Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
© Copyright 2018. Korean Association for the Study of Intestinal Diseases.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
FINANCIAL SUPPORT: The authors received no financial support for the research, authorship, and/or publication of this article.
CONFLICT OF INTEREST: No potential conflict of interest relevant to this article was reported.
AUTHOR CONTRIBUTION: Conception and drafting of manuscript: SNH.
aHigh expression of WNT signaling targets plus stem cell, myoepithelial, and mesenchymal genes with low expression of differentiation markers.
bComparatively high expression of chemokines and interferon-related genes.
cHeterogeneous collection of samples with variable expression of stem cell and WNT-target genes.
dHigh mRNA expression of goblet-specific MUC2 and TFF3.
eHigh expression of enterocyte-specific genes.
CRC, colorectal cancer; qRT-PCR, real-time quantitative RT-PCR; IHC, immunohistochemistry.
aMixed type (15%).
CRC, colorectal cancer; CMS, consensus molecular subtype; CIN, chromosomal instability; SCNA, somatic copy number alteration; MSI, microsatellite instability; MSS, microsatellite stable; CIMP, CpG island methylator phenotype; JAK, Janus kinase; STAT, signal transducers and activators of transcription; TGF, transforming growth factor; EMT, epithelial-mesenchymal transition.
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The SP1-Induced Long Noncoding RNA, LINC00339, Promotes Tumorigenesis in Colorectal Cancer via the miR-378a-3p/MED19 Axis
Group 1 | Group 2 | Group 3 | Group 4 | Group 5 | |
---|---|---|---|---|---|
Molecular features | |||||
MSI status | MSI-H | MSS, MSI-L | MSS, MSI-L | Mainly MSS | MSI-H |
CIMP | High | High | Low | Negative | Negative |
CIN | Stable | Stable | Unstable | Unstable | Stable |
KRAS mutation | + | ||||
BRAF mutation | + | + | - | ||
Clinical features | |||||
Location | Rt>Lt | Rt>Lt | Lt>Rt | Lt>Rt | Rt>Lt |
Sex | F>M | F>M | M>F | M>F | M>F |
Precursor | Serrated polyp | Serrated polyp | Serrated polyp/adenoma | Adenoma | Adenoma |
CRC, colorectal cancer; MSI, microsatellite instability; MSI-H, MSI-high; MSS, microsatellite stable; MSI-L, MSI-low; CIMP, CpG island methylator phenotype; CIN, chromosomal instability; Rt, right; Lt, left; F, female; M, male.
Hypermutated tumor | Non-hypermutated tumor | |
---|---|---|
Frequent mutation | >12 mutations per 106 bases (median number of total mutations, 728) | <8.24 mutations per 106 bases (median number of total mutations, 58) |
Proportion of all CRCs | 16 | 84 |
Tumor site | Colon and rectum | Common in right-side colon |
MSI status | Stable | High |
CIMP status | Low | High |
APC gene mutation | 51 | 81 |
TP53 gene mutation | 20 | 60 |
Frequent affected genes (mutation frequency) | ACVR2A (63), TGFBR2 (51), BRAF (46), MSH3 (40), and MSH6 (40) | KRAS (43), PIK3CA (18), FBXW7 (11), SMAD4 (10), TCF7L2 (9), NRAS (9), FAM123B (7), CTNNB1 (β-catenin) (5), ACVR1B (4), SOX9 (4) |
SCNAs | - | Frequent |
WNT signaling activation | 97 | 92 |
TGF-β signaling inactivation | 87 | 27 |
PI3K signaling activation | 53 | 50 |
RTK/RAS signaling activation | 80 | 59 |
p53 signaling inactivation | 47 | 64 |
Values are presented as percentage.
CRC, colorectal cancer; TCGA, The Cancer Genome Atlas; MSI, microsatellite instability; CIMP, CpG island methylator phenotype; SCNA, somatic copy number alteration; TGF, transforming growth factor; PI3K, phosphoinositide-3 kinase; RTK, receptor tyrosine kinase.
Subtypes | Stem-likea | Inflammatoryb | Transient-amplifyingc | Goblet-liked | Enterocytee | |
---|---|---|---|---|---|---|
Cetuximab resistant | Cetuximab sensitive | |||||
Signature genes | SFRP2, +ZEB1 | RARRES3 | CFTR, FLNA | CFTR, (FLNA) | MUC2, TFF3 | MUC2, (TFF3) |
Biomarkers for qRT-PCR | SFRP2+ | RARRES3+ | CFTR+, FLNA+ | CFTR+, FLNA− | MUC2+, TFF3+ | MUC2+, TFF3− |
Biomarkers for IHC | ZEB1+ | - | CFTR | CFTR | MUC2+, TFF3+ | MUC2+, TFF3− |
Correlated crypt location | Base | NS | Either | Either | Top | Top |
Disease-free survival | Poor | Intermediate | Poor | Good | Good | Intermediate |
Adjuvant treatment | Chemotherapy (FORFIRI) | Chemotherapy (FORFIRI) | Watchful surveillance | Watchful surveillance | Watchful surveillance | Chemotherapy (FORFIRI) |
Metastatic treatment | Chemotherapy (FORFIRI) | Other therapy | c-MET inhibitor | Cetuximab | Chemotherapy (FORFIRI) or other therapy | Other therapy |
aHigh expression of WNT signaling targets plus stem cell, myoepithelial, and mesenchymal genes with low expression of differentiation markers.
bComparatively high expression of chemokines and interferon-related genes.
cHeterogeneous collection of samples with variable expression of stem cell and WNT-target genes.
dHigh mRNA expression of goblet-specific MUC2 and TFF3.
eHigh expression of enterocyte-specific genes.
