High expression of ovarian cancer immunoreactive antigen domain containing 2 (OCIAD2) is associated with poor prognosis in lung adenocarcinoma
Abstract
The clinicopathological implications of ovarian cancer immunoreactive antigen domain containing 2 (OCIAD2) in lung adenocarcinoma were investigated. The expression of OCIAD2 in 191 surgically resected lung adenocarcinomas was examined using immunohistochemistry. OCIAD2 expression was quantified using the H‐score and dichotomized as high or low. High OCIAD2 protein expression was significantly correlated with vascular invasion (P = 0.0018), lymphatic permeation (P = 0.049), T factor (P = 0.0024), and pathological stage (P = 0.0003). High OCIAD2 expression was significantly associated with poorer overall survival (OS) (n = 191, P = 0.0325). In peripheral‐type lung adenocarcinomas (n = 161), high OCIAD2 expression was significantly associated with both poorer OS (P = 0.0214) and poorer disease‐free survival (P = 0.0496). Adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) showed weaker OCIAD2 expression than invasive adenocarcinoma. Among small adenocarcinomas measuring 2 cm or less in greatest dimension classified according to the Noguchi's classification (n = 79), invasive adenocarcinomas showed significantly higher OCIAD2 expression than non‐invasive adenocarcinomas (P = 0.0007). Interestingly, OCIAD2 was expressed heterogeneously even within a tumor, and its expression was higher in areas of invasion than in areas of in situ spread. Our results suggest that OCIAD2 could be a useful prognostic biomarker of lung adenocarcinoma.
Lung cancer is the leading cause of cancer‐related death worldwide. Most lung cancers are diagnosed at an advanced stage and the prognosis remains poor. According to the latest World Health Organization (WHO) classification (4th edition),1 lung cancers are classified histologically into adenocarcinoma, squamous cell carcinoma, neuroendocrine tumors, large cell carcinoma, adenosquamous carcinoma, sarcomatoid carcinoma, and salivary gland‐type tumors. Among them, adenocarcinoma is the most common in Japan and other countries.2 Adenocarcinomas are further subclassified into lepidic adenocarcinoma, acinar adenocarcinoma, papillary adenocarcinoma, micropapillary adenocarcinoma, solid adenocarcinoma, invasive mucinous adenocarcinoma, colloid adenocarcinoma, fetal adenocarcinoma, and enteric adenocarcinoma. Although the outcome of adenocarcinoma is poor, adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA), as newly defined in the WHO classification (4th edition),1 show more a favorable prognosis than invasive adenocarcinoma.3-5 Based on the clinical nature of lung adenocarcinoma, it is considered to show stepwise progression from atypical adenomatous hyperplasia (AAH) to AIS, MIA and lepidic adenocarcinoma.6
On the other hand, according to the Noguchi classification published in 1995, small adenocarcinomas measuring 2 cm or less in greatest dimension are classified into six types (Type A, B, C, D, E and F). Types A, B, and C small adenocarcinomas show lepidic growth, whereas types D, E, and F small adenocarcinomas show non‐lepidic growth.3 Although Types A, B, and C small adenocarcinomas show lepidic growth, the prognoses of patients with those tumors are different. The 5‐year survival rate of type A and B small adenocarcinoma is 100 %, on the other hand, the 5‐year survival rate of type C is 74.8%. Therefore, to elucidate the molecular mechanisms involved in early malignant progression of lung adenocarcinoma, our laboratory has focused on comparing AIS (type A small adenocarcinoma) with early but invasive adenocarcinoma (type C small adenocarcinoma). Using suppression subtractive hybridization (SSH) analysis, Ishiyama et al. have found that ovarian cancer immunoreactive antigen domain containing 2 (OCIAD2) is overexpressed in early but invasive adenocarcinoma (type C small adenocarcinoma) compared to AIS (type A small adenocarcinoma).7 OCIAD2 was identified in 2002 on the basis of its sequential similarity to OCIAD1 through the National Institutes of Health Mammalian Gene Collection Program8 and the N‐ terminal region of OCIAD2 and OCIAD1, especially, have a high degree of similarity.9 OCIAD2 is located on chromosome 4p11, consists of 154 amino acids, which is smaller than OCIAD1 (245 amino acids), and has 7 exons. OCIAD2 and OCIAD1 belong to the OCIA domain family and OCIAD2 is located next to OCIAD1. OCIAD1 was originally detected in ascites from ovarian carcinoma as a tumor‐specific and auto‐immunoreactive protein.10 OCIAD1 is thought to contribute to high metastatic potential11 and resistance to chemotherapy in ovarian cancer.12 However, the function of OCIAD2 in malignant tumors remains to be elucidated. Nagata et al. have reported that the expression of OCIAD2 in ovarian mucinous tumor increased during the course of malignant progression,13 and Nikas et al. have reported that OCIAD2 was overexpressed in gliomas that had a poor prognosis.14, 15 On the other hand, Honda et al. have reported that the methylation of OCIAD2 in hepatoblastoma was significantly associated with poorer prognosis,16 and Zhang et al. have reported that expression of OCIAD2 mRNA was significantly down‐regulated in hepatocellular carcinoma.17 To date, the role and function of OCIAD2 in tumors remain controversial.
