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Mutations of key driver genes in colorectal cancer progression and metastasis

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Abstract

The association between mutations of key driver genes and colorectal cancer (CRC) metastasis has been investigated by many studies. However, the results of these studies have been contradictory. Here, we perform a comprehensive analysis to screen key driver genes from the TCGA database and validate the roles of these mutations in CRC metastasis. Using bioinformatics analysis, we identified six key driver genes, namely APC, KRAS, BRAF, PIK3CA, SMAD4 and p53. Through a systematic search, 120 articles published by November 30, 2017, were included, which all showed roles for these gene mutations in CRC metastasis. A meta-analysis showed that KRAS mutations (combined OR 1.18, 95% CI 1.05–1.33) and p53 mutations (combined OR 1.49, 95% CI 1.23–1.80) were associated with CRC metastasis, including lymphatic and distant metastases. Moreover, CRC patients with a KRAS mutation (combined OR 1.29, 95% CI 1.13–1.47), p53 mutation (combined OR 1.35, 95% CI 1.06–1.72) or SMAD4 mutation (combined OR 2.04, 95% CI 1.41–2.95) were at a higher risk of distant metastasis. Subgroup analysis stratified by ethnic populations indicated that the BRAF mutation was related to CRC metastasis (combined OR 1.42, 95% CI 1.18–1.71) and distant metastasis (combined OR 1.51, 95% CI 1.20–1.91) in an Asian population. No significant association was found between mutations of APC or PIK3CA and CRC metastasis. In conclusion, mutations of KRAS, p53, SMAD4 and BRAF play significant roles in CRC metastasis and may be both potential biomarkers of CRC metastasis as well as therapeutic targets.

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Acknowledgments

The authors thank Prof. Pengyuan Liu (Zhejiang University), an expert bio-statistician, for reviewing the analysis portion of the manuscript.

Funding

This work is supported by the National Natural Science Foundation of China (81672730 to H.Z. and 81572716 to M.L.), the Fundamental Research Funds for the Central Universities (2017FZA7005 to H.Z.), the Natural Science Foundation of Zhejiang Province (LY17H160025 to E.X.) and the Department of Science and Technology of Zhejiang Province (2016C33150 to E.X.)

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Authors and Affiliations

Authors

Contributions

H.Z. and Y.W. contributed to the conception and design of the study. D.H., W.S. and Y.Z. contributed to the conception, design of the study and editing of the manuscript. D.H., Y.Z., P.L., F.C., H.C. and D.X. contributed to the statistical analysis. E.X. and M.L. contributed to the analysis and interpretation of data. All of the authors commented on drafts of the paper and approved the final draft of the manuscript.

Corresponding authors

Correspondence to Yihua Wu or Honghe Zhang.

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Competing interests

The authors declare that they have no conflicts of interest.

Electronic supplementary material

Fig. S1

Forest plots of APC. (A) Forest plots of the association between APC mutations and CRC metastasis, including lymphatic and distant metastases. No association was found between APC mutations and CRC metastasis. (B) Forest plots of the association between APC mutations and CRC distant metastasis. No association was found between APC mutations and CRC distant metastasis. (GIF 168 kb)

High resolution image (TIFF 14235 kb)

Fig. S2

Forest plots of the association between BRAF mutations and CRC metastasis, including lymphatic and distant metastases. No association was found between BRAF mutations and CRC metastasis. (GIF 185 kb)

High resolution image (TIFF 13708 kb)

Fig. S3

Forest plots of the association between BRAF mutations and CRC distant metastasis. No association was found between BRAF mutations and CRC distant metastasis. (GIF 164 kb)

High resolution image (TIFF 12263 kb)

Fig. S4

Forest plots of PIK3CA. (A) Forest plots of the association between PIK3CA mutation and CRC metastasis, including lymphatic and distant metastases. No association was found between PIK3CA mutations and CRC metastasis. (B) Forest plots of the association between PIK3CA mutations and CRC distant metastasis. No association was found between PIK3CA mutations and CRC distant metastasis. (GIF 203 kb)

High resolution image (TIFF 16923 kb)

Fig. S5

Funnel plots for the relationship between 6 genes and CRC metastasis in the current study. (GIF 93 kb)

High resolution image (TIFF 13419 kb)

Table S1

The results of key driver gene screening. (XLSX 9 kb)

Table S2

The results of the Begg’s test for the included studies of each gene. (XLSX 12 kb)

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Huang, D., Sun, W., Zhou, Y. et al. Mutations of key driver genes in colorectal cancer progression and metastasis. Cancer Metastasis Rev 37, 173–187 (2018). https://doi.org/10.1007/s10555-017-9726-5

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  • DOI: https://doi.org/10.1007/s10555-017-9726-5

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