Circulating MACC1 Transcripts in Colorectal Cancer Patient Plasma Predict Metastasis and Prognosis

et al. (2012) Circulating MACC1 Transcripts in Colorectal Cancer Patient Plasma Predict Metastasis and Prognosis. PLoS ONE 7(11): e49249. doi:10.1371/journal.pone.0049249 Circulating MACC1 Transcripts in Colorectal Cancer Patient Plasma Predict Metastasis and Prognosis Ulrike Stein 0 Susen Burock 0 Pia Herrmann 0 Ina Wendler 0 Markus Niederstrasser 0 Klaus- 0 Dieter Wernecke 0 Peter M. Schlag 0 Hassan Brim, Howard University, United States of America 0 1 Experimental and Clinical Research Center, Charite University Medicine Berlin, at the Max-Delbru ck-Center for Molecular Medicine , Berlin, Germany , 2 Charite Comprehensive Cancer Center , Berlin, Germany , 3 Institute of Medical Biometry, Charite University Medicine Berlin , Berlin , Germany Background: Metastasis is the most frequent cause of treatment failure and death in colorectal cancer. Early detection of tumors and metastases is crucial for improving treatment strategies and patient outcome. Development of reliable biomarkers and simple tests routinely applicable in the clinic for detection, prognostication, and therapy monitoring is of special interest. We recently identified the novel gene Metastasis-Associated in Colon Cancer 1 (MACC1), a key regulator of the HGF/Met-pathway. MACC1 is a strong prognostic biomarker for colon cancer metastasis and allows identification of high-risk subjects in early stages, when determined in patients' primary tumors. To overcome the limitation of a restricted number of molecular analyses in tumor tissue, the establishment of a non-invasive blood test for early identification of highrisk cancer patients, for monitoring disease course and therapy response is strongly needed. Methodology/Principal Findings: For the first time, we describe a non-invasive assay for quantification of circulating MACC1 transcripts in blood of more than 300 colorectal cancer patients. MACC1 transcript levels are increased in all disease stages of the cancer patients compared to tumor-free volunteers. Highest MACC1 levels were determined in individuals with metastases (all P,0.05). Importantly, high MACC1 levels correlate with unfavorable survival (P,.0001). Combining MACC1 with circulating transcripts of the metastasis gene S100A4, a transcriptional target of the Wnt/b-catenin-pathway, improves survival prediction for newly diagnosed cancer patients. Conclusion/Significance: This blood-based assay for circulating MACC1 transcripts, which can be quantitated on a routine basis, is clinically applicable for diagnosis, prognosis, and therapeutic monitoring of cancer patients. Here we demonstrate the diagnostic and prognostic value of circulating MACC1 transcripts in patient plasma for metastasis and survival. Since MACC1 represents a promising target for anti-metastatic therapies, circulating MACC1 transcripts may prove to be an ideal read-out for monitoring therapeutic response of future interventions targeting MACC1-induced metastasis in cancer patients. - Metastasis is the most frequent cause of treatment failure and death in colorectal cancer. Early detection of tumors and metastases is crucial for improving treatment strategies and patient outcome. Development of reliable biomarkers and simple tests that are routinely applicable in the clinic for detection, prognostication, and therapy monitoring is of special interest. We recently identified the novel gene Metastasis-Associated in Colon Cancer 1 (MACC1) [13]. MACC1 is a new prognostic biomarker for colon cancer metastasis and metastasis-free survival when determined in patients primary tumors. MACC1 levels in the primary tumors were found to be significantly higher in cancers that metachronously developed distant metastases compared to those which did not metastasize within a 12-year followup. The predictive value of the biomarker on whether a tumor will metastasize or not was 74% and 80% respectively. The 5-yearsurvival rate was 80% for patients with low MACC1, compared to 15% for patients with high MACC1 expression in their primary tumors. MACC1 is a predictor for colorectal cancer metastasis independent of tumor stage, age, sex, tumor infiltration, nodal status and lymph vessel invasion, and thus allows identification of subjects at high risk for metastasis in early stages [1]. This makes MACC1 an important prognostic gene in clinical practice. Furthermore, we found that MACC1 acts a key regulator of the HGF (hepatocyte growth factor)/Met-pathway, which is crucial in colorectal cancer for tumor progression and metastasis formation [1,2,4]. Several groups confirmed meanwhile a correlation of high MACC1 expression in the tumor to progression, metastasis, survival, and therapy response in colorectal cancer (CRC) [59]. The role of MACC1 as a biomarker for cancer progression and survival was meanwhile also reported for other solid cancers, such as gastric [10], lung [11,12], hepatocellular [13,14] and ovarian cancer [15]. Molecular analyses in tumor tissue, e.g. needed for disease prognosis in the context of metastasis formation and survival, are limited to a restricted number of available tissue samples. To overcome this limitation, the establishment of a non-invasive MACC1-based blood test for early identification of high risk cancer patients and for monitoring of the disease course as well as of therapy response is therefore strongly needed. Here, for the first time, we developed a non-invasive assay for MACC1 transcript levels in plasma. We analyzed the diagnostic value of MACC1 levels for detection of tumors and metastases in colon and rectal cancer patients, and its prognostic value for overall survival (survival) of these patients. Furthermore, we evaluated the benefit of combining MACC1 with a further metastasis gene, S100A4, for improved prediction of disease prognosis [1618]. Materials and Methods Objective The metastasis-inducing gene MACC1 is a strong prognostic biomarker for colon cancer metastasis and allows identification of high-risk subjects in early stages, when determined in patients primary tumors. To overcome the limitation of a restricted number of molecular analyses in tumor tissue, we aimed at the establishment of a non-invasive MACC1-based blood test for early identification of high risk cancer patients and for monitoring the disease course. Participants For colon and rectal cancer patients characteristics see Tables 1, 2, 3. Consecutive patients with colon or rectal cancer who were seen at the Robert Rossle Cancer Hospital, Charite University Medicine Berlin, during 2006 until 2007 for inpatient or outpatient care and who gave their written informed consent to take part in our tumor biobank were enrolled. Patients data for histopathological characterization of the tumor (including tumor infiltration, lymph node status, metastasis, grading, lymphatic vessels infiltration, blood vessels infiltration, residual tumor), for treatment and survival were available from the tumor bank of the Charite Comprehensive (...truncated)