In the present study, we examined the intracellular localization of OCIAD2 in a lung adenocarcinoma cell line and then investigated the clinicopathological implications of OCIAD2 expression in surgically resected lung adenocarcinomas.
MATERIALS AND METHODS
Immunofluorescence cytochemistry (IF)
The A549 human lung adenocarcinoma cell line was purchased from RIKEN Cell Bank (Ibaraki, Japan) and maintained in DMEM/F12 medium (Thermo Fisher Scientific, Waltham, MA, USA) supplemented with 10% fetal bovine serum.
A549 cells were seeded in 12‐well plates with coated cover slips (Iwaki Biosciences, Tokyo, Japan) and cultured for 48 h. The cells were then fixed with 10% neutral buffered formalin for 15 min at room temperature. After being thoroughly washed with PBS, the cells were blocked with blocking buffer. They were then incubated with primary antibodies (anti‐OCIAD2 antibody (1: 200, rabbit polyclonal, PA5‐20835, Thermo Fisher Scientific) and anti‐voltage‐dependent anion‐selective channel protein 1 (VDAC1) antibody (1:100, mouse monoclonal, ab14734, Abcam, Cambridge, UK) for 1 h at room temperature. After being thoroughly washed with PBS, the cells were incubated with anti‐rabbit IgG‐conjugated Alexa Fluor 568 secondary antibody and anti‐mouse antibody IgG‐conjugated Alexa Fluor 488 secondary antibody (Thermo Fisher Scientific) for 1 h at room temperature. Slides were mounted with fluorescent mounting medium containing 4′, 6‐diamidino‐2‐phenylindole (DAPI) (VECTASHIELD; Vector Laboratories, Burlingame, CA, USA) and analyzed using a fluorescence microscope (Biorevo BZ 9000; KEYENCE, Osaka, Japan).
Patients
We obtained specimens of lung adenocarcinomas that had been surgically resected and originally diagnosed as adenocarcinoma at the University of Tsukuba Hospital (Ibaraki, Japan) between 1999 and 2007. Tumor slides and blocks from 206 patients were available for histological evaluation and tissue microarray (TMA) construction. Clinical data for all of the corresponding patients were collected from the medical records. Informed consent for study of their materials was obtained from all of the patients. Tumors were classified according to the WHO classification of malignant tumors (4th edition)1 and the UICC TNM classification of malignant tumors (8th edition).18 Small adenocarcinomas measuring 2 cm or less in greatest dimension were also classified according to the Noguchi classification.3, 19 The results of immunohistochemistry for thyroid transcription factor‐1 (TTF‐1) and the epidermal growth factor receptor (EGFR) mutation profile were collected from a previous clinical database and were available for 191 patients and 37 patients, respectively.
Immunohistochemistry using tissue microarrays (TMAs)
Tissue microarrays were constructed from 15% formalin‐fixed and paraffin‐embedded blocks. Two representative tumor areas were marked on hematoxylin and eosin (H&E)‐stained slides. If they contained a non‐invasive area (lepidic component) and an invasive area, both areas were selected and used. If they contained only a non‐invasive area or an invasive area, we selected two representative areas for each block. Totally, TMAs were successfully constructed from 191 lung adenocarcinomas.
