Expression but not genetic variations of the MTDH gene is correlated to clinical outcome of colorectal cancer patients

Objective: Colorectal cancer (CRC) is the third most common cancer in men and the second in women worldwide. The therapy of CRC has been critically improved during the past two decades, but the treatment response varies significantly between different treatments and patients. Therefore it is necessary to search for biomarkers related to more suitable prognosis and treatment. Metadherin (MTDH; MIM#610323), also called Astrocyte elevated gene 1 (AEG-1), is located at chromosome 8q22 and involved in carcinogenesis. Amplification of loci 8q22 has been shown in CRC and other malignancies. MTDH protein is markedly overexpressed in many types of cancers.The MTDH polymorphisms have been related to breast or ovarian cancer susceptibility.The aim of this study was to analyze MTDH genetic alterations and ex­pression and relationship to clinicopathological variables in CRC.

Methods: We analysed variants and expres­sion of MTDH by direct sequencing, qPCR, and/ or immunohistochemistry in 593 CRC tumors (including 158 rectal cancer patients from the Swedish clinical trial of preoperative radiotherapy (preRT)).

Results: We described 29 novel exonic/ intronic variants in the MTDH gene. 4/8 exonic variants were assessed pathogenic (in silico). MTDH mRNA and protein was up-regulated in primary tumors and metastases compared with normal mucosa (p < 0,006). In rectal cancer patients from the Swedish trial of preRT, high MTDH expression correspond with higher risk of distant recurrence and disease-free survival (p = 0,009, p = 0,007 respectively) only in pa­tients receiving preoperative RT, independently of the tumor stage.

Conclusion: Expression of MTDH is an inde­pendent prognostic factorfor distant recurrence and disease-free survival in rectal cancer patients after treatment with preoperative RT. We did not find prognostic or predictive value of the MTDH genetic variants in CRC.

The study was supported by grants from the Swedish Cancer Foundation, Swedish Research Council, the Health Research Council in South-East Sweden, and the LiU cancer network.