Abstract
BackgroundMetastasis 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 high-risk cancer patients, for monitoring disease course and therapy response is strongly needed.Methodology/Principal FindingsFor 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/β-catenin-pathway, improves survival prediction for newly diagnosed cancer patients.Conclusion/SignificanceThis 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.
Highlights
Metastasis is the most frequent cause of treatment failure and death in colorectal cancer
Conclusion/Significance: This blood-based assay for circulating Metastasis-Associated in Colon Cancer 1 (MACC1) transcripts, which can be quantitated on a routine basis, is clinically applicable for diagnosis, prognosis, and therapeutic monitoring of cancer patients
To define the diagnostic value of circulating MACC1 transcripts in plasma, sensitivity and specificity were calculated with a fourfold table for colorectal cancer, colon, and rectal cancer patients, who were newly diagnosed with a primary tumor without or with synchronous metastases compared to the blood samples of 54 tumor-free volunteers
Summary
Metastasis is the most frequent cause of treatment failure and death in colorectal cancer. MACC1 is a new prognostic biomarker for colon cancer metastasis and metastasis-free survival when determined in patients’ 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 allows identification of subjects at high risk for metastasis in early stages [1]. This makes MACC1 an important prognostic gene in clinical practice. 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
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