Colon Cancer Pathology,

Treatment and Genetics

 Key Issues
• Incidence of Colon Cancer

• Causes of Colon Cancer

– Risk factors

• Colon Cancer and age

• Classification and treatment of colon cancer

• The Genetics of Colon

– Tumour Suppressor genes
– Oncogenes
– DNA repair genes

• A Genetic Model of Colon Cancer

 Incidence
• In countries such as the UK, Australia and USA, 1 in 25 will get
colorectal cancer.

• 150,000 new cases every year.

• Colorectal cancer will account for approx 60,000 cancer deaths in

the USA (11% of all cancer deaths)

• Rare in people under 30 years of age.

• Both sexes are affected equally.

• Comparison:
– Nigeria of 3 cases per 100,000 people (very low).
– USA 40 per 100,000
 Incidence
• Some religious groups (Mormons & Seventh Day
Adventists) have much lower rates of colon
cancer.
– No booze or tobacco
– Chaste lifestyle?????

• 70% of people with colon cancer that’s not spread

beyond the colon live for 5 years or more.

• Women survive longer than men

• Older patients do better than younger ones who

tend to have more advanced disease.
Colon Cancer and age

• Strong relationship between

colon carcinogenesis and
increasing age.

• Mainly affects people who are

40 or over.

• Risk increases with advancing

age.

• Accumulation of mutations –
multi-step nature of cancer.
 Other Risk Factors
• Family history. Some colon cancers are hereditary.

• Polyps: Many colon cancers develop from polyps. Tumour

like growths which can develop into “full blown” cancer.

• Ulcerative colitis: An inflammatory bowel disease

associated with high cell turn-over.

• Diet: High fat low fibre, fruit, vegetables is associated with

increase risk.
The Colon
Duke’s Classification
Treatment - Surgery
• Colectomy

• Total

• Hemi

• Depending on
stage of
tumour
 Chemotherapy
• For stage I tumours and above some form of
adjuvant therapy is normally recommended.

• Commonly 5-fluorouracil weekly/every two

weeks for 6 months after surgery.
– Leucovorin (Folic acid substitute)

• Platinum drugs may also be used in

conjunction with 5-FU.
 The Genetics of Colon
Cancer
• Colon cancer can be sporadic, familial or inherited
– Germline mutations – basis of inherited cancer
– Accumulation of somatic mutations – sporadic disease
– In Ashkenazi Jews, high incidence of ‘familial’ colon cancer.

• Mutation in three classes of genes associated with colon

cancer
– Tumour suppressor genes
– Oncogenes
– DNA repair genes

• Greater understanding of molecular genetics and better

treatment may make the majority of colon cancers
preventable.
 Cytogenetic Analysis

Chromosome Frequency of LOH

17p 75%

18q 75%
22q 50%

1q, 4p, 5q, 6p, 6q, 8p, 9q, 15-20%

18p
 The Genes
• Colon cancers are generally regarded as
adenocarcinomas.

• Inherited colon cancers:

• Familial adenomatous polyposis (FAP) – hundreds
of adenomas.
– APC gene mutations on chromosome 5q21.

• Hereditary nonpolyposis colorectal cancer (HNPCC)

– Mutation in genes involved in repairing DNA
mismatches occurring during DNA replication.
– Mismatch repair genes hMSH2 and hMSH1 on
chromosomes 2p16 and 3p21 respectively.
 APC Gene
• A tumour suppressor gene on chromosome 5q21.

• 9.0 kb mRNA; 8538bp open reading frame. 2843 amino

acids protein of 300 kDa.

• Function: interacts with “adherens junction protein A”

and β -catenin suggesting involvement in cell adhesion
and cell motility.

• APC-β -catenin protein complex inhibits the

transcription factors Tcf-Lef: Involved on Cox2
expression.

• Mutational inactivation of APC causes disruption of

tight linkage between cells may promote invasive
tumour growth.
 Mismatch Repair Genes
• HNPCC accounts for 10% of all colon cancers.

• mismatch repair genes (MMR genes): hMSH2, hMLH1,

hPMS1, hPMS2, hMSH6, and hMSH.

• Location: 2p16 (hMSH2), 2q31-33 (hPMS1), 3p21

(hMLH1), 7p22 (hPMS2), 5q (hMSH3).

• Human homologues of E.coli MUT HLS system repairing

mismatches due to replication DNA errors.

• MSI (Micro Satellite Instability): phenotypic characteristic

of HNPCC tumours and many sporadic colon cancers.
 Alpha 1 antitrypsin Gene
• Mutation causes deficiency in alpha-1 antitrypsin
(chromosome 14)
– May increases incidence of MSI (micro-satellite
instability).

• Alpha-1 antitrypsin neutralises certain proteolytic

enzymes and protects cells from chronic damage.

• Inactivation of Alpha-1 antitrypsin exposes cells to greater

damage
– Higher cell turnover
– Genetic instability
– Increased cancer risk

• Associated with liver cancer also.

 Cyclo-oxygenase 1 and 2
(& protaglandins)
• Cox 1 and 2 are enzymes involved in prostaglandin
production.
– Substances that regulate vaso-
constriction/dilatation.

• Cox 2 (chromosome 1p36) major suspect in spread of

colorectal tumours.

• Up-regulates prostaglandin production

– Inhibits apoptosis
– Induces interleukin 6 (IL-6)

• Both associated with cell invasion.

 P53
• A tumour suppressor gene on chromosome 17p13

• Gene span 20 kb of DNA; 11 exons (the first is non-coding).

3.0 kb mRNA; 1179bp open reading frame, 53kDa.

• Highly conserved regions: transactivation, DNA binding,

nuclear localisation signals, tetramersation domain.

• A transcriptional regulator, guardian of the genome

controlling DNA repair/apoptosis pathways following DNA
damage.

• Hotspots of mutation in exons 4 to 8 at codons 175, 245, 248,

273 and 282 (missense, nonsense, deletions insertion and
splicing mutations).
 DCC (Deleted in Colorectal
Carcinoma)
• Chromosome 18q21. Mediates signalling from growth factor receptors

• Signalling pathway for TGFβ .

• DCC is a cell adhesion protein important in intestinal cell differentiation.

• Speculation that loss of gene leads to increased cell motility -

characteristic of metastasis.

• DCC lost in 70% of off colon cancers

 K-Ras (Ki-ras)
• Located on chromosome 12p,

• Consists of six exons, spread over 35kb of genomic DNA.

About 21kDa protein size.

• Alternative RNA splicing gives two different transcripts

of 5.5 and 3.8kb (skipping of exon 4).

• Belongs to the Ras family including N-Ras and H-Ras.

• GTP binding protein with a role in signal transduction

from the cell membrane to nucleus.

• Becomes oncogenic via point mutations in codons 12, 13

and 61 (loss of GTPase activity).
 A Genetic Model of Colon
Cancer
Chrom: 5q 12p 18q 17p
Alteration: Loss Activation Loss Loss/mutation
Gene: APC K-Ras DCC p53
DNA Cox2
Hypomethylation A1AT

Normal Hyperproliferative Early Intermediate Late Secondary

Carcinoma
epithelium epithelium Adenoma Adenoma Adenoma tumour

MSH1/MLH2
 Summary
• Incidence, classification and treatment options for colon
cancer

• Well delineated pathway for colorectal carcinogenesis.

• Classical example of the multistage nature of cancer

development.

• Genetic model is well established.

• Involves 3 gene classes

– Tumour suppressor genes
– Oncogenes
– DNA repair genes