The role of SHP-1 promoter 2 hypermethylation detection of lymph node micrometastasis in resectable stage I non-small cell lung cancer as a prognostic marker of disease recurrence

Abstract

Despite adequate surgical management of stage I non-small cell lung cancer (NSCLC), many patients still relapse. Nodal micrometastases which cannot be detected by the standard hematoxylin and eosin (H&E) method are the postulated mechanism. We conducted a study of an epithelial-specific methylation marker, SHP-1 promoter 2 (SHP1P2) methylation, as a potential molecular marker to determine its association with a high risk of disease relapse. Lymph nodes from stage II-IIIA NSCLC patients were examined to explore the potential role of SHP1P2 methylation in detecting metastatic carcinoma according to H&E staining. Further study was done in lymph nodes from stage I NSCLC patients who underwent curative resection and follow-up at The King Chulalongkorn Memorial Hospital, Bangkok, Thailand. No adjuvant treatment was given, according to the standard treatment in that stage. Patients who relapsed within 40 months after resection were defined as high risk. The nodal SHP1P2 methylation level from stage II-IIIA NSCLC patients was significantly higher in the metastasis group, median 674 [0-3536] ng, compared with the no metastasis group, median 230 [0-3832] ng (p = 0.004). One-hundred and ninety-eight lymph nodes from stage I NSCLC patients were analyzed, including hilar and mediastinal nodes. With a median follow-up period of 65 [46-109] months, high SHP1P2 methylation levels of more than 140 ng in hilar lymph nodes were associated with early relapse, with sensitivity and specificity of 85 and 54 %, respectively (hazard ratio 5.3; 95 % confidence interval 5.0-5.6; p < 0.0001). A high level of SHP1P2 methylation of hilar lymph nodes from stage I NSCLC patients is associated with early relapse of disease.