation, clinical characteristics and survival prognosis as a basis for individualized treatment.
Patients and methods
Patient selection
A total of 122 patients accepted next-generation sequencing for advanced NSCLC at Shanghai Changhai Hospital (Shanghai, China) and were enrolled between January 2015 and December 2016. Missing information and loss to follow-up resulted in the exclusion of 33 patients. Blood samples and clinical data from 89 patients with identified genes were collected, including sex, age, smoking status, symptoms, laboratory test results, chest computed tomography (CT) results, tumor location, pathological type, Tumor-Node-Metastasis stage (7) and site of metastasis. Among the 89 samples, 50 exhibited KRAS, TP53 and PIK3CA mutations. The Ethics Committee of Shanghai Changhai Hospital approved the present study, and written informed consent was obtained from each participant.
Gene sequencing
Circulating Single-Molecule Amplification and Resequencing Technology (cSMART; Illumina CN500; Berry Genomics Co., Ltd., Beijing, China) was used to detect KRAS, PIK3CA and TP53 mutation in all patients with NSCLC. In brief, genomic DNA was extracted from the plasma of the patients using MagMAX Cell-Free DNA Isolation kit, (Thermo Fisher Scientific, Inc., Waltham, MA, USA; Article no. A29319) DNA was purified using a DNA purification kit (Berry Genomics Co., Ltd; Article no. R0037). The libraries were prepared from 10 ng plasma DNA by ligation of universal sequencing adaptors containing unique 6-bp barcodes. Modified DNA was denatured and single strands were circularized by Taq ligase. Bidirectional back-to-back primers, in either singleplex or multiplex format, were annealed close to the mutation loci. Inverse PCR was performed to replicate targeted genes. Amplified products were subjected to massive parallel sequencing on the MiSeq platform (Illumina, Inc., San Diego, CA, USA) to generate paired-end reads of 2×200 bp (8).
Treatment
All patients were administered with a first-line chemotherapy regimen of pemetrexed (500 mg/m2)/paclitaxel (135 mg/m2) and carboplatin (area under the curve=5). All patients provided written informed consent.
Survival analysis
Tumors were evaluated every 2 cycles during chemotherapy treatment or earlier when significant signs of progression, including aggravation of cough or hemoptysis, were present. Progression-free survival (PFS) was determined according to the Response Evaluation Criteria in Solid Tumors guidelines (version 1.1) (9). The PFS time was defined as the time from the beginning of chemotherapy to the presence of objective evidence of progression. The final follow-up date was June 30, 2017.
Statistical analysis
Survival curves were calculated using the Kaplan-Meier method from the beginning of chemotherapy to documented progression or mortality from any cause, differences in PFS were assessed using the log-rank test. Statistical analysis was performed with SPSS version 21 (IBM, Corp., Armonk, NY, USA). The χ2 test was used to compare the categorical variables. P<0.05 was considered to indicate a statistically significant difference.
Results
Patient characteristics
A total of 122 patients with NSCLC received cSMART sequencing and 33 patients were excluded due to missing information or loss to follow-up. A total of 89 patients were therefore enrolled in the present study, and the baseline demographic characteristics are shown in Table I. The study cohort consisted of 52 males and 37 females, with a median age of 61.0 years and a mean (± standard error) age of 59.4 (±12.2) years. Adenocarcinoma was histologically determined in 75 patients. There were 2 patients with adenosquamous carcinoma and 12 with squamous carcinoma. In total, 41 patients were smokers and 48 had never smoked.
Gene mutations
Oncogenic mutations were found in 50 patients, including KRAS (n=21, 23.6%), PIK3CA (n=8, 9.0%) and TP53 (n=40, 44.9%). Among the 21 patients with KRAS mutations, 18 had mutations in exon 2, 3 in exon 3 and 2 in exon 4. There were 8 patients with a PIK3CA mutation in exon 10. A total of 17/40 patients had TP53 mutations located in exon 5, 6 in exon 6, 10 in exon 7 and 19 in exon 8. Coexisting mutations were identified in 17 patients (19.1%), including KRAS/TP53 (n=10, 11.2%), PIK3CA/TP53 (n=4, 4.5%), KRAS/PIK3CA (n=1, 1.1%) and KRAS/PIK3CA/TP53 (n=2, 2.2%). There were 32 cases with EGFR mutations (36.0%), 3 cases with the EMAP-like 4-ALK receptor tyrosine kinase fusion oncogene (3.4%), and 3 cases of c-MET exon 14 skipping (3.4%). The KRAS/TP53/PIK3CA mutations and percentage distribution of the 50 patients are shown in Figs. 1 and 2.
