Open Access

Improvement in the performance of an autoantibody panel in combination with heat shock protein 90a for the detection of early‑stage lung cancer

  • Authors:
    • Qing Chen
    • Shaojin Zhu
    • Nanlin Jiao
    • Ziyu Zhang
    • Guangjian Gao
    • Wenqiang Zheng
    • Gang Feng
    • Wenzheng Han
  • View Affiliations

  • Published online on: January 3, 2023     https://doi.org/10.3892/etm.2023.11781
  • Article Number: 82
  • Copyright: © Chen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The early diagnosis of lung cancer is closely associated with the decline of mortality. A panel consisting of seven lung cancer‑related autoantibodies (7‑AABs) has been shown to be a reliable and specific indicator for the early detection of lung cancer, with a specificity of ~90% and a positive predictive value of ~85%. However, its low sensitivity and negative predictive value limit its wide application. To improve its diagnostic value, the diagnostic efficiencies of 7‑AABs in combination with non‑specific tumor markers were retrospectively investigated for the detection of early‑stage lung cancer. A total of 217 patients with small lung nodules who presented with ground‑glass opacity or solid nodules as well as 30 healthy controls were studied. The concentrations of 7‑AABs and heat shock protein 90a (HSP90a) were assessed using ELISA. Automated flow fluorescence immune analysis was used for the assessment of CEA, CYFRA21‑1, CA199 and CA125 levels. The results showed that 7‑AABs + HSP90a possessed a remarkably improved diagnostic efficiency for patients with small pulmonary nodules or for patients with lung nodules of different types, which suggested that 7‑AABs in combination with HSP90a could have a high clinical value for the improvement of the diagnostic efficiency of early‑stage lung cancer.

Introduction

Lung cancer is currently the leading cause of cancer-related mortality worldwide (1). Non-small cell lung cancer (NSCLC) accounts for the majority of all lung cancer cases. The 5-year survival rate of patients with NSCLC is ~15% (2). Moreover, most patients with NSCLC are at the advanced/metastatic stage when diagnosed, and the 5-year survival rate is only 5.5% (3). However, the 5-year survival rate of patients with early-stage NSCLC is ~60% (4,5). Therefore, the early detection and diagnosis of lung cancer are essential for the improvement of the overall survival rate. However, the techniques for early diagnosis still face challenges.

Recently, lung cancer-related autoantibodies (AABs) have been reported as biomarkers with high specificity, good stability and non-invasion have been identified and have become a focus of research in the early diagnosis of high-risk lung cancer cohorts (6,7). Notably, the positive results of lung cancer-related AABs are observed before lung cancer is clinically diagnosed. Patient cohorts with lung cancer have been screened using computed tomography (CT) at the Mayo Clinic, and studies have reported that lung cancer-related AABs can provide a valuable warning up to 5 years before the clinical diagnosis of lung cancer (8). It has also been reported that lung cancer-related AABs have serve an important role in giving early warnings up to 4 years before the clinical diagnosis of pulmonary carcinoma in 200,000 high-risk postmenopausal women (9). The sensitivities and specificities of a panel consisting of four lung cancer-related autoantibodies (4-AABs), namely tumor protein 53 (p53), melanoma antigen 1 (MAGEA1), protein gene product 9.5 (PGP9.5) and sex-determining region Y-box 2 (SOX2), as a diagnostic tool for monitoring 458 patients at high risk of lung cancers were reported to be 71.8 and 89%, respectively (10). A panel of seven lung cancer-related autoantibodies (7-AABs) in peripheral circulating blood, including p53, PGP9.5, SOX2, cancer/testis G antigen 7 (GAGE7), ATP-dependent RNA helicase 4-5 (GBU4-5), cancer-associated antigen (CAGE) and MAGEA1 was reported to be able to distinguish malignant nodules from benign nodules and healthy controls (HCs), with a sensitivity of 56.53% and a specificity of 91.60% (11). The specificity of 7-AABs can be further increased to 95.80% when combined with CT (11). Another large-scale prospective study consisting of 1,915 Chinese individuals recruited from five research centers reported that the panel of 7-AABs has substantially higher sensitivity and specificity for the early diagnosis of lung cancer compared with non-specific tumor markers, such as carcinoembryonic antigen (CEA), neuron-specific enolase and cytokeratin fragment antigen 21-1 (CYFRA21-1) (12). Therefore, as a specific tumor marker, the lung cancer-related AAB panel possesses marked clinical application value in the diagnosis of pulmonary carcinoma. However, the means to improve its sensitivity remains largely unsolved.

A previous study reported that heat shock protein 90a (HSP90a), which maintains the stability of various protein molecules, is closely related to the occurrence and development of malignant tumors (13). The cutoff value of HSP90a is 50 ng/ml, which can accurately distinguish malignant and benign tumors in multiple tissues, such as the liver, lung, pancreas and breast (14). However, HSP90a alone has limitations in early lung cancer diagnosis due to its non-specificity. Therefore, the aim of the present study was to combine the 7-AABs with HSP90a to improve their diagnostic value in early-stage lung cancer.