Immunohistochemistry was performed on the 3 µm‐thick sections prepared from TMAs. The sections were deparaffinized and rehydrated, then autoclaved in 10 mM citrate buffer (pH 6.0) at 121°C for 10 min for antigen retrieval. The slides were treated with Dako REAL Peroxidase‐Blocking Solution (Agilent Technologies, Santa Clara, CA, USA) for 5 min at room temperature to block any endogenous peroxidase activity. Immunohistochemical staining was performed with rabbit polyclonal anti‐OCIAD2 antibody diluted 1:400 (PA5‐20835; Thermo Fisher Scientific, Waltham, MA, USA) for 30 min at room temperature using HISTOSTAINER (Nichirei Biosciences, Tokyo, Japan). The slides were then incubated with secondary antibody (EnVison+Dual Link; Agilent Technologies) for 30 min at room temperature. Immunoreactivity was detected with DAB (Agilent Technologies) and the slides were counterstained with hematoxylin. Renal tubules were used as a positive control.
Evaluation of immunohistochemistry
Two pathologists (M.S. and S.S.) who were blinded to the patient clinical outcomes evaluated all cases independently. OCIAD2 expression was quantified using the H‐score, which is defined as the summed percentage of positively stained cells (0–100%) multiplied by a weighted intensity of staining.20 We made two TMA cores for each case and the H‐score of each core was recorded. Then, total H‐score was calculated as the average H‐score between the two TMA cores. The H‐score of each of the TMA cores is also used for comparison of the staining between invasive component and non‐invasive component. A cytoplasmic granular staining pattern in the tumor cells was judged as positive: 0, negative; 1+, negative at ×40 magnification but weakly positive at ×400 magnification; 2+, positive at ×40 magnification and partially positive in the cytoplasm at ×400 magnification; 3+, positive at ×40 magnification and diffusely positive in the cytoplasm at ×400 magnification (Fig. 1). The H‐score ranged from 0 to 300. Discrepancies between the two pathologists in assignment of the H‐score were later resolved by discussion.
Statistical analysis
Statistical analysis was performed using GraphPad Prism 6 (GraphPad software, San Diego, CA, USA) and SPSS Statistics version 24 (IBM, Armonk, NY, USA). Statistical significance was defined as P < 0.05. We used the H‐score for OCIAD2 and overall survival (OS) as variables for drawing the ROC curve. Correlations of clinicopathological features with the OCIAD2 H‐score were analyzed using the Chi‐squared test. Disease‐free survival (DFS) and OS were compared with the OCIAD2 H‐score using the Kaplan‐Meier curves and the log‐rank test was used to assess statistical significance. The influence of clinicopathological features and OCIAD2 H‐score on OS was assessed using univariate and multivariate Cox regression analysis. Associations of the OCIAD2 H‐score with EGFR mutation, the Noguchi classification, and the H‐score difference between non‐invasive area and invasive area were analyzed by unpaired t‐test. Associations of the OCIAD2 H‐score with various subtypes of lung adenocarcinoma were examined by one‐way analysis of variance.
RESULTS
Intracellular localization of OCIAD2 in tumor cells
Based on our preliminary data analysis through COMPARTMENTS database21 (http://compartments.jensenlab.org), OCIAD2 is thought to be localized in mitochondria. In addition, Han et al. have reported that OCIAD2 is localized in the mitochondria of HeLa cell.22 Therefore, we hypothesized that OCIAD2 is localized in mitochondria and examined the intracellular localization of OCIAD2 in lung adenocarcinoma. We carried out immunofluorescence cytochemistry of A549 cells using a mitochondrial marker, VDAC1. In A549 cells, OCIAD2 was mainly co‐localized with VDAC1, indicating that OCIAD2 is localized at mitochondria (Fig. 2).
OCIAD2 expression and clinicopathological features
To clarify the clinical implications of OCIAD2 protein expression, TMAs constructed with 191 surgically resected lung adenocarcinomas were examined by immunohistochemistry. Figure 3 shows a representative pathological image; Figure 3a (H&E staining) shows adenocarcinoma that is negative for OCIAD2 (Fig. 3b) and Fig. 3c (H&E staining) shows adenocarcinoma that is positive for OCIAD2 (Fig. 3d). OCIAD2 was detected in the cytoplasm of lung adenocarcinoma cells and showed a granular staining pattern (Fig. 3d). OCIAD2 was not stained (negative) in normal lung tissue. Based on our preliminary data analysis through the HUMAN PROTEIN ATLAS (http://www.proteinatlas.org/), kidney shows high OCIAD2 protein expression. Therefore, as mentioned above, we used renal tubules as a positive control. Expression of OCIAD2 was quantified using H‐score and the tumors were divided into a high or a low OCIAD2 expression group. The cut‐off point was determined by ROC curve (data not shown) and an H‐score 130 or more was judged as high OCIAD2 expression (n = 75) and less than 130 was judged as low OCIAD2 expression (n = 116).