Clinical characteristics
The clinical characteristics of the 89 patients in association with the gene mutations are shown in Table II. Patients with KRAS, TP53, PIK3CA and KRAS/TP53 mutations had a higher incidence of bone metastasis than those with the wild-type gene (61.9 vs. 25.6%, P=0.006; 62.5 vs. 25.6%, P=0.024; 62.5 vs. 25.6%, P=0.042; 70.0 vs. 25.6%, P=0.009). There was also a higher incidence of adrenal metastasis in the TP53 mutation vs. wild-type groups (12.5 vs. 5.1%, P=0.017). Patients with KRAS or KRAS/TP53 mutations had a lower incidence of pleural metastasis than those with the wild-type gene (14.3 vs. 43.6%, P=0.022; 0.0 vs. 43.6%, P=0.010). Infiltrative tumor growth was greater in patients with KRAS, TP53 and KRAS/TP53 mutations than in the wild-type group (71.4 vs. 51.3%, P=0.039; 67.5 vs. 51.3%, P=0.032; 90.0 vs. 51.3%, P=0.009).
KRAS/TP53 mutations were associated with elevated carbohydrate antigen 19-9 (CA19-9) expression, vacuolar signs and margin lobulation in chest CT imaging in patients. Differences in KRAS mutation were observed in margin lobulation and invasive growth in chest CT imaging, meanwhile, first symptoms, including cough and dyspnea, indicated a statistical significance between wild-type patients and those with PIK3CA mutation (P=0.034).
Survival analysis
The PFS times of the KRAS mutation and wild-type group were 8.9±2.3 months (95% CI, 4.3–13.5) and 15.3±1.6 months (95% CI, 12.1–18.4), respectively (P=0.045). Patients with a single TP53 mutation had a PFS time of 7.8±1.5 months (95% CI, 4.9–10.7), which was significantly shorter than that of the wild-type group (P<0.001). Patients with a KRAS/TP53 coexisting mutation had a shorter PFS time of 6.6±1.6 months (95% CI, 3.5–9.7) compared with the wild-type group (P<0.001). This result was similar among PIK3CA/TP53 patients (P=0.012). The difference in the PFS times was not statistically significant between the single KRAS and KRAS/TP53 mutations, the single TP53 and KRAS/TP53 mutations or the single TP53 and PIK3CA/TP53 mutations. (Table III; Fig. 3).
 | Table III.Survival prognosis in non-small cell lung cancer patients with KRAS, PIK3CA and TP53 gene mutations. |
Discussion
NSCLC accounts for 70–80% of lung cancer cases and 60% of patients are diagnosed at stage III or IV (10). Oncogenes such as EGFR and ALK have shifted the treatment model of lung cancer from pathology-guided to molecular-guided precision medicine with targeted therapy (11). With the improvement in examination technology and the increase in available treatment methods, the genetic and clinical characteristics of NSCLC-related genes, including KRAS, PIK3CA and TP53, are highly informative.
The present study evaluated 89 cases of NSCLC patients with KRAS, PIK3CA and TP53 mutations. KRAS mutations were found in 21 cases within exon 2 (n=18), exon 3 (n=3) and exon 4 (n=2). The total mutation rate of KRAS was 23.6%, which was similar to the results of a study undertaken by Mao et al (12), but higher than the mutation rates of 4.4–5.3% reported by Luo et al (13) and Yi et al (14). The mutation rate of PIK3CA was 3% in a study undertaken by Scheffler et al (15), but Liang et al (16) reported a rate of 47.83%. The present study included 8 cases of PIK3CA exon 10 mutations and the total mutation rate was 9.0%. TP53 has the highest mutation rate of all NSCLC-related genes, reported as 39–46% (15,16). The present study identified 40 cases with TP53 mutations within exon 5 (n=17), exon 6 (n=6), exon 7 (n=10) and exon 8 (n=19). In present study the total mutation rate of TP53 was 44.9%, which is in accordance to previous researches (17,18).
Kris et al (19) found that 3% of patients with NSLCL exhibited a double gene mutation. The Cancer Genome Atlas determined that the mutation rate of KRAS/TP53 coexisting mutation could reach 20% (20). The present study identified 17 co-mutated samples with a rate of 19.1%, including 15 double-mutations of KRAS/TP53, PIK3CA/TP53 and KRAS/PIK3CA, and 2 cases of KRAS/PIK3CA/TP53 co-mutation. This difference may result from the sensitivity and sequencing depth of next-generation sequencing by cSMART. The varied sample size between studies may also contribute toward the discrepancies in gene mutation rates.
Clinical characteristics, including the baseline demographics, clinical manifestations, partial laboratory tests, partial pathological features and certain features of chest CT imaging, of patients with mutations were not significantly different from those of wild-type patients (P>0.05). This was consistent with the results of numerous previous studies (6,21–25). By contrast, KRAS/TP53 were associated with elevated CA19-9 expression, vacuolar signs and margin lobulation in chest CT imaging. However, it is possible that the sample size of each subgroup resulted in the difference in certain clinical characteristics to some extent, and further study is required due to the limited sample size used in the present study.