In the present study, the level of each lung cancer-related AAB in patients with malignant lung nodules (MLNs) or benign lung nodules (BLNs), as well as HCs, was investigated. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and relative risk (RR) of the 7-AABs with combinations of the 7-AABs and other non-specific tumor markers, such as HSP90a, CEA, CYFRA21-1, carbohydrate antigen 199 (CA199) or carbohydrate antigen 125 (CA125) were assessed. Furthermore, the diagnostic efficiency of the aforementioned markers in patients with different sizes, types and stages of lung nodules was evaluated.

Patients and methods

Patients

A total of 217 individuals who were in good health, with lung nodules (ground-glass opacity or solid nodule) firstly diagnosed using high-resolution CT (HRCT) scans during routine examinations were enrolled as patients. Patients were recruited from October 2020 to August 2021 in The First Affiliated Hospital of Wannan Medical College (Wuhu, China). There were 78 males and 139 females, and the average age was 54.5±1.3 (mean ± standard deviation) years. The exclusion criteria for patients were as follows: Chronic obstructive pulmonary disease (including chronic bronchitis, pneumonectomies and pulmonary heart disease), pulmonary fibrosis, or a history of treated or untreated pulmonary malignancy. A total of 30 individuals who were in good health without underlying lung diseases, nor other major diseases screened for in the routine examinations were selected as healthy controls. The present study was approved by the Ethics Review Committee of the First Affiliated Hospital of Wannan Medical College (approval no. 202076; Wuhu, China) and the experimental procedures were in agreement with The Declaration of Helsinki. Written informed consent was obtained from all participants.

Laboratory measurements

The serum concentrations of 7-AABs were quantified using the Seven Autoantibodies Detection Kit (ELISA) (cat. no. 20210106. CancerProbe Biotechnology Co., Ltd.). The concentration of HSP90a in the blood was assessed using the Human Heat Shock Protein HSP90-α ELISA kit (cat. no. HUEB0886; Assay Genie Co., Ltd.). CEA, CYFRA21-1, CA199 and CA125 were assessed using a Multiple Tumor Markers Detection Kit (cat. no. LP120280; Shanghai Tellgen Life Science Co., Ltd.) and were quantified using a Tesmi F4000 automated flow fluorescence immune analyzer (Shanghai Tellgen Life Science Co., Ltd.).

Hematoxylin and eosin (H&E) staining

Tissue samples from the patients with lung nodules were immersed and fixed using 4% formaldehyde at room temperature (~20˚C) for 24 h, embedded in paraffin, and then sectioned at 3-5 µm thickness. Sections were baked at 70˚C for 1 h and dewaxed using xylene, before rehydration in a 100, 95, 85 and 75% ethanol series for 5 min at a time. Then, the sections were transferred into distilled water for 5 min. Next, the sections were stained using H&E at room temperature for 5 min, followed by dehydration with absolute ethyl alcohol at room temperature for 5 min and sealed using neutral gum (cat. no. N116470, Shanghai Aladdin Biochemical Technology Co., Ltd.) for assessment. Following the World Health Organization Classification of Tumours (5th Edition)-Thoracic Tumours (15) guidelines, microscopic assessment of the sections was then performed by experienced pathologists.

Statistical analysis

Data were statistically analyzed using SPSS version 22.0 (IBM Corp.). After the Shapiro-Wilk test was performed, comparison of the levels of each AAB (namely, p53, PGP9.5, SOX2, GAGE7, GBU4-5, MAGEA1 and CAGE) and HSP90a among the three groups was performed using the Kruskal-Wallis test followed by Dunn's test for non-parametric data. Comparison of the diagnostic efficiency of 7-AABs for discrimination between MLNs and BLNs in different groups was performed using the χ2 test. Clinical performance was presented in terms of sensitivity (the percentage of true positives) and specificity (the percentage of true negatives). PPV (the probability of MLNs given a positive test result), NPV (the probability of BLNs given a negative test result) and RR (the proportion of cases with a positive outcome in the two groups) were also calculated. McNemar's test was used for comparison of the sensitivity between 7-AABs + HSP90a and other groups (such as 7-AABs, 7-AABs + CEA, 7-AABs + CYFRA21-1, 7-AABs + CA199 and 7-AABs + CA125). For comparison of the NPV between 7-AABs + HSP90a and other groups, the marginal regression model based on the generalized estimation equation was used as follows: Model, g[P(D=1|Z, X=0)]=αN + βNZ, where g represented the contiguous function, Z represented the indicator variable and X represented the diagnostic result. Null hypothesis (H0) β=0 was used to check the difference between tests. When g took the natural logarithmic function, eβ represented an estimate of the relative NPV. The diagnostic efficiencies of 7-AABs, 7-AABs + HSP90a, 7-AABs + CEA, 7-AABs + CYFRA21-1, 7-AABs + CA199 and 7-AABs + CA125 were assessed using receiver operating characteristic (ROC) curves. All tests were two-tailed, and P<0.05 was considered to indicate a statistically significant difference. The data were presented as mean ± standard deviation, number of subjects (n) and percentage (%). Three replicate experiments were performed for each measurement.