First, we assessed the correlation between OCIAD2 expression and various clinicopathological features, including age, sex, smoking status, TTF‐1 positivity, pleural invasion, pulmonary metastasis, vascular invasion, lymphatic permeation, T factor (primary tumor), N factor (regional lymph node), and pathological stage (Table 1). This revealed that high expression of OCIAD2 protein was significantly correlated with vascular invasion (P = 0.0018), lymphatic permeation (P = 0.049), T factor (P = 0.0024), and pathological stage (P = 0.0003).
| Total | OCIAD2 Low | OCIAD2 High | P‐value | |
|---|---|---|---|---|
| Characteristic | n = 191 | n = 116 | n = 75 | |
| Age | 66.45 | 65.75 | 67.32 | 0.50 |
| Sex | 0.051 | |||
| Male | 113 | 62 | 51 | |
| Female | 78 | 54 | 24 | |
| Smoking | 0.07 | |||
| Non‐smoker | 74 | 51 | 23 | |
| Smoker | 117 | 65 | 52 | |
| TTF‐1 | 0.27 | |||
| Positive | 161 | 101 | 60 | |
| Negative | 30 | 15 | 15 | |
| Pleural invasion | 0.45 | |||
| pl0 | 123 | 79 | 44 | |
| pl1 | 35 | 19 | 16 | |
| pl2 | 17 | 8 | 9 | |
| pl3 | 16 | 10 | 6 | |
| Pulmonary metastasis | 0.22 | |||
| pm0 | 179 | 111 | 68 | |
| pm1 | 12 | 5 | 7 | |
| Vascular invasion | 0.0018** P < 0.05. |
|||
| v0 | 106 | 75 | 31 | |
| v1 | 85 | 41 | 44 | |
| Lymphatic permeation | 0.049** P < 0.05. |
|||
| ly0 | 114 | 76 | 38 | |
| ly1 | 77 | 40 | 37 | |
| T factor (primary tumor) | 0.0024** P < 0.05. |
|||
| Tis | 17 | 16 | 1 | |
| T1mi | 21 | 18 | 3 | |
| T1a | 6 | 4 | 2 | |
| T1b | 38 | 23 | 15 | |
| T1c | 14 | 9 | 5 | |
| T2a | 51 | 26 | 25 | |
| T2b | 12 | 5 | 7 | |
| T3 | 18 | 8 | 10 | |
| T4 | 14 | 7 | 7 | |
| N factor (regional lymph nodes) | 0.112 | |||
| N0 | 97 | 62 | 35 | |
| N1 | 23 | 9 | 14 | |
| N2 | 25 | 14 | 11 | |
| N3 | 1 | 0 | 1 | |
| NX | 45 | 31 | 14 | |
| Pathological stage | 0.0003** P < 0.05. |
|||
| 0 | 17 | 16 | 1 | |
| I | 80 | 55 | 25 | |
| II | 62 | 30 | 32 | |
| III | 18 | 8 | 10 | |
| IV | 14 | 7 | 7 |
- * P < 0.05.
OCIAD2 expression and various subtypes of lung adenocarcinoma
Among small adenocarcinomas measuring 2 cm or less in the greatest dimension classified according to the Noguchi classification (n = 79), type D, E, and F small adenocarcinoma (invasive adenocarcinoma, n = 26) showed significantly higher OCIAD2 expression than type A, B, C’ and C small adenocarcinoma (non‐invasive adenocarcinoma, MIA, and lepidic adenocarcinoma, n = 53) (P = 0.0007) (Fig. 4a).
Among several histological subtypes of lung adenocarcinoma, AIS (n = 16) showed significantly lower OCIAD2 expression than papillary adenocarcinoma (n = 30) (P < 0.05), acinar adenocarcinoma (n = 23) (P < 0.05), solid adenocarcinoma (n = 39) (P < 0.05), and invasive mucinous adenocarcinoma (IMA; n = 19) (P < 0.05) (Fig. 4b). MIA (n = 22) showed significantly lower OCIAD2 expression than papillary adenocarcinoma (n = 30) and solid adenocarcinoma (n = 39) (P < 0.05). Lepidic adenocarcinoma showed significantly lower OCIAD2 expression than papillary adenocarcinoma (n = 30) and solid adenocarcinoma (n = 39). There were no significant differences in OCIAD2 expression among invasive adenocarcinomas excluding lepidic adenocarcinoma. The H‐score for OCIAD2 are from low to high in the order of AIS, MIA, and lepidic adenocarcinoma. IMAs with high OCIAD2 expression (n = 10) were significantly more advanced stage than those with low OCIAD2 expression (n = 9, P = 0.0409) (Fig. 4c).
