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SNPs in the coding region of the metastasis-inducing gene MACC1 and clinical outcome in colorectal cancer

Felicitas Schmid1, Susen Burock2, Konrad Klockmeier3, Peter M Schlag24 and Ulrike Stein4*

Author Affiliations

1 Max-Delbrück-Center for Molecular Medicine, Berlin, Robert-Rössle-Straße 10, 13125, Berlin, Germany

2 Charité Comprehensive Cancer Center, Berlin, Invalidenstraße 80, 10117, Berlin, Germany

3 Free University Berlin, Kaiserswerther Str. 16-18, 14195, Berlin, Germany

4 Experimental and Clinical Research Center, a joint cooperation between the Charité Medical Faculty and the Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Straße 10, 13125, Berlin, Germany

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Molecular Cancer 2012, 11:49  doi:10.1186/1476-4598-11-49

Published: 29 July 2012

Abstract

Background

Colorectal cancer is one of the main cancers in the Western world. About 90% of the deaths arise from formation of distant metastasis. The expression of the newly identified gene metastasis associated in colon cancer 1 (MACC1) is a prognostic indicator for colon cancer metastasis. Here, we analyzed for the first time the impact of single nucleotide polymorphisms (SNPs) in the coding region of MACC1 for clinical outcome of colorectal cancer patients. Additionally, we screened met proto-oncogene (Met), the transcriptional target gene of MACC1, for mutations.

Methods

We sequenced the coding exons of MACC1 in 154 colorectal tumors (stages I, II and III) and the crucial exons of Met in 60 colorectal tumors (stages I, II and III). We analyzed the association of MACC1 polymorphisms with clinical data, including metachronous metastasis, UICC stages, tumor invasion, lymph node metastasis and patients’ survival (n = 154, stages I, II and III). Furthermore, we performed biological assays in order to evaluate the functional impact of MACC1 SNPs on the motility of colorectal cancer cells.

Results

We genotyped three MACC1 SNPs in the coding region. Thirteen % of the tumors had the genotype cg (rs4721888, L31V), 48% a ct genotype (rs975263, S515L) and 84% a gc or cc genotype (rs3735615, R804T). We found no association of these SNPs with clinicopathological parameters or with patients’ survival, when analyzing the entire patients’ cohort. An increased risk for a shorter metastasis-free survival of patients with a ct genotype (rs975263) was observed in younger colon cancer patients with stage I or II (P = 0.041, n = 18). In cell culture, MACC1 SNPs did not affect MACC1-induced cell motility and proliferation.

Conclusion

In summary, the identification of coding MACC1 SNPs in primary colorectal tumors does not improve the prediction for metastasis formation or for patients’ survival compared to MACC1 expression analysis alone. The ct genotype (rs975263) might be associated with a reduced survival for younger colon cancer patients in early stages. However, further studies with larger sample sizes are needed.

Keywords:
Colorectal cancer; Metastasis; MACC1; Single nucleotide polymorphisms