Results

Clinical characteristics of the patients

A total of 217 patients with lung nodules and 30 HCs were enrolled in the present study. Table I summarizes the clinical features of these subjects. A total of 159 patients with MLNs including 158 NSCLC cases (41.8% were cases with adenocarcinoma in situ; 57.6% were cases with invasive adenocarcinoma and 0.6% were cases with squamous cell carcinoma) and one case with small cell lung cancer (SCLC) and, 58 patients with BLNs were confirmed by pathological examination (Fig. 1). According to the histopathological results, the 159 patients were divided into one of four stages: Stage 0, 66 patients (41.5%); stage I, 91 patients (57.2%); stage II, 1 patient (0.6%); and stage III, 1 patient (0.6%).

Table I

Clinical characteristics of patients with lung nodules and HCs.

Table I

Clinical characteristics of patients with lung nodules and HCs.

Clinical characteristicLung noduleMLNBLNHC
Number of patients2171595830
Age, years54.5±11.354.5±11.754.5±10.153.2±9.1
Sex (M/F), n78/13950/10928/3011/19
NSCLC, n158158--
Adenocarcinoma in situ, n (%)66 (41.8)66 (41.8)--
Invasive adenocarcinoma, n (%)91 (57.6)91 (57.6)--
Squamous cell carcinoma, n (%)1 (0.6)1 (0.6)--
SCLC, n11--
Stage, n (%)    
     066 (41.5)66 (41.5)--
     I91 (57.2)91 (57.2)--
     II1 (0.6)1 (0.6)--
     III1 (0.6)1 (0.6)--
Size, n (%)21715958 
     <8 mm68 (31.3)42 (26.4)26 (44.8)-
     8-20 mm149 (68.7)117 (73.6)32 (55.2)-
Type, n (%)21715958 
     Pure GGO58 (26.7)45 (28.3)13 (22.4)-
     Mix GGO97 (44.7)85 (53.5)12 (20.7)-
     Solid nodule62 (28.6)29 (18.2)33 (56.9)-

[i] HC, healthy control; MLN, malignant lung nodule; BLN, benign lung nodule; NSCLC, non-small cell lung cancer; SCLC, small cell lung cancer; M, male; F, female; GGO, ground-glass opacity.

Of the 217 enrolled patients, 68 (31.3%) and 149 (68.7%) patients, with lung nodules ≤8 mm and 8-20 mm, respectively, were evaluated using HRCT. Moreover, 58 (26.7%), 97 (44.7%) and 62 (28.6%) patients with pure ground-glass opacity (pGGO), mix ground-glass opacity (mGGO) and solid nodule (SN), respectively, were also evaluated using HRCT (Fig. 2). A total of 159 patients with MLNs and 58 patients with BLNs were classified and were presented in Table I.

The reactivity of each AAB and HSP90a in patients and HCs

The levels of 7-AABs, namely p53, PGP9.5, SOX2, GAGE7, GBU4-5, MAGEA1 and CAGE in serum samples and plasma HSP90a levels in 217 patients and 30 HCs were assessed using ELISA. The levels of p53, PGP9.5, SOX2, GAGE7, MAGEA1 and HSP90a in the MLN group were significantly elevated compared with those in the HC group (Fig. 3). However, there were no significant differences in the levels of GBU4-5 and CAGE among the three groups. These data suggested that the levels of 7-AABs and HSP90a from patients with MLNs showed marked differences compared with patients with BLNs and HCs.

Diagnostic values of 7-AABs alone or in combination with non-specific tumor markers for patients with lung nodules

The diagnostic values of 7-AABs alone or in combination with non-specific tumor markers for patients with lung nodules were evaluated. It was found that although the 7-AABs demonstrated a high specificity (77.6%; 95% CI, 64.4-87.1%) and PPV (84.0%; 95% CI, 73.8-90.8%) in patients with lung nodules, a low sensitivity (42.8%; 95% CI, 35.0-50.9%) and NPV (33.1%; 95% CI, 25.4-41.7%) were also demonstrated. Moreover, 7-AABs reflected a 1.3-fold increase in RR of MLNs, which demonstrated a good diagnostic efficiency (AUC=0.612, P=0.012). However, statistical analysis indicated that 7-AABs + HSP90a exhibited an elevated sensitivity (87.4%; 95% CI, 81.0-92.0%; P<0.0001) and NPV (66.1%; 95% CI, 52.5-77.6%; P<0.0001) compared with 7-AABs alone or in combination with other non-specific tumor markers, such as CEA, CYFRA21-1, CA199 or CA125. Furthermore, a positive result for 7-AABs + HSP90a reflected a 2.6-fold increase in RR for MLNs, which was significantly higher compared with 7-AABs alone or other combinations (Table II). ROC curves of 7-AABs + HSP90a (AUC=0.842; P<0.0001) also demonstrated that such a combination possessed significantly improved diagnostic efficiency for the discrimination between MLNs and BLNs compared with 7-AABs (AUC=0.612; P=0.012), 7-AABs + CEA (AUC=0.612; P=0.012), 7-AABs + CYFRA21-1 (AUC=0.612; P=0.012), 7-AABs + CA199 (AUC=0.612; P=0.012) and 7-AABs + CA125 (AUC=0.674; P<0.0001) (Fig. 4A), which indicated that 7-AABs + HSP90a exhibited better diagnostic efficiency for patients with pulmonary nodules.

