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ORIGINAL ARTICLE
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Year : 2017  |  Volume : 54  |  Issue : 3  |  Page : 580--583

Prognostic significance of p16INK4a alteration in soft tissue sarcomas: A meta-analysis

Gang Lin, Yue Lou 
 Department of Orthopedics, Children's Hospital of Nanjing Medical University, Nanjing 210000, People's Republic of China

Correspondence Address:
Dr. Yue Lou
Department of Orthopedics, Children's Hospital of Nanjing Medical University, Nanjing 210000
People's Republic of China

Abstract

PURPOSE: Numerous studies have investigated the role of p16INK4a alteration in patients with soft tissue sarcomas (STSs) yielding inconsistent and inconclusive results. Hence, we conducted a meta-analysis to precisely assess its prognostic value. MATERIALS AND METHODS: Electronic literature databases such as PubMed, EMBASE, Web of Science were searched, and five studies with a total of 536 patients were eligible for this meta-analysis. Pooled hazard ratio (HR) with 95% confidence interval (95% CI) of overall survival (OS) was used to assess the prognostic role of p16INK4a alteration. RESULTS: Overall, the pooled HR for all five eligible studies evaluating decreased p16INK4a expression on OS was 1.47 (95% CI: 1.14–1.90); sensitivity analysis suggested that the pooled HR was stable and omitting a single study did not change the significance of the pooled HR. There is no evidence of publication bias in the meta-analysis. CONCLUSIONS: In conclusion, this meta-analysis showed that decreased p16INK4a expression is associated with lower OS rate in patients with STS, and it is an effective biomarker of prognosis.



How to cite this article:
Lin G, Lou Y. Prognostic significance of p16INK4a alteration in soft tissue sarcomas: A meta-analysis.Indian J Cancer 2017;54:580-583


How to cite this URL:
Lin G, Lou Y. Prognostic significance of p16INK4a alteration in soft tissue sarcomas: A meta-analysis. Indian J Cancer [serial online] 2017 [cited 2020 Aug 12 ];54:580-583
Available from: http://www.indianjcancer.com/text.asp?2017/54/3/580/233144


Full Text



 Introduction



Soft tissue sarcomas (STSs) that develop in various soft tissues, including muscles, ligaments, fibrotic tissue, fat tissue, and synovial tissue, are relatively rare tumors accounting for only 1% of all malignant tumors.[1] These tumors frequently affect adolescents and young adults. Even though the prognosis for these sarcomas has improved with the recent development of neoadjuvant therapy, local recurrence is common (20%) and metastases occur in one-third of the patients.[2],[3] It is difficult to predict the prognosis using the clinical characteristics of STS because of the pathologic variations. Thus, STS needs further investigation regarding their molecular profiles to identify prognostic biomarkers, which has been previously done for other types of cancer.

p16INK4a is an important factor in carcinogenesis. The p16INK4a gene is located on the short arm of chromosome 9, region 9p21, and encodes for a nuclear protein that can block cell-cycle progression by effectively inhibiting the kinase activity of CDK4/6 and exerting negative control on cell proliferation.[4],[5] In the absence of a functional p16INK4a protein, CDK4 binds to cyclin D and phosphorylates pRb, releasing E2F and stimulating cell-cycle progression. Such activity has been reported in many types of malignancy. It has been suggested that decreased p16INK4a expression correlates with tumor progression and decreased survival among patients with various types of carcinoma.[6],[7] Similarly, decreased p16INK4a expression has been associated with decreased survival in patients with pediatric osteosarcoma and Ewing sarcoma.[8],[9] This loss may be due to point mutation,[10] homozygous deletion,[11] or methylation of the promoter region.[12]

Many retrospective studies have evaluated whether p16INK4a alteration may be a prognostic factor for survival in patients with STS.[13],[14],[15],[16],[17] However, the results of these studies are inconclusive. Some studies have suggested a poorer outcome for patients with decreased p16INK4a expression whereas others do not. It is unknown whether differences in these investigations have been mostly due to their limited sample size or genuine heterogeneity. Thus, we conducted a meta-analysis of all available studies relating p16INK4a alteration with the prognosis of patients with STS.

 Materials and Methods



Search strategy

PubMed, EMBASE, and Web of Science databases were searched using combinations of the terms STS (or soft-tissue sarcoma) and p16INK4a (or p16). Only studies published in English were included, and no unpublished reports were considered. References of retrieved articles were also screened for relevance. Studies eligible for inclusion in this meta-analysis met the following criteria: (1) prospective or retrospective cohort study; (2) tumors histologically confirmed as STSs; (3) studies examining the relation between p16INK4a alteration and clinical outcome; and (4) studies providing sufficient information to estimate the hazard ratio (HR) and 95% confidence interval (95% CI) of overall survival (OS). When the same authors reported two or more publications on possibly the same patient population, only the most recent or complete study was included in the meta-analysis.

Data extraction

Each paper was attentively analyzed to extract relevant data, including first author, publication year, country of patients, age of patients, number of cases, and follow-up time. When studies involve time-to-event data, the most appropriate statistics to use are the log HR (logHR) and its variance; however, these are not always explicitly stated in each study. Thus, the logHR and standard error of each study were obtained using the following methods: (1) directly extracting the unadjusted HR and 95% CI from each article; (2) estimating the HR using the log-rank test, P values, total events, high level, and control group figures; and (3) estimating the HR using data from Kaplan–Meier survival curves read by the Engauge Digitizer software as well as the minimal and maximal follow-up times.

Quality assessment

The quality of each study was assessed using the Newcastle Ottawa Quality Assessment Scale (NOQAS) by two independent reviewers. These scales were used to allocate a maximum of nine points for quality of selection, comparability, exposure, and outcome of study participants.