Invasive growth of the tumor tissue in patients was associated with KRAS, TP53 and KRAS/TP53, which was consistent with the clinical features observed. The incidence of distant metastasis was higher than that of local metastasis in patients with KRAS and TP53 mutations. The possible mechanism of this is the activation of the EGFR downstream Rat sarcoma/Rapidly Accelerated Fibrosarcoma/mitogen-activated protein kinases signaling pathways by KRAS mutations to regulate cell differentiation and proliferation. Prolonged activation of the KRAS signal is hypothesized to cause tumor cell proliferation and progression (26). TP53 gene mutations result in an oncogenic transformation of the tumor suppressor gene due to a conformational change; therefore, the regulation of cell growth, apoptosis and DNA repair is disrupted, which allows tumor cells to proliferate, grow and metastasize (27,28).
The biological significance of these mutations remains uncertain, but to some extent specific driver genes have prognostic value. Mascaux et al (29) first reported a poor prognosis in NSCLC patients with KRAS mutations, and other studies have confirmed this hypothesis (30). Recent studies have found that TP53 gene mutations may generate the same results in patients with NSCLC (31–33). PIK3CA encodes the type I phosphatidylinositol-3-kinase p110α catalytic subunit (34) and is important for the development of NSCLC. PIK3CA phosphorylates the EGFR bypass pathway, PI3K/AKT/mTOR, to activate downstream signaling that promotes the proliferation, survival, adhesion and differentiation of tumor cells (35). Liang et al (16) proposed that PIK3CA gene mutations are more likely to co-exist with other oncogenic mutations and that they may weakly induce independent carcinogenesis.
In the present study, patients with NSCLC who underwent first-line chemotherapy were divided into groups according to their genotype. For all patients who have EGFR mutation in Changhai hospital, targeted therapy is discussed and anti-EGFR tyrosine kinase inhibitors are recommended as the first-line treatment. The majority of these patients do receive targeted therapy. However, due to economic problems or for other reasons, certain patients cannot afford targeted therapy. For the baseline balance of the present study, the 89 patients who received first-line chemotherapy were chosen. Patients with a single KRAS or TP53 mutation experienced shorter PFS times than the wild-type patients, which was consistent with the results of the studies by Molina-Vila et al (36) and Meng et al (37). Shepherd et al (6) hypothesized that a double gene mutation, such as KRAS/TP53, in NSCLC patients may indicate a poor prognosis. Patients with KRAS/TP53 or PIK3CA/TP53 mutations experienced a shorter PFS time than those patients with the wild-type. The PFS time of the KRAS/TP53 group was shorter than that in the single KRAS and single TP53 groups, as was the time in the PIK3CA/TP53 group compared with the single TP53 group (P>0.05). We hypothesized that there could be a ‘gene superposition’ effect in NSCLC patients with a co-mutated gene, which leads to a shortened PFS compared with a single gene mutation. However, the trend observed in the present study was not statistically significant, which was in agreement with the results of a study by Jao et al (38). The mean PFS time of patients with KRAS/PIK3CA/TP53 gene co-mutations was 6.2 months, which was shorter than that of the double and single mutation groups. Only 2 patients had this co-mutation and therefore, a larger sample size is necessary for further study. Sampling error may also exist due to the next-generation sequencing technology and the limited sample size. The subgroups of gene mutations, as well as the chemotherapy regimen and doses, were not identical; therefore, further evidence should be obtained in a large clinical study.
In conclusion, the treatment strategy for NSCLC patients with KRAS, PIK3CA and TP53 mutations has not yet been defined. The present study determined the predictive value of KRAS, PIK3CA and TP53 mutations in patients with NSCLC. Additionally, the results of the present study suggested that patients with NSCLC should undergo routine KRAS, PIK3CA and TP53 sequencing to determine single or multiple gene mutations for the analysis of patient clinical characteristics and prognosis.
Acknowledgements
The authors would like to thank the staff of the Department of Respiratory and Critical Care Medicine, Shanghai Changhai Hospital (Shanghai, China) for providing assistance in data management and statistical analysis.
Funding
The present study was supported by the Shanghai Scientific Research Projects (grant no. 15411960400).
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
JZ, YH, RC and CB conceived and designed the study. JL analyzed the statistics. CB provided a part of patients' clinical data and monitored the whole study; JZ and RC wrote the original draft, YH and CB reviewed and edited the draft. All authors have read and approved the final version of this manuscript.
Ethics approval and consent to participate
The study was approved by the Ethics Committee of Changhai Hospital affiliated to Second Military Medical University (Shanghai, China).
Patient consent for publication
Written nformed consent and permission for publication was obtained for all patients in the present study.
Competing interests
The authors declare that they have no competing interests.
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