GENE LOCATION ROLE RECENT RESEARCH APPLICATION

APC Tumor suppressor gene - Germline mutations of APC are responsible for familial - More recent work shows that APC restoration drives tumor
located on the long (q) arm of adenomatous polyposis. regression and reestablishes crypt homeostasis in CRC,
chromosome 5, encodes a - Mutations in APC lead to production of short and abnormal validation the Wnt pathway as a therapeutic target for CRC
protein of 312 kDa with 2843 protein which cannot suppress the cellular overgrowth, leading to treatment.
GC
acid amin. Approximately the formation of polyps and become cancerous.
75% of coding sequence is - APC inhibits the members of Wnt signaling pathway the
located on exon 15, which promotes β-catenin expression as a stimulator of cell division
appears to be the most within the intestinal crypts.
CRC common region for both - APC proteins maintain low levels of cytosolic β-catenin thereby
germline and somatic preventing excessive cell proliferation.
- TASIN-1 induced cholesterol depletion => conformational
mutation of APC. - APC controls metaphase-anaphase transition and mitotic exit
change of SCAP which is then released from INSIG and
and regulates G1 phase. Over expression of APC lead to arrest of
assists SREBPs transport from endoplasmic reticulum (ER)
G1 phase in cell cycle.
to Golgi. SREBP is cleaved by proteases S1P and S2P in the
- APC in mitosis is critical for regulation of genomic stability and
Golgi and the cleaved form of SREBP then translocate into
chromosome segregation
the nucleus and activates expression of genes involved in
- Exons 14, 15 are most frequently mutated region for CRC and
cholesterol synthesis and uptake. This compensates for
GC
reduced cellular level of cholesterol; thus, cells survive. In
contrast, truncated APC compromises the normal feedback
mechanism in response to TASIN-1 treatment when cultured
in low serum conditions, therefore cells undergo apoptotic
cell death due to cholesterol depletion. HMGCR=3-hydroxy-
3-methylglutaryl-CoA reductase; LDLR=low density
lipoprotein receptor; TASIN-1=truncated APC selective
inhibitor.
- Problems: potential toxicity of Wnt pathway inhibitors on
 normal intestinal epithelium as well as off-target effects may
limit their clinical application.
- Other: Aminoglycoside and macrolide agents that promote
readthrough of premature stop codons.
- DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine :
APC expression has been successfully restored.
- Other antagonists of WNT signal transduction currently in
TP53 Located on chromosome 17p,
consists of 11 exons and 10
introns. Wild type p53 protein
consists of 393 amino acid
residues, and several
functional domains.
GC

CRC Located on chromosome 17p, consists of 11 exons and 10 In recent year, we witness an array of small molecule
 inhibitors modulating the p53 pathway being developed.
Some of these compounds have been tested as potential
therapeutic agents in CRC
introns. Wild type p53 protein consists of 393 amino acid
residues, and several functional domains. Once activated, p53
upregulates its negative regulator, MDM2. MDM2 functions as
an E3 ubiquitin-ligase, to regulate the ubiquitination of p53
which leads to its degradation. This forms a negative feedback
loop that maintains low levels of p53 in normal cells. Depending
on specific context, it can induce cell cycle arrest, apoptosis, or
senescence, in the presence of cellular stress, such as DNA
damage, hypoxia, oncogene activation.
- MI43 and Nutlin-3 bound to MDM2 blocking MDM3-p53
For development of CRC: majority of these mutations occur in
interaction. α-lipoic acid increased p53 protein stability and
exon 5 to 8 (DNA binding domain), and mainly in some hotspot
its apoptotic effect. Quinacrine induced the autophagy-
codons, such as 175, 245, 248, 273 and 282, comprising of G to
associated cell death in a p53-dependent manner. NSC17632
A, C to T transition and leading to the substitutions most
activated p53-like activatity dependent on p73.
commonly cluster in the DNA binding domain, causing the
PRIMA-1/PRIMA-1MET restored mutant p53 to exert
disruption of specific DNA binding and sequential
apoptotic effect. Maslinic acid and Epicatechin gallate as
transactivation.
plant extraction modulated the expression of p53 and its
target genes in p53-dependent apoptotic and cell cycle arrest
pathway.
PIK3CA GC A key step in the PI3K/AKT pathway is the generation of - Pan-class I inhibitors have inhibitory effects against each
phosphatidylinositol-3, 4, 5-trisphosphate (PIP3) by PI3K. The isoform of p110 (PIK3CA). Several pan-class I inhibitors are
PI3K family exists as three subfamilies, one of which is under investigation for GC targeted therapy, since PIK3CA
composed of a p110 catalytic subunit coupled to a regulatory gene mutation comprise 25% of gastric tumors, resulting in
subunit. p100α, the gene product of phosphatidylinositol-4, 5- PI3K dysregulation in GC. Some molecular agents inhibiting
bisphosphate3-kinase, catalytic subunit alpha (PIK3CA), is of PI3K such as: Wortmannin, PX-866, NVP-BKM120
 particular importance in signaling through the canonical PI3K (Buparlisib), ZSTK474, BAY80-6946.
pathway. The phosphatidylinositol 3-kinase (PI3K) pathway is - Isoform specific PI3K inhibitors were designed with an aim
one of the most commonly activated and altered signaling to provide comparable of superior efficacy than pan-class I
pathways in cancer, including GC. Since the PI3K pathway plays inhibitors. Some of them under investigation for GC
an essential role in several cellular processes, including cell treatment. BYL719, INK117
growth, metabolism, and survival, it is not surprising that its
dysregulation is also of critical importance to pathological
CRC ASPIRIN
processes such as the development, progression, and metastasis
of cancer.
KRAS gene, an oncogene from the mammalian RAS gene
GC family, encodes the KRAS protein, which is involved in multiple
pathways, including proliferation, differentiation, and apoptosis.
KRAS
KRAS mutation in exon 2 leads to increased KRAS protein
CRC activity, which constitutively activates the mitogenic signal
transduction pathway.
The phosphatase and tensin homolog (PTEN), a well-known
tumor suppressor gene, is involved in double-strand break repair,
GC and nucleotide excision repair, and regulates the DDR pathways
by interacting with Chk1 and p53. In addition, PTEN is a dual-
specificity protein and lipid phosphatase that regulates various
PTEN
cellular processes and signal pathways, such as the induction of
apoptisis by inhibiting phosphatidylinositol 3-kinase (PI3K)/Akt
CRC pathway and control of cell adhesion, migration, and tumor
invasion, by downregulating the activity of focal adhesion
kinases (FAKs)
MDH2 GC
 CRC
GC
MLH1
CRC
GC
RHOA
CRC