We then selected lung adenocarcinomas based on EGFR mutation analysis (n = 37) and examined the relationship between OCIAD2 expression and EGFR mutation status. All cases were positive for TTF‐1, and adenocarcinomas harboring EGFR mutation (n = 10) showed significantly higher OCIAD2 expression than those with EGFR wild‐type (n = 27, P = 0.0403) (Fig. 4d).
OCIAD2 expression and prognosis
To investigate the clinical implications of OCIAD2 expression, we examined the relationship between OCIAD2 expression and patient outcome. In all lung adenocarcinoma patients (n = 191), a high OCIAD2 expression group showed significantly poorer OS than a low OCIAD2 expression group (P = 0.0325, Fig. 5a). However, there was no significant difference in DFS between the high OCIAD2 expression group and the low OCIAD2 expression group (P = 0.21, Fig. 5b). Ishiyama et al. studied OCIAD2 by using type A and type C small lung adenocarcinoma7 and these tumors are invariably positive for TTF‐1 since they contain lepidic components,23 therefore, we also examined correlation between OCIAD2 expression and prognosis in lung adenocarcinoma based on TTF‐1 positivity. In patients with TTF‐1‐positive lung adenocarcinoma (n = 161), high OCIAD2 expression was significantly associated with poorer OS (P = 0.0152) and DFS (P = 0.0496) (Fig. 5c, d). Analysis of Stage I adenocarcinoma didn't show significant difference in OS between the high OCIAD2 expression group and low expression group (P = 0.12), and multivariate analysis didn't show significant difference between H‐score and prognosis (Table S1).
Intratumoral heterogenity of OCIAD2 expression
As described above, levels of OCIAD2 expression differed among histological subtypes, especially between lepidic (non‐invasive) areas and non‐lepidic (invasive) areas. As the TMAs were constructed from both lepidic and non‐lepidic areas, when tumors contained both areas, we compared the levels of OCIAD2 expression between them (34 cases in total). Figure 6a shows three representative histological images. OCIAD2 tended to be positive in invasive areas (Fig. 6a, lower), on the other hand, negative in non‐invasive areas (Fig. 6a, upper). H‐score of invasive area was significantly higher than that of non‐invasive area (Fig. 6b, P < 0.0001).
DISCUSSION
In this study, we initially examined the intracellular localization of OCIAD2 in the lung adenocarcinoma cell line A549 by staining both OCIAD2 and the mitochondrial marker protein, VDAC1. Both proteins were found to be co‐localized, as shown in Figure 2. This indicated that OCIAD2 is localized at mitochondria in the cytoplasm and this expectation satisfied the granular staining pattern of OCIAD2 in resected lung adenocarcinomas (Fig. 3).
Originally, Ishiyama et al. compared the expression profiles of AIS (Type A according to Noguchi classification) with those of early but invasive adenocarcinoma (Type C according to Noguchi classification)7 and found that OCIAD2 expression was significantly higher in type C than in type A tumors. Here, we showed that OCIAD2 expression was correlated with various clinicopathological factors, such as vascular invasion, lymphatic permeation, tumor size (T factor), and pathological stage (Table 1). These results are in accord with the conclusion by Ishiyama et al.
We also examined the prognostic implications of OCIAD2 in lung adenocarcinoma and found that high OCIAD2 protein expression was correlated with poor prognosis (Fig. 5). In particular, high OCIAD2 expression in TTF‐1‐positive adenocarcinoma was significantly associated with both poorer DFS and OS. According to previous reports, approximately 75% of invasive adenocarcinomas show positive TTF‐1 staining.23 Among various adenocarcinoma growth patterns, the lepidic and papillary pattern tend to be positive for TTF‐1, whereas the solid component is less likely to be positive for TTF‐1. In addition, mucinous bronchioloalveolar carcinoma, which is consider to be classified as invasive mucinous adenocarcinoma according to the latest WHO classification,1 show a lack of TTF‐1 expression.24 Type C and Type A adenocarcinoma which were examined by Ishiyama et al. have lepidic components and those tumors are not invasive mucinous adenocarcinoma, therefore, we also analyzed TTF‐1 positive adenocarcinoma. To date, only three reports have indicated that high OCIAD2 expression is associated with poorer prognosis in patients with ovarian mucinous tumor13 and glioma.14, 15 On the other hand, two studies have found that low expression of OCIAD2 was correlated with poorer outcome in patients with hepatocellular carcinoma and hepatoblastoma.16, 17 These findings overall suggest that the association between the expression level of OCIAD2 and prognosis might vary among tumors originating from different organs.
