Pathogenesis of Colorectal Cancer

JA Uwuratuw
Surgery Department, Hasanuddin Medical Faculty
 INTRODUCTION
• Globocan 2018; CRC is the 3rd most common cancer in the world about
10,2% & mortality 6,1%
• Colorectal cancer (CRC) is the 3rd most frequently diagnosed cancer in
US, Estimated to cause 53.200 dead, 147,950 new cases in 2020 [1]

• Indonesia, incidents colon cancer about 8,6%, Rectal Cancer ±4,65 %,

mortalities rate about 5,7% & 3,8%. [4]
• Sporadic colorectal cancer account nearly 70 %, [1]

• 20 – 30 % of patients have a family history of CRC, no associated or

known germline mutation [1,2]
• Lynch Syndrome (LS) and Familial Adenomatous Polyposis (FAP)
account for 5% - 10% of CRC [1,2]
1Kasi A et al Molecular Pathogenesis and Classification of Colorectal carcinoma. Current Colorectal Cancer Report, 2020
2Valle R et al. Update in genetic predisposition to colon rectal cancer and polyposis. Molecular Aspect of Medicine 2019; 69 : 10 – 26
3Gupta S et al. Genetic / Familial High Risk Assessment : Colorectal. Version 2. 2019. JNCCN Org 2019; 17(9):1033-4
4Rompis AY, Dewi NYA. Journal Sains Kes. Vol 2. no 3.
 Carcinogenesis of Colorectal Cancer

COLORECTAL
CARCINOMA

Microsatellite Instability Chromosomal Instability

MSI-H (15%) CIN (85%)

Lynch Syndrome Sporadic CRC Sporadic Familial Adenomatous

(3-5%) (12-15%) CRC 85% Polyposis (FAP) 0,5%
Germline mutation Epigenetic Silencing Somatic mutation Germline mutation
MMR genes MLH1 of MSH1 by Polymorphism of APC gene
MSH2 MSH6 PMS2 hypermethylation

[de la Chapalle A. Hampel H. Clinical relevance of Microsatellite Instability in Colorectal Cancer. J.Clin 0100 2010; 28(20)3380
 Three major genetic pathways
• CIN pathway; accumulation of mutations in specific oncogenes and tumor
suppressor genes; APC, KRAS, PIK3CA, BRAF, SMAD4, and TP53 (± 70% of
sporadic)

• MSI pathway, caused by dysfunction of DNA MMR genes. MMR

deficiency in sporadic CRCs is due mainly to silencing of the MMR genes,
mostly MLH1 (>80% of cases)

• The third pathway, CIMP, is characterized by a widespread CpG island

methylation . 30%–40% of sporadic proximal CRCs are CIMP-positive,
compared with 3%–12% of distal CRCs

Yamagishi et al. Chin J Cancer (2016) 35:4

 Chromosomal Instability Pathway
• Approximately 70% of sporadic CRCs(1)
• Most frequent at left side colon/Rectal (2)
• Earliest event is APC gene Mutation (80-90% of CRC) (2)
• K-RAS mutation
• Accumulation of mutations in specific oncogenes and tumor
suppressor genes; APC, KRAS, phosphatidylinositol-4,5-
bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA), B-Raf
proto-oncogene, serine/ threonine kinase (BRAF), SMAD4, and
TP53 (1)
• Late event: DCC ( deleted in colonic carcinoma) gene mutation
• Advanced event : DPC4/ SMAD4 mutation (18q21)

1.Yamagishi et al. Chin J Cancer (2016) 35:4

2. Kasi A et al Molecular Pathogenesis and Classification of Colorectal carcinoma. Current Colorectal Cancer Report, 2020
3. PINO AND CHUNG, GASTROENTEROLOGY 2010;138:2059 –2072
PINO AND CHUNG, GASTROENTEROLOGY 2010;138:2059 –2072
 CIN Pathway

Rompis AY, Dewi NYA J. Sains Kes. 2020. Vol 2. No 3 .

Rompis AY, Dewi NYA J. Sains Kes. 2020. Vol 2. No 3 .
KRAS mutation BRAF Mutation

Rompis AY, Dewi NYA J. Sains Kes. 2020. Vol 2. No 3

Wnt/β Catenin Pathway
P53 Pathway
 Microsatellite DNA
• MS are 1 – 6 bp long and are repeated many
thousand times

• MS are identical in each cell of an individual, normal

and malignant

• MS are susceptible to insertions or deletions at the

point of replication.

