A3- Colorectal Cancer Flashcards
Malignant neoplasm of the colon or rectum, usually an __________
Malignant neoplasm of the colon or rectum, usually an adenocarcinoma.
Is colorectal cancer the 1st 2nd or 3rd most common cancer in the UK
Third
Colorectal cancer is commoner with advancing age
TURE OR FALSE
TRUE
Colonic carcinoma affects men and women equally; rectal cancer appears
to be more common in women
TURE OR FALSE
FALSE
Colonic carcinoma affects men and women equally; rectal cancer appears
to be more common in men
Which •Inflammatory bowel disease can cause colorectal cancer
ulcerative colitis
nherited gene mutations conditons that relate to colorectal cancer?
FAP and lynch
How does colorectal cancer present?
Change in bowel habit
•Constipation/diarrhoea
•Mucus
•Bleeding
•Intestinal obstruction
•Intestinal perforation
- Jaundice
- Abdominal distension
- Anaemia
- Anorexia (loss of appetite)
- Weight loss
Difference in Right and Left Sided Colon Cancers
Right sided tumour: Polypoid carcinoma Symptoms: Blood loss,Weight loss
Left sided tumour:Stricturingcarcinoma Symptoms: Altered bowel habit, Obstruction, Rectal Bleeding
Investigation Co Ca
- Simple blood tests
- FBC
- CEA
•Sigmoidoscopy or colonoscopy and tissue biopsy
Difference between grade and stage?
- Grade –how similar to normal tissue the tumour appears under the microscope
- Stage –how far the tumour has spread
Explain curative and palliative management for Colorectal Ca
•Curative
•Surgery +/‐adjuvant therapy
•Neo‐adjuvant therapy and subsequent surgery
•Palliative
•Chemotherapy
•Radiotherapy
What is a somatic mutation
•Alteration in DNA that occurs after conception
Hallmarks of cancer?
What is meant by clonal evolution of cancer?
The clonal evolution model holds that genetic and epigenetic changes occur over time in individual cancer cells, and that if such changes confer a selective advantage they will allow individual clones of cancer cells to out-compete other clones.
Clonal evolution involves the interplay of selectively advantageous or ‘driver’ lesions, selectively neutral or ‘passenger’ lesions, and deleterious lesions, as well as lesions that increase the rate of other genetic changes
Explain the different hit targets in clonal evolution
1st oncogenic mutation:
•stem cell/progenitor/differentiated cell
•growth of genetically homogeneous benign lesion
2nd hit targets one of the cells in the benign lesion
•growth of a more malignant and invasive clone
3rd hit targets cell within the malignant subclone
•further transformation
•genetically independent subclonescan coexist within tumour
Final mutational hit
•tumour entirely taken over by cells that behave as cancer stem cells
Cancer of colon and rectum relatively well understood at ______ mutation
level
point
Vogelstein’s adenoma‐carcinoma sequence in 1990
What did they measure?
His group measured the frequency of mutations in adenomas and
carcinomas and suggested a model for how a typical colorectal cancer
might develop
•APC
- Tumour suppressor gene
- Point mutation creates a truncated protein
- Loss of function
- Considered initiation step in pathway
RAS
•KRAS, NRAS oncogenes
•Encode GTP binding protein involved in signalling pathway from tyrosine kinase
pathway (MAPK pathway)
•Mutation prevents intrinsic GTPaseactivation
•Gain of function
•p53
•DNA damage results in p53 mediated arrest in G1 phase of cell cycle
•This allows either DNA repair or p53 induced apoptosis
•Loss of function leads to accumulated mutations, continued cell proliferation and
decreased apoptosis
What is DNA Mismatch Repair
System for recognising and repairing incorrect insertion, deletion and mis‐
incorporation of bases in DNA replication
•Defects in MMR increase the spontaneous mutation rate
What is Microsatellite Instability (MSI)
Microsatellite instability (MSI) is a unique molecular alteration and hyper-mutable phenotype, which is the result of a defective DNA mismatch repair (MMR) system, and can be defined as the presence of alternate sized repetitive DNA sequences which are not present in the corresponding germ line DNA.
•Microsatellite means
- Sequence (motif) of 1 to 5 nucleotides repeated between 10 –100 times
- E.g. AAAAAAAA, TTTTTTTT
•Prone to mutation during replication due to transient separation of the helical
strands and slippage of DNA polymerase complex
RAS Mutation and its Consequences
RAS mutation
•Protein turned on all the time
•Blocking EGFR is not effective because the activation point in the pathway
is “downstream”
NICE guidance is that all colorectal cancers should be tested for _____ _______
NICE guidance is that all colorectal cancers should be tested for Lynch Syndrome
How is MMR Tested?
•Immunohistochemistry for expression of the four MMR protein in FFPE tumour
tissue
•If the protein is not expressed, there is loss of staining in the tumour tissue and
maintained staining in normal (control) tissue
- Immunohistochemistry (IHC) is generally preferred to MSI testing of the tumour
- Simpler
- Cheaper
- Can be offered in most pathology laboratories
Benefits of MMR Testing
Finding cases of Lynch Syndrome
•Germline mutation in MMR proteins
•Reduces morbidity and mortality
•Identify relatives with disease
Finding sporadic MSI‐H colorectal cancers
•Approximately 10‐15%
•Known to have a better prognosis –no need for adjuvant therapy in most cases
•Potential for treatment with PD1 inhibitors
