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?????
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70% of people with colon cancer that’s not spread beyond the colon live for 5 years or more.
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Women survive longer than men
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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.
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Ulcerative colitis: An inflammatory bowel disease associated with high cell turn-over.
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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.
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Mutation in three classes of genes associated with colon cancer – Tumour suppressor genes – Oncogenes – DNA repair genes
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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, 18p
15-20%
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 vasoconstriction/dilatation.
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Cox 2 (chromosome 1p36) major suspect in spread of colorectal tumours.
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Up-regulates prostaglandin production – Inhibits apoptosis – Induces interleukin 6 (IL-6)
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Both associated with cell invasion.
P53 •
A tumour suppressor gene on chromosome 17p13
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Gene span 20 kb of DNA; 11 exons (the first is non-coding). 3.0 kb mRNA; 1179bp open reading frame, 53kDa.
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Highly conserved regions: transactivation, DNA binding, nuclear localisation signals, tetramersation domain.
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A transcriptional regulator, guardian of the genome controlling DNA repair/apoptosis pathways following DNA damage.
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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
Alteration: Loss Gene:
12p
18q
Activation
Loss
Loss/mutation
K-Ras
DCC
p53
APC
17p
DNA Hypomethylation
Normal epithelium
Hyperproliferative epithelium
Early Adenoma
Cox2 A1AT
Intermediate Adenoma
Late Adenoma
Carcinoma
MSH1/MLH2
Secondary tumour
Summary •
Incidence, classification and treatment options for colon cancer
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Well delineated pathway for colorectal carcinogenesis.
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Classical example of the multistage nature of cancer development.
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Genetic model is well established.
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Involves 3 gene classes – Tumour suppressor genes – Oncogenes – DNA repair genes