Ishiyama et al. also examined the expression of OCIAD2 in resected lung adenocarcinomas using in situ hybridization and reported that expression of OCIAD2 mRNA was associated with better prognosis in lung adenocarcinoma. This conclusion is different from our study. This discrepancy could be interpreted by several causes. First, the number of cases analyzed by Ishiyama et al. (56 cases) was limited in comparison to the present study, and all of the cases they examined were adenocarcinomas with a BAC (lepidic) component. Therefore, the background of the examined cases would have differed. Secondly, we examined the expression of OCIAD2 protein using immunohistochemistry, whereas Ishiyama et al. examined the expression of mRNA using in situ hybridization. It is possible that OCAID2 protein might be modified after translation. Thirdly, we examined various histological subtypes, such as papillary, acinar, solid, micropapillary, and invasive mucinous adenocarcinomas, which showed high OCIAD2 expression, whereas Ishiyama et al. examined a very limited group of adenocarcinomas that had a BAC (lepidic) component, as mentioned above. In other words, they did not examine Noguchi classification type D, E, and F small adenocarcinomas.
Interestingly, lung adenocarcinomas including both invasive and non‐invasive areas showed heterogeneous immunoexpression of OCIAD2 (Fig. 6). OCIAD2 expression was significantly higher in invasive area than in non‐invasive area (Fig. 6). Moreover, invasive adenocarcinomas excluding lepidic adenocarcinoma showed higher OCIAD2 expression in comparison to AIS and MIA (Fig. 4b). Two possible explanations for these results can be suggested. One is that OCIAD2 overexpression is not a genetic event but rather represents a phenotypic change from the course of sequential progression in lung adenocarcinoma. The other is that the heterogeneity of OCIAD2 expression between the in situ component and the invasive area is due to a genetic abnormality which usually occurs in the course of malignant progression from lepidic adenocarcinoma to other invasive forms. A molecular biological approach will be needed to examine abnormal OCIAD2 expression in future study.
It is also interesting that lung adenocarcinomas harboring EGFR mutation showed higher expression of OCIAD2 than those with EGFR wild‐type (Fig. 4d). Recently, Sinha et al. reported that OCIAD2 regulates signal transducer and activator of transcription 3 (STAT3) activation in HEK293 cells overexpressing OCIAD2.9 STAT3 is involved in the downstream pathway of EGFR.25 In addition, it has been reported that STAT3 is a critical mediator of the oncogenic effects caused by EGFR mutations.26 Greulich et al. reported that in lung cancer cells, STAT3 is activated by various kinds of EGFR mutations and STAT3 may contribute to oncogenic effects.27 Even though the number is limited, the finding that OCIAD2 expression is higher in lung adenocarcinoma harboring EGFR mutations might indicate that OCIAD2 is associated with STAT 3 activation and the mechanism will be investigated in the future. We also showed that IMAs with high OCIAD2 expression showed a significantly more advanced stage than IMAs with low OCIAD2 expression (Fig. 4c). These results suggest that the function of OCIAD2 might vary among lung adenocarcinomas based on gene alterations and subtypes.
Our study has demonstrated that high OCIAD2 expression is associated with poor prognosis in lung adenocarcinoma and the level of OCIAD2 expression increases during the course of sequential progression from in situ adenocarcinoma to invasive adenocarcinoma. OCIAD2 expression is associated with outcome, especially in patients with TTF‐1‐positive lung adenocarcinomas. OCIAD2 expression may be a useful biomarker of lung adenocarcinoma.
DISCLOSURE STATEMENT
None declared.
AUTHOR CONTRIBUTION
All authors have contributed significantly, and that all authors are in agreement with the content of the manuscript.
ACKNOWLEDGMENT
This work was supported by JSPS KAKENHI Grant Number JP 17K08715.