Figure 4

Diagnostic efficiency of 7-AABs alone or in combination with non-specific tumor markers. (A) Diagnostic efficiency was assessed using the ROC curve for patients with lung nodules. The results of 7-AABs, 7-AABs + CEA, 7-AABs + CYFRA21-1 and 7-AABs + CA199 were very similar to the ROC analysis using the overlapped data. (B) Diagnostic efficiency was assessed using the ROC curve for patients with lung nodules of different sizes. The results of 7-AABs, 7-AABs + CEA, 7-AABs + CYFRA21-1, 7-AABs + CA199 and 7-AABs + CA125 were similar to the ROC analysis using the overlapped data in the <8 mm group. The results of 7-AABs, 7-AABs + CEA, 7-AABs + CYFRA21-1 and 7-AABs + CA199 were very similar to the ROC analysis using the overlapped data in the 8-20 mm group. (C) Diagnostic efficiency was assessed using the ROC curve for patients with lung nodules of different types. The results of 7-AABs, 7-AABs + CEA, 7-AABs + CYFRA21-1, 7-AABs + CA199 and 7-AABs + CA125 were similar to the ROC analysis using the overlapped data in the pGGO and mGGO groups. The results of 7-AABs alone or in combination with non-specific tumor markers were identical to the ROC analysis using the overlapped data in the SN group. 7-AABs, seven lung cancer-related autoantibodies; ROC, receiver operating characteristic; CEA, carcinoembryonic antigen; CYFRA21-1, cytokeratin fragment antigen 21-1; CA199, carbohydrate antigen 199; CA125, carbohydrate antigen 125; pGGO, pure ground-glass opacity; mGGO, mix ground-glass opacity; SN, solid nodule; HSP90a, heat shock protein 90a.

Table II

Diagnostic values of 7-AABs alone or in combination with non-specific tumor markers for patients with lung nodules.

Table II

Diagnostic values of 7-AABs alone or in combination with non-specific tumor markers for patients with lung nodules.

Diagnostic value7-AABs7-AABs + HSP90a7-AABs + CEA7-AABs + CYFRA21-17-AABs + CA1997-AABs + CA125
Specificity, %77.667.270.772.475.977.6
Sensitivity, %42.887.4a45.949.144.047.8
PPV, %84.088.081.183.083.385.4
NPV, %33.166.1a32.334.133.135.2
RR (95% CI)1.3 (1.1-1.5)2.6 (1.8-3.7)1.2 (1.0-1.4)1.3 (1.1-1.5)1.2 (1.1-1.5)1.3 (1.1-1.5)

[i] aP<0.0001 compared with other groups, namely 7-AABs, 7-AABs + CEA, 7-AABs + CYFRA21-1, 7-AABs + CA199 or 7-AABs + CA125, respectively. McNemar's test was used for the comparison of the sensitivity between 7-AABs + HSP90a and other groups. The marginal regression model based on the generalized estimation equation was used for the comparison of the NPV between 7-AABs + HSP90a and other groups. 7-AABs, seven lung cancer-related autoantibodies; CEA, carcinoembryonic antigen; CYFRA21-1, cytokeratin fragment antigen 21-1; CA199, carbohydrate antigen 199; CA125, carbohydrate antigen 125; HSP90a, heat shock protein 90a; PPV, positive predictive value; NPV, negative predictive value; RR, relative risk; CI, confidence interval.

Diagnostic values of 7-AABs alone or in combination with non-specific tumor markers for patients with lung nodules of different sizes

