Abstract #LB-254: SHOX2, a novel biomarker for the detection of lung cancer in bronchial fluid
Authors: John Field, Volker Liebenberg, Dimo Dietrich, Triantafillos Liloglou, Olaide Raji, Martin Walshaw, Thomas Schlegel, Christoph Kneip, Juergen Distler, Reimo Tetzner, Anke Seegebarth, Sabine Weickmann, Christian Witt, Michael Fleischhacker, Bernd Schmidt
Journal: Cancer Research (2009)

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

The workup of patients with suspected lung cancer aims to establish a definitive diagnosis with the least invasive diagnostic procedures. Confirming malignancy often remains a challenge, because the tumor may not be accessible for biopsy by bronchoscopy and cytology is inconclusive. This potentially triggers additional diagnostic procedures bearing risks for the patient and eventually causing a delay in diagnosis. This retrospective clinical study aims to demonstrate that a recently developed Heavy Methyl (HM) sensitive detection methylation assay of the SHOX2 gene can be translated into clinical practice as a marker to diagnose bronchial carcinoma in patients undergoing workup for suspected lung cancer. 423 patients with suspected lung cancer consisting of 237 lung cancer Cases and 186 Controls with benign lung disease had flexible bronchoscopy with bronchial lavage specimens taken from suspicious regions. 272 Saccomanno fixed bronchial lavage samples (160 cases and 112 Controls with more than 12 months of cancer free survival) were provided by the Liverpool Lung Project, UK. 151 fresh frozen lavage sediments showing inconclusive or negative cytology results were collected at the Charite, Berlin. Accurate methylation quantification was carried out measuring the total and the methylated copies of the SHOX2 locus, respectively. A calibrator, a DNA sample with known methylation, was used in order to normalize for lot-to-lot and site-to-site variability and therefore to allow for routine clinical usage of the test. The same methylation cut-point, which was established in a previous study, was used for accurate classification of single patients and applied to all measurements. Patients showing methylation above the cut-point were called SHOX2 methylation positive. Results 75% (63/84) of patients with squamous cell lung cancer were found to be SHOX2 methylation positive at a specificity of 99% (2/186). The stage specific analysis of these patients showed a sensitivity of 70%, 89% and 76% for stage (UICC) I, II, III respectively. The sensitivity for all lung carcinomas (84 squamous-, 98 adeno-, 12 SCLC and 43 other types) resulted in 59% sensitivity at 99% specificity. Conclusion The described Heavy Methyl (HM) sensitive detection assay measuring methylation of the SHOX2 gene holds great potential as a diagnostic tool in the workup of patients with suspected lung cancer. This study has demonstrated the feasibility of utilizing SHOX2 as a diagnostic test especially for individuals with squamous cell lung carcinoma. Predominantly when histology and cytology following bronchoscopy are inconclusive, the assay can simplify and speed up the diagnostic process by identifying patients with malignant lung disease without requiring additional invasive procedures. This assay may facilitate earlier diagnosis of lung cancer at a stage in which cure rates are higher. We plan to further validate this biomarker in a prospective clinical trial.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr LB-254.