Table 1.
Common genetic and epigenetic alterations in colorectal cancer*
| Gene or biomarker | Chromosome | Function | Molecular lesion | Frequency (%) | Predictive? | Prognostic? | Diagnostic? |
|---|---|---|---|---|---|---|---|
| Tumour suppressors | |||||||
| APC | 5 | Regulates Wnt signalling pathway | Inactivating mutations | 40–70 | No | No | Familial Adenomatous Polyposis |
| ARID1A | 1 | Member of SWI/SNF family, regulates chromatin structure and gene transcription | Inactivating mutations | 15 | No | No | NA |
| CTNNB1 | 3 | Regulates Wnt signalling pathway | Activating mutations | 1 | No | No | No |
| DCC | 18 | Netrin receptor; regulates apoptosis, deleted but not mutated in colorectal cancer, role in primary cancer still unclear | Deletion/LOH | 9 (mutations)/ 70(LOH) | No | Possible | No |
| FAM123B | X | Involved in Wnt signalling pathway | Inactivating mutations [ | 10 | No | No | No |
| FBXW7 | 4 | Regulates proteasome mediated protein degradation | Inactivating mutations | 20 | No | No | No |
| PTEN | 10 | Regulates PI3K–AKT pathway | Inactivating mutations, loss of protein by immunohistochemistry | 10(mutation) 30 (loss of expression) |
Possible | No | Cowdens syndrome‡ |
| RET | 10 | Regulates GDNF signalling pathway | Inactivating mutations, aberrant DNA methylation | 7 (mutation); 60(methylation) | No | No | No |
| SMAD4 | 18 | Regulates TGF-β and BMP pathways | Inactivating mutations, deletion | 25 | Possible | Possible | Juvenile Polypsis |
| TGFBR2 | 3 | Regulates TGF-β pathway | Inactivating mutations | 20 | No | No | No |
| TP53 | 17 | Regulates expression of target genes involved in cell-cycle progression, DNA repair and apoptosis | Inactivating mutations | 50 | Possible | Possible | Li Fraumeni Syndrome |
| Proto-oncogenes | |||||||
| BRAF | 7 | Involved in MAPK signalling pathway | V600E activating mutation | 8–28 | Probable | Probable | Lynch syndrome |
| ERBB2 | 17 | Involved in EGF–MAPK signalling pathway | Amplification | 35 | No | No | No |
| GNAS | 20 | Regulates G-protein signalling | Mutation | 20 | No | No | No |
| IGF2 | 11 | Regulates IGF signalling pathway | Copy number gain, loss of imprinting | 7(mutations)/ 10(methylation) | No | No | No |
| KRAS | Regulates intracellular signalling via the MAPK pathway | Activating mutations in codon 12 or 13 but rarely in codons 61, 117 and 146 | 40 | Yes | Possible | NA | |
| MYC | 8 | Regulates proliferation and differentiation | Amplification | 2(mutations)/ 10 (CNV- gain) | No | No | No |
| NRAS | 1 | Regulates the MAPK pathway | Mutation in codon 12 or 13 | 2 | Yes | No | No |
| PIK3CA | 3 | Regulates PI3K–AKT pathway | al and kina20Mutase mutations in kinase (exon 20) and helical(exon 9) domain | 20 | Probable | Possible | No |
| RSPO2 and RSPO3 | 1 | Ligand for LGR family receptors, and activate Wnt signalling | Gene fusion translocation and | 10 | No | No | No |
| SOX9 | 17 | Regulates apoptosis | Copy number gain | 9(mutations)/ <5 (CNV gain) | No | No | No |
| TCF7L2 | 10 | Regulates Wnt signalling | Gene fusion and translocation | 10 | No | No | No |
| Other molecular alterations | |||||||
| Chromosome Instability (CIN) | N/A | NA | Aneuploidy | 70 | Probable | Probable | No |
| CpG Island Methylator Phenotype (CIMP | N/A | NA | Methylation of >20% loci from a selected panel of markers | 15 | Probable | Probable | No |
| Microsatellite Instability (MSI) | N/A | NA | Unstable microsatellite repeats in consensus panel | 15 | Probable | Yes | Lynch syndrome |
| Mismatch Repair Genes | N/A | Regulate DNA mismatch repair | Loss of protein by immunohistochemistry; methylation; inactivating mutations | 1–15 | Possible | Probable | Lynch Syndrome |
| SEPT9 | 17 | NA | Methylation | >90 | No | No | Serum based assay for cancer detection |
|
VIM NDRG4, BMP3 |
10, 16 and 4, respectively | NA | Methylation | 75 | No | No | Stool based test for early detection |
| 18qLOH | 18 | NA | Deletion of the long arm of chromosome 18 | 50 | Probable | Probable | No |
APC, adenomatous polyposis coli; ARID1A, AT-rich interactive domain 1A; BMP, bone morphogenetic protein; CNV, copy number variation; CTNNB1, catenin-β1; DCC, DCC netrin 1 receptor; EGF, epidermal growth factor; FAM123B, family with sequence similarity 123B; FBXW7, F-box and WD repeat domain-containing 7, E3 ubiquitin protein ligase; GDNF, glial cell-derived neurotrophic factor; GNAS, guanine nucleotide-binding protein, α-stimulating complex locus; IGF, insulin-like growth factor; LGR, leucine-rich repeat-containing G protein-coupled receptor; LOH, loss of heterozygosity; MAPK, mitogen-activated protein kinase; N/A, not applicable; NDRG4, NDRG family member 4; PI3K, phosphatidylinositol 3-kinase; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit-α; PTEN, phosphatase and tensin homologue; RSPO, R-spondin; SEPT9, septin 9; SMAD4, SMAD family member 4; SOX9, SRY (sex-determining region Y) box 9; TCF7L2, transcription factor 7-like 2; TGFβ, transforming growth factor-β; TGFBR2, TGFβ _receptor 2; VIM, vimentin.
Includes alterations in gene expression, gene deletions and amplifications, somatic mutations and aberrant promoter methylation.
Germline mutation, not somatic.