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ORIGINAL ARTICLE
Year : 2020  |  Volume : 16  |  Issue : 3  |  Page : 434-439

Sex determining region Y-box 2 is a prognostic factor for head and neck squamous cell carcinoma: Evidence from 11 published investigations


Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi Zhuang Autonomous Region, 541001, China

Date of Submission12-May-2016
Date of Decision04-Jun-2016
Date of Acceptance10-Jun-2016
Date of Web Publication25-Aug-2016

Correspondence Address:
Bo Li
Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Guilin Medical University, Lequn Road No. 15, Guilin, Guangxi Zhuang Autonomous Region, 541001
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.189238

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 > Abstract 


Objective: The aim of this study was to review the published literature and investigate whether sex determining region Y-box 2 (SOX2) is a prognostic factor in head and neck squamous cell carcinoma (HNSCC) by conduct a meta-analysis.
Materials and Methods: Trials were identified from the major electronic databases (MEDLINE, EMBASE, and Cochrane Library) using the key words “HNSCC” and “SOX2.” The overall survival (OS), disease-specific survival (DPS), and disease-free survival (DFS) were the primary outcome measures.
Results: We identified 371 articles, 9 articles 11 studies with a total number of 1334 cases were eligible for inclusion of this meta-analysis. The results showed that OS (DPS) in low-expression group was higher than that in high-expression group. However, the difference between the two groups was not significant (hazard ratio [HR] = 1.30, 95% confidence interval [95% CI] = [0.88, 1.91]; P = 0.18), and there was great statistical heterogeneity (I2 = 66%, P = 0.002). After subgroup analysis, the HR for OS of the patients with reduced expression of SOX2 was 1.34 (95% CI = [1.04, 1.74], P = 0.03), and the heterogeneity became acceptable (I2 = 32%, P = 0.16). The HR for DFS of the patients with reduced expression of SOX2 was 1.39 (95% CI = [1.00, 1.93]; P = 0.05).
Conclusion: The findings of this meta-analysis are indicative of that high SOX2 expression is a negative prognostic factor of HNSCC and exhibit both worse OS and DFS. However, the small sample size available for this systematic review limited the power of this quantitative meta-analysis. It may therefore be too early to place complete confidence in these results.

Keywords: Disease-free survival, head and neck squamous cell carcinoma, immunohistochemistry, overall survival, prognosis, sex determining region Y-box 2


How to cite this article:
Li B, Chen M, Pan MX. Sex determining region Y-box 2 is a prognostic factor for head and neck squamous cell carcinoma: Evidence from 11 published investigations. J Can Res Ther 2020;16:434-9

How to cite this URL:
Li B, Chen M, Pan MX. Sex determining region Y-box 2 is a prognostic factor for head and neck squamous cell carcinoma: Evidence from 11 published investigations. J Can Res Ther [serial online] 2020 [cited 2020 Aug 9];16:434-9. Available from: http://www.cancerjournal.net/text.asp?2020/16/3/434/189238




 > Introduction Top


Head and neck squamous cell carcinoma (HNSCC) accounts for nearly 3% of all cancer cases and is the sixth most common cancer in the world.[1],[2] HNSCC is one of the most devastating malignancies, despite improvements in treatment strategies against HNSCC. Significant advancements have been made in prevention, diagnostics, and treatment strategies, but only modest progress has been made in improving the survival rates in patients with progression or metastatic disease over the last 30 years.[3],[4],[5],[6],[7] New biomarkers are needed in urgent to predict accurate survival evaluation for HNSCC patients.