Horvat M, Stabuc B. Microsatellite instability in colorectal cancer. Radiology and oncology. 2011;45(2):75-
81
 MICROSATELLITE IBSTABILITY
pathway (MSI)
• Microsatellite instability (MSI) is a hypermutable phenotype
caused by the loss of DNA MMR activity. (2)
• Mutations in the DNA MMR that are responsible for
correcting DNA replication errors (1)

• CRC is defined as being MSS if there are no mutations in the

MS of CRC cancer cells.
• About 15% of all colorectal cancers; 3% are of these are
associated with Lynch syndrome and the other 12% are caused
by sporadic.
• 89% of tumors with MSI were in the proximal colon (2)

1. Tariq K, Ghias K, Cancer Biol Med Vol 13, No 1 March 2016

2. Boland and Goel, Gastroenterology. 2010 June ; 138(6): 2073–2087
 Defect in MMR gene

Reduced capacity of cells to repair specific types of DNA damage

Increased rate of mutation accumulation in microsatellite DNA

Boland and Goel, Gastroenterology. 2010 June ; 138(6): 2073–2087

Boland and Goel, Gastroenterology. 2010 June ; 138(6): 2073–2087
 Mismatch repair genes
• MSH1, MSH2 (2p21), MSH3, MSH4, MSH5, MSH6
• MLH1 (3p21,3), MLH2, MLH3
• PMS1, PMS2 (1)

• The important components of the DNA MMR system

are; hMSH2, hMSH6, hMSH3, hMLH1, hPMS2,
hPMS1, and hMLH3 (2)

1.Boland and Goel, Gastroenterology. 2010 June ; 138(6): 2073–2087

2.Tariq K, Ghias K, Cancer Biol Med Vol 13, No 1 March 2016
 Defect in MMR genes
• There are 4 definite Lynch syndrome genes: MSH1, MLH2,
MSH6, and PMS2
• Defect in DNA mismatch repair (MMR) gene:
MLH1, MSH2, MSH6, PMS2.
→ Microsatellite Instability (MSI – H)
• Characteristic features of sporadic CRC with MSI;
– methylation of the MLH1 promoter
– absence of MLH1 and PMS2 proteins; and
– frequent mutation (usually V600E ) in BRAF

Boland and Goel, Gastroenterology. 2010 June ; 138(6): 2073–2087

 CpG Island Methylation Phenotype
(CIMP)

Vast majority of sporadic MSI-H CRCs are thought to arise in CIMP-H

sessile serrated adenomas with BRAF mutation, through methylation-
associated inactivation of MLH1 (1)

1. Rhee YY, et al: CIMP-High Colorectal Cancer Gut and Liver, Vol. 11, No. 1, January 2017, pp. 38-46
2. Yamagishi et al. Chin J Cancer (2016) 35:4
• CpG sites(1):
– DNA methylation occurs at these sites by an
enzyme called DNA methyltransferases
– Regions of DNA where a cytosine occurs next to a
guanine
• In humans, 70-80% of all CpGs are
methylated (2)
• This methylation results in the conversion of
the cytosine to 5-methylcytosine (1)

1. Rhee YY, et al: CIMP-High Colorectal Cancer Gut and Liver, Vol. 11, No. 1, January 2017, pp. 38-46
2. Jabbari K, Bernardi G (May 2004). "Cytosine methylation and CpG, TpG (CpA) and TpA
frequencies". Gene. 333: 143–9
• The remaining 10% non methylated CpGs are grouped in a
cluster forming gCpG island, and is usually located in the
promoter regions towards 5’ end.
• The unique property of CpG island is that is unmethylated in
the germ line
• Methylation of CpG island within the promoters of genes 
silencing mutation of tumor suppressor genes  cancer

1. Rhee YY, et al: CIMP-High Colorectal Cancer Gut and Liver, Vol. 11, No. 1, January 2017, pp. 38-46
2. Jabbari K, Bernardi G (May 2004). "Cytosine methylation and CpG, TpG (CpA) and TpA
frequencies". Gene. 333: 143–9
 CIMP
• DNA methylation-related deficiencies in the MMR system can
result in mutation rate that is 100-fold greater than normal cells

• Defects in MMR first became apparent as germline mutations in

human MutL and mutS homologues hMLH1 and hMSH2, and
more rarely MSH6, PMS1 and PMS2, in HNPCC

• Older age, female sex, smoking, family history of CRC, proximal

location in the colon, mucinous cell differentiation, specific
precursor lesions (e.g., serrated adenomas), MSI, BRAF and KRAS
mutations

Bardhan and Liu Cancers 2013, 5, 676-713

 Conclusions
• CRCs are developed through three pathway;
CIN, MSI and CIMP
• Gene expression profiles as predictors of
response to therapy will pave the way for
precision medicine
Thank you