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Review
. 2021 Mar 17;10(3):667.
doi: 10.3390/cells10030667.

Recent Updates on the Significance of KRAS Mutations in Colorectal Cancer Biology

Loretta László  1 , Anita Kurilla  1 , Tamás Takács  1 , Gyöngyi Kudlik  1 , Kitti Koprivanacz  1 , László Buday  1   2 , Virag Vas  1
Affiliations
Review

Recent Updates on the Significance of KRAS Mutations in Colorectal Cancer Biology

Loretta László et al. Cells. .

Abstract

The most commonly mutated isoform of RAS among all cancer subtypes is KRAS. In this review, we focus on the special role of KRAS mutations in colorectal cancer (CRC), aiming to collect recent data on KRAS-driven enhanced cell signalling, in vitro and in vivo research models, and CRC development-related processes such as metastasis and cancer stem cell formation. We attempt to cover the diverse nature of the effects of KRAS mutations on age-related CRC development. As the incidence of CRC is rising in young adults, we have reviewed the driving forces of ageing-dependent CRC.

Keywords: CRC with age; KRAS; RAS signalling; RAS-driven metastasis; cancer stem cells; colorectal cancer.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 2
Figure 2
(A) Visualisation of the colorectal cancer (CRC)-related mutations in the KRAS G domain. The glutamine residue at position 61, the glycine residues at positions at 12 and 13, and the alanine residue at position 146, which form the GDP/GTP pocket, are indicated with colours. Image from the RCSB PDB (rcsb.org (accessed on 3 March 2021)) of PDB ID: 6MBT [22]. (B) Schematic representation of the summary of the RAS-driven signalling pathways.
Figure 1
Figure 1
Structure of the KRAS4A and KRAS4B isoforms, showing the amino acid positions of posttranslational modifications with different colours. The hypervariable region sequences are presented separately for the two isoforms due to their high variability. The CAAX motifs and the polybasic residues on KRAS4B are also colour-coded. The posttranslational modifications are listed in the box with the affected amino acid sites and (where known) the enzyme or compound responsible for the reaction. NEDD4-1, neural precursor cell expressed developmentally downregulated 4-1; LZTR1, leucine-zipper-like transcriptional regulator 1; SRC, proto-oncogene tyrosine-protein kinase Src; PKC, protein kinase C; ExoS, exoenzyme S; PIAS4, protein inhibitor of activated STAT protein 4; PATs, protein acetyltransferases; FTase, farnesyltransferase; ICMT, isoprenylcysteine carboxyl methyltransferase.
Figure 3
Figure 3
(a) Frequency of metastasis sites in CRC patients. Distributions of the metastatic sites in colorectal cancer patients (n = 27,506) were extracted from cohort data of Riihimaki et al. and Holch et al. [80,81]. (b) Frequency of single (liver or lung) metastasis and the combined appearance (liver and lung) metastasis among codon-12 and codon-13 mutant and wild type KRAS patients. Raw cohort data from He et al., 2020 and Jones et al., 2017 were normalised and pooled [85,86].
Figure 4
Figure 4
Modifiable and non-modifiable risk factors associated with early- or late-onset CRC.
Figure 5
Figure 5
Prevalence of metastatic status among wild type and mutant KRAS CRC patients (n = 142–183). Metastasis is more frequent in mutant KRAS patients in both (<66 and ≥66 years) age cohorts. CRC patients carrying KRAS mutations (183 KRASwt and 142 KRASmut patients) and metastatic stage (M0 or M1) were extracted from PANCAN TCGA COADREAD (colorectal cancer) database on the Xena platform [135].
See this image and copyright information in PMC

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