Sex determining region Y-box 2 (SOX2) is a transcription factor that is involved in the maintenance of embryonic stem cell pluripotency and in multiple developmental processes.[8],[9] More and more studies of the correlation of SOX2 and malignant tumor had been reported. A lot of studies have proved that SOX2 had a function in tumor genesis, such as skin squamous cell carcinoma, gastric cancer, glioblastoma, colorectal cancer, lung cancer, breast cancer, and HNSCC.[10],[11],[12],[13],[14],[15],[16] However, the correlation between SOX2 expression pattern and clinicopathological features and clinical outcome were highly variable among HNSCC. Some research reported that there was an association between high expression of SOX2 and adverse prognosis, including recurrence, lymph node, and distant metastasis.[17],[18] However, the others believed the high expression of SOX2 conferred a better prognosis.[14],[18],[19],[20] Moreover, most of the published researches are not only small size and heterogeneous but also generally ambivalent in their findings. That is to say, it is difficult to evaluate HNSCC patients' clinical prognosis of SOX2.

The aims of this article are to review the published studies (which researched in the relationship between expressions of SOX2 and patient survival in HNSCC) and conduct a meta-analysis which is specifically to investigate whether SOX2 is a prognostic factor in HNSCC.


 > Materials and Methods Top


Inclusion criteria

Researches were included if they meet all the following inclusion criteria: (1) patients who were diagnosed with HNSCC and biopsy confirmed (2) studies focused on the evaluations of the expression pattern of SOX2 in primary tumor and correlation between SOX2 expression and patients' prognosis, (3) outcome indicators included overall survival (OS), disease-free survival (DFS), disease-specific survival (DPS), and other clinicopathological indicators were the main outcomes of interest.

Exclusion criteria

(1) No clear survival analysis or could not provide enough data required for prognostic evaluation; (2) not used immunohistochemistry (IHC) to assess SOX2 expression pattern; (3) did not publish in English; and (4) reviews, comments, letters to the author, or case reports.

Literature search

MEDLINE (Until July 2015), EMBASE (Until July 2015), and Cochrane Library (Until July 2015) were used to search for the original articles analyzing the prognostic value of SOX2 in HNSCC. The database was searched with the following search terms as keywords: (“SOX2” OR “SOX-2” OR “sex determining region Y-box 2” OR “SRY-related HMG-box gene 2”) AND (“head and neck neoplasms” OR “head and neck cancer” OR “head and neck squamous cell carcinoma” OR “head and neck carcinoma”). Reference lists within the retrieved articles were used as secondary reference sources. If multiple publications from a particular research group reported data from overlapping samples, we would include the study reporting the largest dataset.

Quality assessment and data analysis

The quality of all included studies was evaluated independently by the two reviewers: Bo Li ( first author) and Mei Chen (second author). Any conflicts in opinion were resolved by discussion. We extracted data for the studies using a standardized data extraction form Review Manager (RevMan 5.3, Cochrane Collaboration, http://tech.cochrane.org/revman). We did our best to try to contact study authors for relevant missing or unclear data. We excluded the studies that did not meet the inclusion criteria in terms of study protocol. One reviewer (Bo Li) extracted the data, which were checked by another reviewer (Mei Chen). Differences in opinion were resolved by discussion.

Statistical analysis

All the individual outcomes were pooled using the statistical software RevMan 5.3. The hazard ratio (HR) and its 95% confidence interval (95% CI) were the recommended summary statistics for meta-analysis of OS, DFS, or DPS. We chose the random-effects model to merge HR when the heterogeneity is acceptable (I2 <50%), use the fixed effects when the heterogeneity is unacceptable (I2 ≥50%). Statistical heterogeneity, the variation in results between researches, was evaluated by using the I2. Sensitivity analyses and subgroup analyses were performed when the heterogeneity was unacceptable.


