What is cancer a disease of?
Where do inherited cancer syndromes arise from?
Mutations in the germline cells
What are the genetic processes involved in the clonal expansion of tumours?
Tumour supressor genes
DNA damage-response genes
How do oncogenes work?
Proto-oncogenes are normal genes that code for proteins to regulate cellular growth and differentiation. Mutations can change a proto-oncogene into an oncogene, which accelerates cell division- cancer arises when these oncogenes are activated.
Are oncogenes recessive or dominant?
How do tumour suppressor genes work?
These are the cellular brakes for cell growth- the genes inhibit the cell cycle or promote apoptosis, or both. Cancer arises when both brakes fail- this is reffered to as the 2-hit hypothesis.
Are tumour suppressor genes recessive or dominant?
How do DNA damage-response genes work?
These are the repair mechanics for DNA- cancer arises when both genes fail, spreading the accumulation of mutations in other critical genes.
(HNPCC results from failure of mismatch repair genes, MMI corrects errors).
What do MMR do?
MMR (mismatch repair genes) correct errors that spontaneously occur during DNA replication like single base mismatches or short insertions and deletions.
How does MSI show disfunction in MMR?
- Cells with abnormally functioning MMR tend to accumulate errors.
- Microsatellites (aka Simple Sequence Repeats SSR) are repeated sequences of DNA, can be made of repeating units of 1 – 6 base pairs
- MSI (changes in microsatellite sequences) is the phenotypic evidence that MMR is not functioning normally – genetic hypermutability.
Describe a benign tumour.
Benign- lacks ability to metastasise, rarely becomes cancerous, can still cause health effects due to localized pressure on organs.
Describe a dysplastic tumour.
Dysplastic- benign but could progress into malignancy, cells show abnormalities in appearance and cell maturation, sometimes referred to as pre-malignant.
Describe a malignant tumour.
Malignant- Metastasises, not benign, spreads throughout body.
How are inherited cancer syndromes spotted in examination?
What are de novo mutations?
New mutations in germline cell of parent, no family history of hereditary cancer syndrome.
What are most inherited cancer genes like?
Most cancer susceptibility genes are dominant with incomplete penetrance- they often appear to skip generations and individuals inherit the cancer susceptibility gene, not the cancer.
What are the forms of retinoblastoma?
Inherited/non-inherited, paediatric diagnosis
What are the risk factors for breast cancer?
Ageing, family history, diet (alcohol), lack of expertise. There are high and moderate risk genes.
What cancers are associated with the BRCA1 gene?
Lifetime risk of breast cancer, second primary breast cancer, and ovarian cancer. Also additional risk of colon and prostate cancer.
What cancers are associated with the BRCA2 gene?
Lifetime risk of breast cancer, male breast cancer and ovarian cancer. Additional risk of prostate, pancreatic and laryngeal cancers.
What are the risk factors for colorectal cancer?
Risk factors include ageing, previous history of CRC or adenomas, high-fat/low-fibre diet, inflammatory bowel disease, family history.
Describe the pathway of adenoma to carcinoma formation.
Normal epithelium > Hyperproliferative epithelium > Adenoma > Carcinoma
What are the hereditary CRC syndromes?
• Few to no adenomas
• Multiple adenomas- FAP/AFAP/MAP
What are the clinical features of HRPCC?
Early but variable age at CRC diagnosis, tumour site throughout colon rather than descending colon, extracolonic cancers including endometrium, ovary, urinary tract, small bowel, bile ducts, sebaceous skin tumours.
What are the clinical features of FAP?
Estimated penetrance for adenomas >90%
Risk of extracolonic tumors (upper GI, desmoid, osteoma, thyroid, brain, other)
CHRPE may be present
Untreated polyposis leads to 100% risk of cancer. Attenuated = later onset
What distinguishes attenuated FAP?
What is recessive MYH polyposis distinguished by?
Similar clinical features of FAP.
What can multiple gene mutations of lower risk explain?
- May explain families with history of cancer and no identified mutation
- May explain differences in cancer penetrance in families with same mutation
How are these inherited cancer syndromes controlled?