CRC, colorectal cancer; qRT-PCR, real-time quantitative RT-PCR; IHC, immunohistochemistry.
CMS1 (MSI-immune) | CMS2 (canonical) | CMS3 (metabolic) | CMS4 (mesenchymal) | |
---|---|---|---|---|
% of all CRCsa | 14 | 37 | 13 | 23 |
Mutation profile | BRAF, TGFBR2 | APC, TP53, CIN | KRAS, APC | - |
SCNA | Low | High | Intermediate | High |
MSI status | MSI-high | MSS/MSI-low | MSS/MSI-low | MSS/MSI-low |
CIMP | High/low | Negative | Low | Negative |
Pathway analysis | JAK/STAT and caspases pathway | WNT and MYC activation; cell cycle pathway | Metabolic dysregulation; epithelial signature | TGF-β activation; stromal infiltration, EMT activation, matrix remodeling; angiodysplasia |
MicroRNA | - | High expression of the miR-17-92 cluster | Low expression of let-7 miR family | Low expression of miR-200 family |
Clinical and pathological variables | ||||
Clinical characteristics | Female, old-onset | - | - | - |
Site | Right colon | Left colon and rectum | Left, right colon, and rectum | Left colon and rectum |
Stage | - | - | - | Advanced stage (III and IV) |
Histologic grade | Higher histologic grade | - | - | - |
Prognosis | Worse survival after relapse | Superior survival after relapse | - | Worse relapse-free and overall survival |
aMixed type (15%).
CRC, colorectal cancer; CMS, consensus molecular subtype; CIN, chromosomal instability; SCNA, somatic copy number alteration; MSI, microsatellite instability; MSS, microsatellite stable; CIMP, CpG island methylator phenotype; JAK, Janus kinase; STAT, signal transducers and activators of transcription; TGF, transforming growth factor; EMT, epithelial-mesenchymal transition.
Type 1 | Type 2 | Type 3 | Type 4 | Type 5 | |
---|---|---|---|---|---|
% of CRCs | 7 | 4 | 26 | 47 | 7 |
MSI | MSI-high | MSS/MSI-low | MSS/MSI-low | MSS/MSI-low | MSS/MSI-low |
CIMP | Positive | Positive | Negative | Negative | Negative |
BRAF | Mutation | Mutation | Wild-type | Wild-type | Wild-type |
KRAS | Wild-type | Wild-type | Mutation | Wild-type | Wild-type |
CRC specific 5-yr survival (%) | 89.5 | 49.2 | 72.4 | 82.5 | 93.1 |
Clinical characteristics | Oldest-onset, female | Old-onset, female | - | Male | Youngest-onset, CRC family history |
Site | Proximal colon | Proximal colon | - | Distal colon and rectum | Proximal colon |
Proposed molecular pathway | MSI BRAF mutation CIMP-positive | BRAF mutation CIMP-positive | KRAS mutation | Canonical pathway with APC mutation | MSI |
CRC, colorectal cancer; MSI, microsatellite instability; CIMP, CpG island methylator phenotype; MSS, microsatellite stable.
CRC, colorectal cancer; MSI, microsatellite instability; MSI-H, MSI-high; MSS, microsatellite stable; MSI-L, MSI-low; CIMP, CpG island methylator phenotype; CIN, chromosomal instability; Rt, right; Lt, left; F, female; M, male.
Values are presented as percentage. CRC, colorectal cancer; TCGA, The Cancer Genome Atlas; MSI, microsatellite instability; CIMP, CpG island methylator phenotype; SCNA, somatic copy number alteration; TGF, transforming growth factor; PI3K, phosphoinositide-3 kinase; RTK, receptor tyrosine kinase.
aHigh expression of WNT signaling targets plus stem cell, myoepithelial, and mesenchymal genes with low expression of differentiation markers. bComparatively high expression of chemokines and interferon-related genes. cHeterogeneous collection of samples with variable expression of stem cell and WNT-target genes. dHigh mRNA expression of goblet-specific eHigh expression of enterocyte-specific genes. CRC, colorectal cancer; qRT-PCR, real-time quantitative RT-PCR; IHC, immunohistochemistry.
aMixed type (15%). CRC, colorectal cancer; CMS, consensus molecular subtype; CIN, chromosomal instability; SCNA, somatic copy number alteration; MSI, microsatellite instability; MSS, microsatellite stable; CIMP, CpG island methylator phenotype; JAK, Janus kinase; STAT, signal transducers and activators of transcription; TGF, transforming growth factor; EMT, epithelial-mesenchymal transition.
CRC, colorectal cancer; MSI, microsatellite instability; CIMP, CpG island methylator phenotype; MSS, microsatellite stable.