 > Results Top


Search findings

A total of 371 articles were retrieved by the database search, including 358 articles from MEDLINE, EMBASE, and Cochrane Library, and 13 articles from the reference lists of articles obtained. Three hundred and forty-four articles were excluded as being irrelevant to HNSCC or due to lack of clinicopathological or prognostic data. The remaining 27 articles were further assessed for eligibility, and another 18 articles were eventually excluded. Nine articles 11 studies with a total number of 1334 cases were selected of inclusion for meta-analysis. Five studies have the data of both OS and DFS, five studies only have the data of OS or DPS, and only one study only have the data of DFS. The search process is shown in [Figure 1].
Figure 1: Flow diagram of literature search

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The characteristics and treatment of these studies

The key information extracted from each included studies is summarized in [Table 1], including the first author, publication year, country of origin, number of cases, tumor locations, tumor stage, and other necessary data. As shown in [Table 1], these 11 eligible studies investigating OS, DFS, DPS, or pathological features were published between 2010 and 2015.[16],[17],[18],[19],[20],[21],[22],[23],[24] The sample sizes of the included studies ranged from 51 to 436 patients. The median follow-up period ranged from 18 to 86.4 months. As the paper by González-Márquez included three cohorts focused on three types of HNSCC and reported their clinical outcome separately, we marked them as González-Márquez (HPSCC), González-Márquez (LSCC), and González-Márquez (SNSCC), respectively, in the following analysis.[18]
Table 1: Characteristics of the included studies

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Methodology assessment of sex determining region Y-box 2 expression

As shown in [Table 1], the detection methods of SOX2 in all these included studies were IHC, and all these studies have provided IHC staining figures.

Meta-analysis

Sex determining region Y-box 2 expression and overall survival (disease-specific survival)

In this meta-analysis, there were nine researches that have provided the HR values and their 95% CI. Therefore, we directly utilized them for the evaluation of the value of SOX2 expression and OS.[16],[17],[18],[19],[20],[21],[24] There was only one study from which the HR values and their 95% CI can be calculated according to the data provided by the researchers by the reported methods.[22],[25] The association between SOX2 expression and OS (DPS) for HNSCC was meta-analyzed in terms of the average HR (95% CI) in 1280 patients from ten trials. The overall HR was 1.30 (95% CI = [0.88, 1.91]; P = 0.18). The effect measure was not significant, and there was great statistical heterogeneity that was driven by Fu's study (I2 = 66%, P = 0.002). When Fu's study was excluded, heterogeneity became acceptable and the effect measure was significant (I2 = 32%, P = 0.16; HR = 1.34, 95% CI = [1.04, 1.74], P = 0.03) [Figure 2] and [Figure 3].
Figure 2: Forest plot for overall survival (disease-specific survival): The overall hazard ratio was 1.30 (95% confidence interval = [0.89, 1.91]; P = 0.181). The effect measure was not significant, and there was great statistical heterogeneity (I2 = 65.7%, P = 0.002). After heterogeneity analysis, the difference between the two groups was significant (hazard ratio: 1.42; 95% confidence interval = [1.03, 1.97]; P = 0.035). Moreover, the heterogeneity was acceptable (I2 = 31.8%, P = 0.164)

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Figure 3: Forest plot for disease-free survival: The difference between the two groups was not significant (hazard ratio: 1.37; 95% confidence interval = [0.99, 1.90]; P = 0.055). The heterogeneity was acceptable (I2 = 25.5%, P = 0.243)

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Sex determining region Y-box 2 expression and disease-free survival

In this meta-analysis, there were five researches that have provided the HR values and their 95% CI.[16],[17],[18] Therefore, we directly utilized them for the evaluation of the value of SOX2 expression and DFS. There was only one study from which the HR values and their 95% CI can be calculated according to the data provided by the researchers. There was no significant heterogeneity between each study (I2 = 32%, P = 0.19).[23] The HR for DFS of the patients with reduced expression of SOX2 was 1.39 (95% CI = [1.00, 1.93]; P = 0.05) [Figure 4].
Figure 4: Forest plot for disease-free survival (subgroup analysis): The difference between the two groups was significant (hazard ratio: 1.44; 95% confidence interval = [1.03, 2.00]; P = 0.032). Moreover, the heterogeneity was acceptable (I2 = 13.1%, P = 0.330)

