Table 1.
Summary of the various gene mutations in CRC characterized in the TCGA [9] and DFCI [175] sequencing projects
| Gene | Sample size (#) | Proximal colon cancer (%) | Distal colon cancer (%) | Rectal cancer (%) | Pathway | Function |
|---|---|---|---|---|---|---|
| MLH1 (P) | 25 | 59.6 | 25.2 | 15.2 | DNA mismatch repair | MMR after DNA replication; forms heterodimer with PMS2 |
| MLH3 (P) | 22 | 68.2 | 14.4 | 17.4 | DNA mismatch repair | MMR after DNA replication; competes against PMS2 to from heterodimer with MLH1 |
| MSH2 (P) | 12 | 48.8 | 23.2 | 28.1 | DNA mismatch repair | MMR after DNA replication; binds to MSH6 or MSH3 to form heterodimer |
| MSH3 (P) | 20 | 54.3 | 36.8 | 8.9 | DNA mismatch repair | MMR after DNA replication; binds with MSH2 to form heterodimer that recognizes insertion-deletion loops |
| MSH6 (P) | 27 | 62.5 | 16.9 | 20.5 | DNA mismatch repair | MMR after DNA replication; binds MSH2 to form heterodimer |
| PMS1 (P) | 16 | 69.5 | 30.5 | 0 | DNA mismatch repair | MMR after DNA replication; forms heterodimer with MLH1 |
| PMS2 (P) | 18 | 49.6 | 31.4 | 19.0 | DNA mismatch repair | MMR after DNA replication; forms heterodimer with MLH1 |
| POLE (P) | 47 | 49.2 | 36.2 | 14.6 | DNA mismatch repair | Involved in chromosomal DNA replication, recombination, and DNA repair via base and nuclear excision pathways |
| APC | 361 | 29.7 | 32.0 | 38.3 | Wnt signaling | Tumor suppressor; regulator of Wnt pathway and involved in cell cycle and cell adhesion |
| AXIN1 | 23 | 63.6 | 20.1 | 16.3 | Wnt signaling | Tumor suppressor; component of β-catenin destruction complex |
| AXIN2 | 49 | 55.1 | 26.9 | 18.1 | Wnt signaling | Tumor suppressor; component of β-catenin destruction complex |
| CTNNB1 | 36 | 49.6 | 31.4 | 19.0 | Wnt signaling | Oncogene; makes protein product β-catenin ligand of Wnt pathway |
| TCF7L2 | 44 | 34.8 | 37.3 | 27.9 | Wnt signaling | Tumor suppressor; TF for many genes by altering the chromatin structure around those genes, suppresses transcription of CTNBB1 |
| ARID1A (P) | 67 | 43.6 | 34.4 | 22.0 | Wnt signaling | Tumor suppressor; TF for many genes by altering the chromatin structure around those genes, suppresses transcription of CTNBB1 |
| FBXW7 | 86 | 35.5 | 30.7 | 33.7 | Wnt signaling | Tumor suppressor; involved in the ubiquitination and degradation of the cell-cycle regulators |
| RNF213 (P) | 80 | 59.3 | 22.5 | 18.2 | Wnt signaling | Tumor suppressor; ubiquitin ligase that acts on frizzled receptors in Wnt pathway |
| RNF43 (P) | 72 | 81.7 | 9.6 | 8.7 | Wnt signaling | Tumor suppressor; ubiquitin ligase that acts on frizzled receptors in Wnt pathway |
| ZNRF3 (P) | 38 | 68.6 | 21.1 | 10.3 | Wnt signaling | Tumor suppressor; ubiquitin ligase that acts on frizzled receptors in Wnt pathway |
| SOX9 | 62 | 41.2 | 25.4 | 33.4 | Wnt signaling | Tumor suppressor; TF for intestinal stem-cell differentiation; promotes ubiquitination and degradation of β-catenin |
| FAM123B/WTX | NA | NA | NA | NA | Wnt signaling | Tumor suppressor; promotes ubiquitination and degradation of β-catenin, stabilizes Axin2 |
| KLF5 | 14 | 38.9 | 27.6 | 33.5 | Wnt signaling | Oncogene; plays a critical role in β-catenin activation by increasing interaction with TCF4 |
| TGFBR1 (P) | 8 | 42.0 | 0 | 58.0 | TGF-β signaling | Tumor suppressor; component of TGF-β receptor |
| TGFBR2 (P) | 29 | 60.3 | 20.8 | 18.8 | TGF-β signaling | Tumor suppressor; component of TGF-β receptor |
| SMAD2 | 32 | 47.4 | 21.4 | 31.2 | TGF-β signaling | Tumor suppressor; downstream signaling molecule for TGF-β signaling, when phosphorylated forms SMAD2-SMAD4 heterodimer to modify transcription of TGF-β target genes |
| SMAD3 (P) | 21 | 39.2 | 30.9 | 29.9 | TGF-β signaling | Tumor suppressor; downstream signaling molecule for TGF-β signaling, when phosphorylated forms SMAD3-SMAD4 heterodimer to modify transcription of TGF-β target genes |