The diagnostic values of 7-AABs alone or in combination with non-specific tumor markers for patients with pulmonary nodules of 8-20 mm or <8 mm was assessed. The results demonstrated a better diagnostic value of 7-AABs for discrimination between MLNs and BLNs in the 8-20 mm group (χ2=5.4, P=0.02) compared with the <8 mm group (χ2=2.9, P=0.09). Furthermore, 7-AABs + HSP90a demonstrated an elevated sensitivity (all P<0.0001) and NPV (all P<0.0001) compared with 7-AABs alone or in combination with other non-specific tumor markers, such as CEA, CYFRA21-1, CA199 and CA125, in both the 8-20 mm and <8 mm groups. A positive result for 7-AABs + HSP90a indicated a 2.2-fold and 4.0-fold increase in the RR of MLNs in the 8-20 mm and <8 mm groups, respectively (Table III). ROC curves of 7-AABs + HSP90a (AUC=0.868, P<0.0001; AUC=0.784, P<0.0001) also demonstrated that such a combination possessed markedly improved diagnostic efficiency for the discrimination between MLNs and BLNs compared with 7-AABs (AUC=0.595, P=0.099; AUC=0.630, P=0.074), 7-AABs + CEA (AUC=0.595, P=0.099; AUC=0.630, P=0.074), 7-AABs + CYFRA21-1 (AUC=0.595, P=0.099; AUC=0.630, P=0.074), 7-AABs + CA199 (AUC=0.595, P=0.099; AUC=0.630, P=0.074) and 7-AABs + CA125 (AUC=0.696, P=0.001; AUC=0.630, P=0.074) in the 8-20 mm and <8 mm groups, respectively (Fig. 4B). These data demonstrated that 7-AABs + HSP90a exhibited improved diagnostic values for patients with small pulmonary nodules (<20 mm).

Table III

Diagnostic values of 7-AABs alone or in combination with non-specific tumor markers for patients with lung nodules of different sizes.

Table III

Diagnostic values of 7-AABs alone or in combination with non-specific tumor markers for patients with lung nodules of different sizes.

A, tumor size <8 mm
Diagnostic value7-AABs7-AABs + HSP90a7-AABs + CEA7-AABs + CYFRA21-17-AABs + CA1997-AABs + CA125
Specificity, %73.161.573.169.273.173.1
Sensitivity, %47.690.5a50.052.447.647.6
PPV, %74.179.275.073.374.174.1
NPV, %46.380.0a47.547.446.346.3
RR (95% CI)1.4 (1.0-1.4)4.0 (1.6-9.6)1.4 (1.0-2.1)1.4 (1.0-2.0)1.4 (1.0-2.0)1.4 (1.0-2.0)
B, tumor size 8-20 mm
Diagnostic value7-AABs7-AABs + HSP90a7-AABs + CEA7-AABs + CYFRA21-17-AABs + CA1997-AABs + CA125
Specificity, %81.371.968.875.078.181.3
Sensitivity, %41.086.3a44.447.942.747.9
PPV, %88.991.883.987.587.790.3
NPV, %27.460.0a25.328.227.229.9
RR (95% CI)1.2 (1.0-1.4)2.2 (1.5-3.3)1.1 (1.0-1.3)1.2(1.0-1.4)1.2 (1.0-1.4)1.3 (1.1-1.5)

[i] aP<0.0001 compared with other groups, namely 7-AABs, 7-AABs + CEA, 7-AABs + CYFRA21-1, 7-AABs + CA199 or 7-AABs + CA125, respectively. McNemar's test was used for the comparison of the sensitivity between 7-AABs + HSP90a and other groups. The marginal regression model based on the generalized estimation equation was used for the comparison of the NPV between 7-AABs + HSP90a and other groups. 7-AABs, seven lung cancer-related autoantibodies; CEA, carcinoembryonic antigen; CYFRA21-1, cytokeratin fragment antigen 21-1; CA199, carbohydrate antigen 199; CA125, carbohydrate antigen 125; HSP90a, heat shock protein 90a; PPV, positive predictive value; NPV, negative predictive value; RR, relative risk.

Diagnostic values of 7-AABs alone or in combination with non-specific tumor markers for patients with lung nodules of different types

The diagnostic values of 7-AABs alone or in combination with non-specific tumor markers for patients with pGGO, mGGO or SN were evaluated. Statistical analysis indicated that a better diagnostic value of 7-AABs for discrimination between MLNs and BLNs was demonstrated in the pGGO group (χ2=3.9, P=0.048) compared with the mGGO (χ2=1.2, P=0.27) and SN (χ2=2.1, P=0.15) groups. It was noteworthy that 7-AABs + HSP90a exhibited an increased sensitivity and NPV compared with 7-AABs alone or in combination with other non-specific tumor markers, such as CEA, CYFRA21-1, CA199 and CA125, in the three groups. A positive result for 7-AABs + HSP90a indicated a 3.3-fold, 1.5-fold and 5.5-fold increase in the RR for MLNs in the pGGO, mGGO and SN groups, respectively (Table IV). ROC curves of 7-AABs + HSP90a (AUC=0.925, P<0.0001; AUC=0.836, P<0.0001) also indicated that such a combination possessed improved diagnostic efficiency for discrimination between MLNs and BLNs compared with 7-AABs (AUC=0.803, P=0.001; AUC=0.724, P=0.012), 7-AABs + CEA (AUC=0.803, P=0.001; AUC=0.724, P=0.012), 7-AABs + CYFRA21-1 (AUC=0.803, P=0.001; AUC=0.724, P=0.012), 7-AABs + CA199 (AUC=0.803, P=0.001; AUC=0.724, P=0.012) and 7-AABs + CA125 (AUC=0.803, P=0.001; AUC=0.724, P=0.012) in the pGGO and mGGO groups; however, no significance was detected in the SN group (AUC=0.5, P=1.0) (Fig. 4C). The above results demonstrated the improved diagnostic efficiency of 7-AABs + HSP90a for patients with lung nodules of different types, especially pGGO and mGGO.