Statistical analysis

We measured the impact of serum p16INK4a alteration on survival by HR between the two survival distributions. HR and 95% CI were used to combine as the effective value. Heterogeneity test with inconsistency index (I2) statistic and Q-statistic was performed. The random effects' model was used for the analysis when an obvious heterogeneity was observed among the included studies (I2 > 50%). The fixed effects model was used, while there was no significant heterogeneity between the included studies (I2 ≤ 50%). By convention, HR >1 implies worse survival for the group with decreased p16INK4a expression. The impact of decreased p16INK4a expression on survival was statistically significant if the 95% CI did not overlap with one. To validate the credibility of outcomes in this meta-analysis, sensitivity analysis was performed by sequential omission of individual studies. For visually assessing the symmetry, Begg's funnel plots and Egger's test were used to assess the possibility of publication bias. STATA version 12 (StataCorp LP, College Station, TX, USA) was used for statistical analysis. A two-tailed P < 0.05 was considered statistically significant.

 Results



Study characteristics and quality assessment

By searching in PubMed, EMBASE, and Web of Science, 87 studies were initially identified. Subsequently, fifty-nine reports that did not meet the inclusion criteria were excluded. [Figure 1] shows a flow diagram of the selection process for relative articles. Finally, five studies published between 2003 and 2014 with a total of 536 STS patients were included in the analysis.[13],[14],[15],[16],[17] The major characteristics of the five eligible publications are reported in [Table 1]. All studies reported the prognostic value of p16INK4a alteration for survival in STS patients. Three of the five studies identified decreased p16INK4a expression as an indicator of poor prognosis, and the other two studies showed no statistical impact of p16INK4a alteration on survival. Quality assessments revealed average NOQAS scores from the two reviewers of 8.4 and 8.6, indicating that all five included studies were of moderate quality.{Figure 1}{Table 1}

Meta-analysis

No significant heterogeneity existed across the included studies (I2 = 21.5%, P = 0.278); thus, the fixed effect model was used. Overall, the pooled HR for all five eligible studies evaluating decreased p16INK4a expression on OS was 1.47 (95% CI: 1.14–1.90), suggesting that decreased p16INK4a expression was an indicator of poor prognosis for STS patients [Figure 2]. Sensitivity analysis suggested that the pooled HR was relatively stable and omitting a single study did not change the significance of the pooled HR [Figure 3].{Figure 2}{Figure 3}

Publication bias

The assessment of publication bias of literatures was performed by Begg's test and Egger's test. The funnel plot for this meta-analysis revealed some evidence of symmetry, and the P value of Egger's test was 0.299 [Figure 4]. Thus, no evidence of publication bias was observed from Egger's test in the meta-analysis.{Figure 4}

 Discussion



STSs are a heterogeneous and highly malignant group of tumors originating from mesenchymal lineage. Local recurrence is common and metastases occur in one-third of patients. Neoadjuvant therapy is increasingly used and may improve prognosis in high-risk cases but requires prognostic factors that can be evaluated preoperatively.[18] At present, prognostic factors mainly include clinicopathological variables such as tumor type, size, malignancy grade, necrosis, vascular invasion, and growth pattern, which are not very precise due to the pathological variations.[19],[20],[21] p16INK4a is an important factor in carcinogenesis and encodes for a nuclear protein that can block cell-cycle progression. In the absence of a functional p16INK4a protein, CDK4 binds to cyclin D and phosphorylates pRb, releasing E2F and stimulating cell-cycle progression. Such activity has been reported in many types of malignancy and correlates with poor prognosis among patients with various types of carcinoma.[22]

p16INK4a alteration has been proposed as a prognostic factor in STS in some researches; however, the results are conflicting. Thus, to derive a more precise estimate of the prognostic role of p16INK4a alteration in patients with STS, we systematically reviewed the published studies and carried out a meta-analysis. Overall, the present meta-analysis has combined five studies with a total of 536 patients to yield statistics, indicating a statistically significant role of p16INK4a alteration on OS in STS patients. Sensitivity analysis suggested that the pooled HR was relatively stable and omitting a single study did not change the significance of the pooled HR [Figure 3]. Therefore, the meta-analysis suggests that STS patients with decreased p16INK4a expression have poorer prognosis of OS compared with those with normal p16INK4a expression. The findings from our data help get a precise estimate of the prognostic role of p16INK4a alteration in patients with STS.

Several limitations of this meta-analysis are acknowledged. First, there were only five documents with a total of 536 STS patients in our meta-analysis. The comparatively modest size of the sample can unavoidably increase the risk of bias in this meta-analysis. Thus, more research with large sample size are needed to further clarify the prognostic significance of p16INK4a alteration in the patients with STS. However, given that STS are not very common on a population basis, the sample size of this investigation is one of the largest to-date among studies targeting this malignancy. Second, all the inclusion researches were limited to English literatures, so some related published studies in other languages that might meet the inclusion criteria might be missed. Therefore, publication bias may be present. Third, another potential source of bias is related to the method of HR and 95% CI extrapolation. Different methods of extracting HR mentioned before may induce bias. Data for multivariate survival analysis reported in the article were included in the present meta-analysis; if these data were not available, data calculated from survival curves by univariate analysis were included in the study. These results should be confirmed by an adequately designed prospective study. Fourth, the studies included in our meta-analysis were published from 2003 to 2014. The articles published 5 years ago whose methods were applied to the therapy of STS may differ from the nearest published.

 Conclusions



The meta-analysis shows that decreased p16INK4a expression is associated with lower OS rate in STS patients, and it is an effective biomarker of prognosis. To strengthen our findings, well-designed prospective studies with better standardized assessment of prognostic markers should help explore the relation between p16INK4a alteration and survival of STS.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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