| SMAD4 | 73 | 39.8 | 34.1 | 26.1 | TGF-β signaling | Tumor suppressor; downstream signaling molecule for TGF-β signaling, when phosphorylated forms SMAD2/3-SMAD4 heterodimer to modify transcription of TGF-β target genes |
| ACVR2A (P) | 59 | 73.6 | 19.6 | 6.8 | TGF-β signaling | Activin receptor type 2A; component of activin receptor; complex phosphorylates SMAD2/3 |
| ACVR1B (P) | 29 | 40.7 | 31.8 | 27.5 | TGF-β signaling | Activin receptor type 1B; component of activin receptor; complex phosphorylates SMAD2/3 |
| ATM | 64 | 53.9 | 29.5 | 16.6 | TGF-β signaling | Tumor suppressor; kinase that phosphorylates multiple targets including TGF-β receptor to activate TGF-β signaling and p53 to activate DNA damage pathways |
| ERBB2 (HER 2) (P) | 38 | 45.6 | 32.5 | 21.9 | MAPK signaling | Oncogene; EGFR; activates oncogenic Ras–Raf–MEK–ERK signaling pathway |
| ERBB3 (HER3) (P) | 36 | 51.0 | 11.6 | 37.5 | MAPK signaling | Oncogene; EGFR; activates oncogenic Ras–Raf–MEK–ERK signaling pathway |
| ERBB4 (HER4) (P) | 37 | 42.2 | 40.1 | 17.7 | MAPK signaling | Oncogene; EGFR: activates oncogenic Ras–Raf–MEK–ERK signaling pathway |
| KRAS (D) | 173 | 39.3 | 28.7 | 31.9 | MAPK signaling | Oncogene; component of oncogenic Ras–Raf–MEK–ERK signaling pathway |
| NRAS (P) | 27 | 31.0 | 36.2 | 32.9 | MAPK signaling | Oncogene; component of oncogenic Ras–Raf–MEK–ERK signaling pathway |
| BRAF (P) | 127 | 71.9 | 21.9 | 6.1 | MAPK signaling | Oncogene; component of oncogenic Ras–Raf–MEK–ERK signaling pathway |
| IGF1 (P) | 4 | 56.6 | 0 | 43.4 | PI3K signaling | Oncogene; ligand for IGF1R; Regulates cell proliferation |
| IGF2 (P) | 4 | 100.0 | 0 | 0 | PI3K signaling | Oncogene; ligand for IGF1R; Regulates cell proliferation |
| IGF1R (P) | 26 | 72.4 | 12.5 | 15.1 | PI3K signaling | Oncogene; RTK receptor phosphorylates ISR1 and ISR2 |
| IRS1 (P) | 47 | 44.8 | 14.1 | 41.1 | PI3K signaling | Oncogene; once phosphorylated, activates PI3K-AKT/mTOR pathway and Ras–Raf–MEK–ERK signaling pathway |
| IRS2 (P) | 15 | 35.0 | 24.8 | 40.2 | PI3K signaling | Oncogene; once phosphorylated, activates PI3K-AKT/mTOR pathway and Ras–Raf–MEK–ERK signaling pathway |
| PIK3CA (P) | 132 | 50.1 | 35.6 | 14.3 | PI3K-signaling | Oncogene; triggers PI3K-Akt/mTOR pathway |
| PIK3R1 (P) | 30 | 50.2 | 38.2 | 11.6 | PI3K signaling | Tumor suppressor; regulates PI3CA gene |
| mTOR (P) | 50 | 47.4 | 16.3 | 36.3 | PI3K signaling | Oncogene; kinase activating PI3K-AKT/mTOR pathway |
| AKT1 (P) | 11 | 81.3 | 0 | 18.7 | PI3K signaling | Triggers PI3K-Akt/mTOR pathways that have a central regulatory role in promoting cell growth and proliferation and inhibiting apoptosis |
| PTEN (P) | 51 | 51.6 | 28.0 | 20.4 | PI3K signaling | Tumor suppressor; negatively regulates PI3K-ATK/mTOR pathway |
| TP53 (p53) (D) | 320 | 24.2 | 36.3 | 39.5 | p53 signaling | Tumor suppressor; regulates cell cycle and activates DNA damage pathways |
| MYC (D) | 12 | 59.6 | 25.2 | 15.2 | MYC signaling | Oncogene; codes for family of TFs |
The most frequent mutations were obtained from cBioPortal and compiled according to the weighted incidence in the various sections of the colon and rectum. Key pathways associated with the genes are listed. A weighted incidence was calculated by assuming an equal representation of each section of the colon and rectum in the sample size and accounting for both the overrepresentation of proximal CRC and underrepresentation of distal and rectal CRC in the original data. Gene names followed by "D" in parenthesis have higher tendency to be mutated in distal colon cancers while those followed by "P" in parenthesis tend to be mutated in proximal colon cancers.
CRC, colorectal cancer; MMR, mismatch repair; TF, transcription factor.