Table IV

Diagnostic values 7-AABs alone or in combination with non-specific tumor markers for patients with lung nodules of different types.

Table IV

Diagnostic values 7-AABs alone or in combination with non-specific tumor markers for patients with lung nodules of different types.

A, pure ground-glass opacity type lung nodules
Diagnostic value7-AABs7-AABs + HSP90a7-AABs + CEA7-AABs + CYFRA21-17-AABs + CA1997-AABs + CA125
Specificity, %84.676.984.684.684.684.6
Sensitivity, %51.191.1a51.157.851.153.3
PPV, %92.093.292.092.992.092.3
NPV, %33.371.4a33.336.736.736.7
RR (95% CI)1.4 (1.1-1.8)3.3 (1.4-7.5)1.4 (1.1-1.8)1.5 (1.1-2.0)1.4 (1.1-1.8)1.4 (1.1-1.9)
B, mix ground-glass opacity type lung nodules
Diagnostic value7-AABs7-AABs + HSP90a7-AABs + CEA7-AABs + CYFRA21-17-AABs + CA1997-AABs + CA125
Specificity, %83.366.775.075.083.383.3
Sensitivity, %37.684.7a41.242.438.843.5
PPV, %94.194.792.192.394.394.9
NPV, %15.938.1a15.515.516.116.1
RR (95% CI)1.1 (1.0-1.3)1.5 (1.1-2.1)1.1 (1.0-1.3)1.1 (1.0-1.3)1.1 (1.0-1.3)1.1 (1.0-1.3)
C, solid type lung nodules
Diagnostic value7-AABs7-AABs + HSP90a7-AABs + CEA7-AABs + CYFRA21-17-AABs + CA1997-AABs + CA125
Specificity, %72.763.663.666.769.772.7
Sensitivity, %44.889.7a51.755.248.351.7
PPV, %59.168.455.659.358.362.5
NPV, %60.087.5b60.062.960.563.2
RR (95% CI)1.5 (0.9-2.5)5.5 (1.9-16.1)1.4 (0.8-2.4)1.6 (0.9-2.7)1.5 (0.9-2.5)1.7 (1.0-2.9)

[i] aP<0.0001 and

[ii] bP<0.001 compared with other groups, namely 7-AABs, 7-AABs + CEA, 7-AABs + CYFRA21-1, 7-AABs + CA199 or 7-AABs + CA125, respectively. McNemar's test was used for the comparison of the sensitivity between 7-AABs + HSP90a and other groups. The marginal regression model based on the generalized estimation equation was used for the comparison of the NPV between 7-AABs + HSP90a and other groups. 7-AABs, seven lung cancer-related autoantibodies; CEA, carcinoembryonic antigen; CYFRA21-1, cytokeratin fragment antigen 21-1; CA199, carbohydrate antigen 199; CA125, carbohydrate antigen 125; HSP90a, heat shock protein 90a; PPV, positive predictive value; NPV, negative predictive value; RR, relative risk.

Discussion

Early-stage NSCLC has a notably better prognosis compared with advanced-stage NSCLC, and can usually be treated radically with relatively benign outcomes (16). It has been reported that lung cancer-related AABs have high specificity and PPV in diagnosing early-stage lung cancer. However, the relatively low sensitivity and NPV greatly limit their wider application in clinical practice (11,12,17). 7-AABs consisted of seven antibodies against p53, MAGEA1, GAGE7, CAGE, GBU4-5, SOX2 and PGP9.5. p53 was first reported as a tumor suppressor, and has been reported to be associated with tumorigenesis, regulation and apoptosis (18,19). It is an important biological indicator for the evaluation of tumor biological behavior and the screening of high-risk patients with lung cancer (20-22). MAGEA1, GAGE7 and CAGE are members of the cancer-testis antigen family, which can accelerate tumor formation, resist apoptosis, promote tumor proliferation and metastasis, and cause cellular and humoral immune responses (23,24). Their increased expression in NSCLC has been reported, including squamous cell carcinoma and adenocarcinoma (6,25). GBU4-5 is an ATP-dependent DNA helicase, which regulates transposon methylation and inhibits gene expression in the process of cell differentiation. The expression of GBU4-5 is increased in lung cancer (26). SOX2 activates the expression of oncogenes in lung cancer cells through regulation of the RAS-MAPK-survivin signaling pathway, which promotes the occurrence of lung cancer (27,28). SOX2 also serves a vital role in modulation of the growth and regulation of lung cancer stem cells, and it has a relatively high expression level in lung cancer cells compared with those in normal lung cells (29,30). PGP9.5 can increase the deubiquitination of functional proteins and regulate the expression of cell cycle genes (31). The upregulation of PGP9.5 is associated with lung cancer progression, and it is highly expressed in both squamous cell carcinoma and non-squamous cell carcinoma (32). The combined detection of 7-AABs has a much higher specificity and accuracy than a single marker, improving the detection rate of lung cancer (11).

