Mutations of key driver genes in colorectal cancer progression and metastasis

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.

SSRP1 promotes colorectal cancer progression and is negatively regulated by miR‐28‐5p

“…1 CRC is often diagnosed at an advanced stage, is accompanied by metastasis, which is negatively correlated with patient survival, and CRC remains incurable. [2][3][4] Therefore, the discovery of new diagnostic and prognostic markers and a better understanding of the molecular mechanisms of colorectal tumorigenesis and metastasis are urgently needed.…”

Clinical Implication of Concordant or Discordant Genomic Profiling between Primary and Matched Metastatic Tissues in Patients with Colorectal Cancer

“…Indeed, the accumulation of molecular alterations of these key driver genes plays a crucial role in the tumorigenesis and progression of CRC. However, it remains controversial, as previous studies usually rely on a limited sample of cancer tissue that cannot represent heterogeneity between and within patients [18]. This study is an integrated analysis of intra-tumor and inter-tumor heterogeneity.…”

Exploiting DNA repair defects in colorectal cancer

“…The other 84% of cases were classified as microsatellite stable (MSS) and exhibited a higher frequency of somatic copy number alterations, suggesting chromosomal and subchromosomal defects (Network, 2012). The most frequently identified gene mutations in CRC tumors occur in APC, TP53, and KRAS (Huang et al, 2018;Wolff et al, 2018;Yaeger et al, 2018). Recent analysis of TCGA data identified mutations associated with DNA damage response genes and found that cases in the colon adenocarcinoma (COAD) and rectal adenocarcinoma (READ) datasets carried mutations in several DNA damage response and repair (DDR) genes (Knijnenburg et al, 2018).…”