Download Colorectal cancer : Three pathways

Colorectal cancer : Three pathways
Molecular genetics lab Kwak bomi
Index
• Introductoin
• Three pathways
-CIN pathway
-CIMP pathway
-MSI pathway
• Colorectal polyps: pathway precursors
• summary
Introduction
Colorectal cancer
→ CIN pathway(Chromosomal instability)
→ CIMP pathway (CpG island methylator phenotype)
→ MSI pathway(microsatellite instability)
http://www.davincisurgery.com/kr/da-vinci-colorectal/conditions/colon-cancer/stages.php
Colorectal cancer: the pathways
Colorectal cancer: the pathways
1. CIN pathway (Chromosomal instability)
Tumor progression
Nature Reviews Cancer 9, 489-499 (July)/doi:10.1038/nrc22009645
Colorectal cancer: the pathways
1. CIN pathway (Chromosomal instability)
1) APC
•APC is an extremely important tumor suppressor gene.
•The binding of APC to b-catenin helps to suppress the wntsignaling regulates growth, apoptosis and differentiation.
•Loss of functional APC might also interfere with the careful
regulation of mitosis contributing to CIN.
•APC mutation → wnt-signaling dysregulation → tumor progression
World J Gastroenterol. 2014 Jun 21;20(23):7137-51. doi: 10.3748/wjg.v20.i23.7137
Colorectal cancer: the pathways
1. CIN pathway (Chromosomal instability)
2) KRAS
•KRAS encodes a GTP-binding protein which, when mutated,
can cause a loss of inherent GTPase activity and thus constitutive
signalling through the downstream, RAS-RAF-MEK-ERK pathway.
Cancers (Basel). 2016 Apr 18;8(4). pii: E45. doi: 10.3390/cancers8040045.
Colorectal cancer: the pathways
1. CIN pathway (Chromosomal instability)
2) KRAS
•EGFR(Epidermal Growth Factor Receptor) + EGF
↓
Tyrosine kinase receptor phosphorylation
↓
Grb2(adaptor protein)
↓
RAS signaling activation
↓
Cell proliferation activation
•Activating KRAS mutations are found in 35-42%
of CRCs and in a similar number of advanced
adenomas.
Colorectal cancer: the pathways
1. CIN pathway (Chromosomal instability)
3) SMAD2, SMAD4
•TGF-beta(Transforming Growth Factor-beta) signaling
: important in regulating growth as well as apoptosis.
•SMAD2 and SMAD4 are all located at 18q21.1 and allelic loss at this
site is found in up to 60% of CRCs.
https://blogs.scientificamerican.com/guest-blog/the-hallmarks-of-cancer-6-tissue-invasion-and-metastasis/
Colorectal cancer: the pathways
1. CIN pathway (Chromosomal instability)
*SMAD4 mutation : juvenile polyposis
Commonest polyp in childhood.
presence of ≥ 10 juvenile polyps in the GI tract
Autosomal dominant
Mutation of SMAD4 gene on chromosome 18
Colorectal cancer: the pathways
1. CIN pathway (Chromosomal instability)
4) TP53 (Tumor protein P53)
Colorectal cancer: the pathways
1. CIN pathway (Chromosomal instability)
4) TP53 (Tumor protein P53)
•TP53 abnormalities, either mutation or loss of heterozygosity, increase
relative to the advancing histological stage of the lesion being studied, with
4-26% of adenomas, 50% of adenomas with invasive foci, and 50-75% of
CRCs having impaired function of TP53.
Colorectal cancer: the pathways
2. MSI pathway(Microsatellite instability)
Micro satellite : SSR(Simple Sequence Repeat)
STR(Short Tandem Repeat)
Microsatellites are nucleotide repeat sequences scattered
throughout the genome and MSI refers to a discrepancy, and
thus instability, in the number of nucleotide repeats found
within these microsatellite regions in tumour versus germline
DNA.
http://www.brassica.info/resource/markers/ssr-exchange.php
Colorectal cancer: the pathways
2. MSI pathway(Microsatellite instability)
•DNA polymerase is particularly susceptible to making
errors when copying these short repeat sequences and
thus mismatch repair (MMR) dysfunction results in MSI.
•MMR: MLH1, MLH3,MSH2, MSH3, MSH6, PMS1 and PMS2
•the majority of MSI-H CRCs occur sporadically in the
context of DNA methylation of the MLH1 promoter and
the consequent transcriptional silencing of MLH1
expression.
http://helicase.pbworks.com/w/page/17605644/Kimberly-Youngblood
Colorectal cancer: the pathways
3. CIMP pathway (CpG island methylator phenotype)
•The CIMP pathway provides the epigenetic instability necessary
for sporadic cancers to methylate the promoter regions of, and
thus epigenetically inactivate the expression of, key tumour
suppressor genes such as MLH1.
•The ultimate phenotype is influenced by the presence or absence
of concomitant microsatellite instability, which may arise from
gene promoter methylation-induced transcriptional silencing of
MLH1.
Colorectal polyps: pathway precursors
http://www.hopkinscoloncancercenter.org/CMS/CMS_Page.aspx?CurrentUDV=59&CMS_Page_ID=0B34E9BE-5DE6-4CB4-B387-4158CC924084
Colorectal polyps: pathway precursors
• CIN pathway precursor: adenomatous polyps
• CIMP pathway precursor: hyperplastic polyps – microvescular
– goblet cell rich
– mucin poor
Adenomatous polyp
Hyperplastic polyp
2013 Nov;11(11):1374-84. doi: 10.1016/j.cgh.2013.03.019. Epub 2013 Apr 10.
Summary
CIN
Apc, KRAS, SMAD2/4, TP53
MSI
Genes lost by mutation
at repetitive sequence
MLH1 methylation
CIMP
Genes silenced by promoter methylation
Colorectal cancer
reference
Clin Biochem Rev. 2010 May;31(2):31-8./Colorectal cancer: molecular features and clinical opportunities./Worthley DL1,
Leggett BA.
Oncogene. 2015 Mar 19;34(12):1608. doi: 10.1038/onc.2014.462.
World J Gastroenterol. 2014 Jun 21;20(23):7137-51. doi: 10.3748/wjg.v20.i23.7137
Cancers (Basel). 2016 Apr 18;8(4). pii: E45. doi: 10.3390/cancers8040045.
Current State-of-the-Science Adjuvant and Neoadjuvant Therapy in Surgically Resected Colorectal Cancer/By I.H. Sahin
and C.R. Garrett /DOI: 10.5772/57481
J Biomed Sci. 2011 Jun 7;18:36. doi: 10.1186/1423-0127-18-36.
2013 Nov;11(11):1374-84. doi: 10.1016/j.cgh.2013.03.019. Epub 2013 Apr 10.
Thank you