In the present study, 217 patients with different types of small pulmonary nodules (≤20 mm), such as pGGO, mGGO and SN, were assessed. The results indicated that p53, PGP9.5, SOX2, GAGE7 and MAGEA1 protein expression levels were significantly increased in MLNs compared with BLNs and HCs. The specificity, sensitivity, PPV and NPV of 7-AABs for discrimination between MLNs and BLNs were 77.6, 42.8, 84.0 and 33.1%, respectively, which was similar those values previously reported (11,12). HSP90a is closely associated with numerous human cancers, and it has previously been employed for the early screening of certain tumors, including liver, lung and colorectal cancer, due to its high sensitivity (33-37). Chen et al (38) have reported that HSP90a is frequently over-expressed in human liver carcinoma cells, and its expression level is negatively correlated to the prognosis of patients with liver cancer. HSP90a, as a target of G-Rh2, serves a vital role in liver cancer therapy (38). The inhibition of HSP90a also enhances anti-tumor immunity (39). In a parallel study comparing alpha-fetoprotein (AFP), plasma HSP90a demonstrated a significantly higher diagnostic performance in distinguishing hepatocellular carcinoma (HCC) from HCs. Moreover, plasma HSP90a exhibited excellent diagnostic accuracy in discriminating AFP-negative patients with HCC (sensitivity, 93.9%; specificity, 91.3%) and AFP-limited liver cancer (sensitivity, 96.6%; specificity, 90.3%) (40). Furthermore, Zhong et al (41) reported that HSP90a, a valuable predictor of early chemotherapy effectiveness in advanced NSCLC, was closely correlated with tumor remission after chemotherapy, while HSP90a was not correlated with tumor diameter and pathological type. Targeting HSP90a suppresses the growth of lung cancer (42), promotes apoptosis and inhibits migration (43). A large-sample and multi-center survey reported a significantly increased level of HSP90a in early-stage NSCLC. Moreover, when the cutoff of HSP90a was 56.33 ng/ml, the sensitivity was 72%, the specificity was 78% and the coincidence rate was 75% (44). In the present study, further evaluation demonstrated that 7-AABs + HSP90a displayed remarkable advantages compared with 7-AABs alone or in other combinations. For pulmonary nodules of <8 mm, the specificity, sensitivity, PPV and NPV of 7-AABs + HSP90a were 61.5, 90.5, 79.2 and 80.0%, respectively, in discrimination between MLNs and BLNs, which was markedly higher compared with 7-AABs alone or in other combinations. Furthermore, 7-AABs + HSP90a reflected a 4.0-fold increase in the RR of MLNs, which indicated a better diagnostic efficiency. Notably, the diagnostic value of 7-AABs + HSP90a for pulmonary nodules of 8-20 mm was superior to that of pulmonary nodules of <8 mm. However, the diagnostic value of 7-AABs + HSP90a for pulmonary nodules of >20 mm required further assessment. For different nodule types, 7-AABs exhibited a good diagnostic value in patients with pGGO (χ2=3.9, P=0.048) compared with mGGO (χ2=1.2, P=0.27) and SN (χ2=2.1, P=0.15). 7-AABs + HSP90a demonstrated a significantly increased diagnostic efficiency for MLNs in patients with pGGO, mGGO and SN. In the present study, besides the significantly increased sensitivity, NPV and RR, it was demonstrated that the specificity of 7-AABs + HSP90a showed a slight decrease compared with 7-AABs. However, based on the results of diagnostic efficiencies assessed using the ROC curve, 7-AABs + HSP90a exhibited much better diagnostic performance than 7-AABs in the discrimination of MLNs from BLNs. However, a greater number of relevant biomarkers require assessment to improve the specificity in future research. Moreover, the diagnostic values of 7-AABs alone or in combination with non-specific tumor markers for patients with stage 0 and I lung cancer was evaluated. However, based on the χ2 test, the results demonstrated no significant effects on the discrimination of stage 0 and I lung cancer (Table SI). ROC analysis also demonstrated no diagnostic value for the use of 7-AABs alone or in combination with non-specific tumor markers (AUC=0.5, P=1.0) (Fig. S1). Once produced, an antibody can exist in the peripheral circulating blood for a long time and will not disappear quickly. Therefore 7-AABs are only used to diagnose lung cancer instead of evaluating its prognosis. To assess whether 7-AABs (+/- HSP90a) were correlated with age of diagnosis, 159 patients with lung cancer in the present study were divided into two groups as follows: i) A low-age group (≤50 years old, n=48); and ii) an advanced-age group (>50 years old, n=111). The results demonstrated no significant differences in the detection rate of 7-AABs (+/- HSP90a) in lung cancer between the two groups (χ2=0.6, P=0.42; χ2=0.8, P=0.38). Moreover, there were also no significant differences in the detection rate of 7-AABs (+/- HSP90a) in lung cancer between male and female patients (χ2=0.07, P=0.93; χ2=2.96, P=0.09). As is well known, histopathological character affects the treatment and prognosis of patients with lung cancer. Furthermore, the tumor markers against adenocarcinoma, squamous cell carcinoma and SCLC are different. In the present study, when two patients with squamous cell carcinoma (1 case with a solid nodule of 8-20 mm) and SCLC (1 case with a solid nodule of 8-20 mm) were excluded, 7-AABs + HSP90a demonstrated elevated sensitivity (patients with lung nodule, 88.5 vs. 87.4%; patients with lung nodule of 8-20 mm, 87.8 vs. 86.3%; patients with solid nodule, 96.3 vs. 89.7%).

