Colon Cancer: Molecular Pathogenesis and Precision Medicine Flashcards
What are the common risk factors of colon cancer (aka rectal cancer, colorectal cancer)?
old age, poor diet (high in carcinogens like barbecued meat), obesity, smoking, excess alcohol, family history (common first world cancer as a result) third most common cancer in the world
symptoms of colorectal cancer?
early stages often don’t have symptoms - abdominal discomfort/bloating - significant unexplained weight loss - bloody stools - unexplained anaemia/fatigue - changes in bowel movements (constipation or diarrhoea) - pelvic pain - occurs in later stages of disease
Describe the first mutations in colon cancer
1) mutation in the APC (adenomastosis polyposis coli) gene - mutated in about 60% of colon cancers 2) mutation in the K-ras oncogene - which is a protooncogene - mutated in 50% of all sporadic CC 3) Loss of gene DCC in CC- it is a tumour suppressor - 4) Loss of P53- it is critical in regulating cell cycle progression -
describe the progression of colon cancer physiologically
stage 0 = hyper proliferation in mucosa Stage 1= invasion in submucosa and hyper proliferation Stage 2= invasion beyond mucosa and into the muscle layers Stage 3= tumour has breached into the membrane and the lymph is positive for tumour cell Stage 4 = large tumour - may be enough to obstruct the bowel - stage four is defined as the presence of tumour cells at other sites
What is the TNM staging system?
T= size of tumour N= spread to lymph nodes M= spread to other parts of body (metastasis )
Difference between a colonoscopy and a sigmoidoscopy
colonoscopy = runs the entire length of colon sigmoidoscopy = only involves the lower third of the sigmoid colon
Colon Cancer occurrence Stats
of 100 with colon cancer 5- have hereditary syndrome 20- will have familial risk (phenotype that occurs in more than 1 family member- may be genetic or non-genetic like environment) 75- are sporadic mutations If we know the exact genetic defect - then it is a hereditary syndrome -
What is the most important gene in the context of colon cancer?
APC= adenomatosis polyposis coli It is a tumour suppressor gene that is mutated in large % of sporadic and inherited colon cancers People with this genetic mutation will have “FAP”= familial adenomatous polyposis - results in many polyps- much higher risk of developing cancer
What is FAP?
Familial adenomatous polyposis = inherited mutated APC gene- near 100% chance of developing cancer over their lifetime
What risk in particular do Ashkenazi Jews have in relation to colon cancer?
This family line has a particular risk of colorectal cancer due to a mutation in the APC gene (same gene effected in FAP) - causes an increased risk of cancer
What is hereditary nonpolyposis colorectal cancer?
HNPCC= the cancer can occur with only a small number of polyps present or even with none at all - people with this syndrome have an inherited mutation in one of several DNA mismatch repair genes - they have an 80% lifetime chance of developing CC
What is Peutz- Jeghers syndrome?
associated with mutation in the STK11 gene = which is a signal transduction molecules- increased risk of colon cancer
Why is the BRCA1 and 2 gene clinically relevant ?
mutation in this gene (a tumour suppressor gene) leads to an increased risk of breast cancer.- This gene plays a role in double strand DNA repair
What is a mutation associated with retinoblastoma?
mutation in Rb- tumor suppressor gene- which would normally prevent excessive cell growth
What is the treatment for Stage 1 or 2 colon cancer?
usually colonoscopy would be sufficient for treatment - however sometimes with stage 2 you would have adjuvant chemotherapy - dependent on the country
Why is it important to test for KRAS and BRAF genes before treating a metastatic colon cancer patient with Cetuximab?
Because the cetuximab works to inhibit the EGFR pathway - but if the patient has a mutated form of the KRAS or BRAF gene, then the tumour will bypass the EGFR pathway- therefore the cetuximab will be rendered useless
