Molecular Diagnosis of MACC1 Status in Lung Adenocarcinoma by Immunohistochemical Analysis

Background: Recently, we reported that overexpression of metastasis-associated colon cancer-1 (MACC1) mRNA may be a useful marker for predicting postoperative recurrence in patients with lung adenocarcinoma following surgery. However, the biological significance of mRNA overexpression is difficult to determine and is not widely used because mRNA expression analysis is relatively expensive and time- and labor-intensive. On the other hand, immunohistochemical (IHC) staining is easy to perform, well- established, inexpensive, and is a useful method which can be routinely applied in solid tumor diagnosis in clinical laboratories. Patients and Methods: Tumor specimens were collected from 197 consecutive patients who underwent a complete resection for lung adenocarcinoma from 1998 to 2007. We analyzed the MACC1 status of the primary lung adenocarcinoma by IHC analysis. Results: The average postoperative observation period was 46.7 months. Forty (20.3%) of the 197 patients developed recurrences after surgery. Positive expression of MACC1 was identified in 129 (65.5%) patients. Furthermore, MACC1 IHC was positive in 33 (82.5%) out of the 40 patients and 96 (61.1%) out of the 157 patients, with and without recurrence, respectively (p=0.011). Both univariate and multivariate logistic regression models indicated that positive staining for MACC1 was an independent factor for tumor recurrence. Furthermore, positive staining for MACC1 was associated with poorer disease-free survival (DFS), according to the univariate survival analysis (p=0.080). Conclusion: Positive staining for MACC1 expression in resected specimens was associated with a poorer DFS. Therefore, positive staining of IHC for MACC1 may be a useful marker for predicting postoperative recurrence in patients with lung adenocarcinoma following surgery. There are two important issues regarding surgery as a main method used to cure cancer. One is to define the treatment indications for patients who are unlikely to develop a recurrence. The other is the selection of the type of adjuvant chemotherapy for tumors with micrometastasis and to identify the patients who might benefit most from postoperative adjuvant chemotherapy. These criteria would not only precisely select the patients who require additional treatment, but would also prevent the induction of adverse events in patients who do not require treatment. Therefore, predictive biomarkers for recurrence are urgently needed to help in patient treatment decisions. Since non-small cell lung cancer (NSCLC) is a heterogeneous disease with significant variability in prognosis and individual response to treatment (2), it is important to evaluate the biological and molecular characteristics of each tumor in order to identify the factors related to recurrence following surgery. However, no useful markers that can predict clinical recurrence exist at present. The MACC1 gene was identified by differential display RT- PCR by analyzing the colon mucosa, primary tumors, and metastatic lesions of patients with colorectal cancer (CRCs) (3). MACC1 expression was reported to be a predictor of tumor growth, invasion, metastasis, and tumor recurrence in patients with colon cancer (4). Lung adenocarcinoma appears to be similar to CRC from the standpoint of histological type and carcinogenesis. We therefore hypothesized that MACC1 may also be a useful prognostic indicator of tumor recurrence in patients following lung adenocarcinoma resection, and that overexpression of MACC1 mRNA may be a useful marker for predicting postoperative recurrence in patients with lung adenocarcinoma following surgery (1). However, the biological significance of mRNA overexpression is unclear and the evaluation of mRNA expression is not widely performed in the clinical setting due to its high cost and time- and labor-intense