However, due to the limitation in the number of patients with SCLC, larger pulmonary nodules (>20 mm) or advanced progression (such as, stage III-IV lung cancer), the diagnostic values of 7-AABs, alone or in combination with non-specific tumor markers, were not evaluated in these patients in the present study. Therefore, these aspects require further study.

In conclusion, the findings of the present study demonstrated that 7-AABs + HSP90a had good clinical value for the diagnosis of early-stage lung cancer, including patients with different types of small nodules, which suggested its value for further application in clinical practice.

Supplementary Material

Diagnostic values of 7-AABs alone or in combination with non-specific tumor markers for patients with early-stage malignant lung nodules. (A) The specificity, sensitivity, PPV and NPV of 7-AABs, 7-AABs + HSP90a, 7-AABs + CEA, 7-AABs + CYFRA21-1, 7-AABs + CA199 and 7-AABs + CA125. (B) The RR of 7-AABs, 7-AABs + HSP90a, 7-AABs + CEA, 7-AABs + CYFRA21-1, 7-AABs + CA199 and 7-AABs + CA125. (C) Diagnostic efficiency was assessed using the ROC curve. The results of 7-AABs, 7-AABs + HSP90a, 7-AABs + CEA, 7-AABs + CYFRA21-1, 7-AABs + CA199 and 7-AABs + CA125 were identical to the ROC analysis using the overlapped data. 7-AABs, seven lung cancer-related autoantibodies; ROC, receiver operating characteristic; CEA, carcinoembryonic antigen; CYFRA21-1, cytokeratin fragment antigen 21-1; CA199, carbohydrate antigen 199; CA125, carbohydrate antigen 125; HSP90a, heat shock protein 90a; PPV, positive predictive value; NPV, negative predictive value; RR, relative risk; CI, confidence interval.
Clinical findings and evaluation of 7-AABs alone or in combination with non-specific tumor markers for patients with early-stage malignant lung nodules.

Acknowledgements

Not applicable.

Funding

Funding: The present study was supported by the Natural Science Foundation of Universities in Anhui Province (grant no. KJ2021A0835 and KJ2021ZD0102), the National College Students' Innovation and Entrepreneurship Training Program (grant no. 202210368023), and the Natural Science Foundation of Anhui Province (grant no. 1908085QH325).

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

QC, SZ, WH and GF conceived and designed the study. QC, SZ, GG, WZ, ZZ, GF and NJ performed the data analysis and drafted the manuscript. QC, SZ and WH performed data collection. GG, WZ, GF, NJ and WH analyzed the results. WH and GF edited the manuscript and confirm the authenticity of all the raw data. All authors have read and approved the final manuscript.

Ethics approval and consent to participate

The present study was approved by the Ethics Review Committee of The First Affiliated Hospital of Wannan Medical College (approval no. 202076; Wuhu, China), and the experimental procedures were in agreement with The Declaration of Helsinki. Written informed consent was obtained from all participants.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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February-2023
Volume 25 Issue 2

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Chen Q, Zhu S, Jiao N, Zhang Z, Gao G, Zheng W, Feng G and Han W: Improvement in the performance of an autoantibody panel in combination with heat shock protein 90a for the detection of early‑stage lung cancer. Exp Ther Med 25: 82, 2023
APA
Chen, Q., Zhu, S., Jiao, N., Zhang, Z., Gao, G., Zheng, W. ... Han, W. (2023). Improvement in the performance of an autoantibody panel in combination with heat shock protein 90a for the detection of early‑stage lung cancer. Experimental and Therapeutic Medicine, 25, 82. https://doi.org/10.3892/etm.2023.11781
MLA
Chen, Q., Zhu, S., Jiao, N., Zhang, Z., Gao, G., Zheng, W., Feng, G., Han, W."Improvement in the performance of an autoantibody panel in combination with heat shock protein 90a for the detection of early‑stage lung cancer". Experimental and Therapeutic Medicine 25.2 (2023): 82.
Chicago
Chen, Q., Zhu, S., Jiao, N., Zhang, Z., Gao, G., Zheng, W., Feng, G., Han, W."Improvement in the performance of an autoantibody panel in combination with heat shock protein 90a for the detection of early‑stage lung cancer". Experimental and Therapeutic Medicine 25, no. 2 (2023): 82. https://doi.org/10.3892/etm.2023.11781