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Publication bias analysis

Publication bias of this meta-analysis was analyzed by STATA 12.0 software (Stata Corporation, College Station, TX, USA) and RevMan 5.3. According to the funnel plots (for OS) [Figure 5], we could see there is an unconspicuous asymmetry, either visually or from Begg's test (P = 0.175), or Egger's test (P = 0.055). In other words, it indicates there is no significant publication bias, and the result of the study is credible.
Figure 5: Funnel plot of this meta-analysis of overall survival: According to the funnel plot, there is an unconspicuous asymmetry

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 > Discussion Top


Lots of studies reported that SOX2 is a predictor for cancer prognosis.[16],[17],[18],[19],[20],[21] The impact of the SOX2 in the carcinogenesis is ascribed to their performances involved in the regulation of proliferation, cell differentiation, and survival in multiple essential processes.[26] On the one hand, some trials have identified that high expression of SOX2 is associated with poor prognosis in many cancers.[27],[28] On the other hand, many researches take the opposite viewpoint.[24],[29] Similarly, the prognostic value of SOX2 in patients with HNSCC is still controversial. Some researches supported that high SOX2 expression is a positive prognostic factor of HNSCC and exhibit a better OS or DFS.[17],[24] The reports of González-Márquez et al.[18] also were in line with the findings mentioned above. However, Du et al. and Tang et al.[16],[20] believed that low SOX2 expression is a positive prognostic factor of HNSCC. In addition, many scholars harbored the idea that SOX2 expression was not an independent prognostic factor of HNSCC. The purpose of this study was a retrospective analysis of published literature to assess the prognostic value of SOX2 expression in patients with HNSCC.

In this present study, we selected eleven studies which are clear on not only diagnostic criteria but also inclusion criteria and exclusion criteria. OS, DFS, and DPS were the primary outcome measures. HR values and their 95% CI were the statistical indicators to evaluate the impact of SOX2 expression for prognosis of patients with HNSCC. This meta-analysis confirmed the impact of SOX2 expression on OS (DPS) of HNSCC patients. However, the effect measure was not significant (HR = 1.30; 95% CI = [0.88, 1.91]; P = 0.18) and statistical heterogeneity was unacceptably large (I2 = 66%, P = 0.002). The great statistical heterogeneity was driven by Fu's study. Because the measurement standard of Fu's study was DPS, other nine studies were OS. When Fu's study was excluded, the association between SOX2 expression and OS for HNSCC was meta-analyzed again. Heterogeneity became acceptable and the effect measure was significant (I2 = 32%, P = 0.16; HR = 1.34; 95% CI = [1.04, 1.74]; P = 0.03). Moreover, this meta-analysis also confirmed that low SOX2 expression was significantly associated with positive DFS. However, the effect measure was not significant. The included patients of Attramadal's study were all early stages, the included patients of other studies were both early and advanced stage. That is to say, the inclusion criteria of Attramadal's study were very different from other research. After subgroup analysis, the effect measure was significant.

Every systematic review or meta-analysis, including our own, has its limitations. First, all the included researches were retrospective study, rather than prospective study. What is more, some studies of these included researches did not provide the HR values and their 95% CI. We could not directly utilize them for the evaluation of the value of SOX2 expression and OS and have to calculate HR values and their 95% CI according to the data provided by the researchers. The calculation results may be a little deviation is inevitable. Second, the number of included researches was low at only ten, and the number of patients was also small. In other words, our findings required more trials to further confirm. Last but not least, selective reporting of individual researches also limited this meta-analysis. Due to various reasons, obtaining all the data for a complete review of SOX2 in HNSCC is impossible. To resolve these above problems, we calculated HR values and their 95% CI by the reported methods.[25] Hence, we can increase the sample size for this meta-analysis and make our findings more reliable. All these factors have an impact on the outcomes measured and might have influenced the findings. More researches are required to further confirm our results.


 > Conclusion Top


Our findings showed that there is exact evidence that high SOX2 expression is a negative prognostic factor of HNSCC and exhibit both worse OS and DFS.[30] However, some limitations weakened the power of our findings. In other words, further researches are required to substantiate our findings.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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