Genetic Predisposition to Cancer Flashcards
What causes cancer?
- chance
- environmental factors
- inherited predisposition
Somatic vs Germline mutations
- Somatic mutations occur in non-germline tissues and are nonheritable.
- Germline mutations are present in egg or sperm and are heritable. They cause cancer family syndromes.
What is a proto-oncogene?
Normal genes that code for proteins to regulate cell growth and differentiation
How does a proto-oncogene become an oncogene?
by mutation
What do oncogenes do?
- accelerate cell division
- can cause cancer if stuck in ‘on’ mode
What are tumour suppressor genes?
Genes that inhibit the cell cycle or promote apoptosis. They act as the cell’s brakes for cell growth.
What are DNA damage-response genes?
the repair mechanics for DNA
How does cancer arise from DNA damage-response genes?
Cancer arises when both genes fail, speeding the accumulation of mutations in other critical genes
What does HNPCC result from?
Failure of mismatch repair (MMR) genes
What does failure of MMR lead to?
Microsatellite Instability (MSI)=addition of nucleotide repeats
What does MMR do?
MMR corrects errors that spontaneously occur during DNA replication like single base mismatches or short insertions and deletions.
What evidence is there that MMR is not functioning normally?
MSI is the phenotypic evidence
What happens to cells with abnormally function MMR?
Thy tend to accumulate errors as novel microsatellite fragments (simple sequence repeats, SSR) are created
What is an example of an autosomal recessive syndrome?
MYH polyposis
What are other causes of cancer?
- autosomal recessive disorders
- multiple modifier genes of lower genetic risk
What is a De Novo mutation?
A new mutation which occurs in the germ cell of a parent. There is no family history of hereditary cancer syndrome.
What are 3 conditions in which de novo mutations are common in?
- Familial adenomatous polyposis
- Multiple endocrine neoplasia 2B
- Hereditary retinoblastoma
What is retinoblastoma?
The most common eye tumour in children which occurs in heritable and nonheritable forms
What are the risk factors involved in breast cancer? (8)
- ageing
- family history
- early menarche
- late menopause
- nulliparity
- estrogen use
- dietary factors
- lack of exercise
What genes can cause hereditary susceptibility to breast cancer?
- BRCA1
- BRCA2
- TP53
- PTEN
- Undiscovered genes
What are the functions of the BRCA1 gene?
- checkpoint mediator
- DNA damage signalling and repair
- chromatin remodelling (inactive X chromosome)
- transcription (not essential for this)
What is the function of the BRCA2 gene?
DNA repair by homologous recombination
What are the associated cancers of BRCA1?
- breast cancer
- secondary breast cancer
- ovarian cancer
- possible increased risk of other cancers
What are the associated cancers of BRCA2?
- breast cancer
- male breast cancer
- ovarian cancer
- increased risk of prostate, laryngeal and pancreatic cancers
What are the risk factors associated with colorectal cancer?
- ageing
- personal history of CRC or adenomas
- high fat, low fibre diet
- inflammatory bowel disease
- family history of CRC
What syndromes are associated with CRC?
- non-polyposis (few to no adenomas)
- polyposis (multiple adenomas)
Give an example of a non-polyposis syndrome.
Hereditary non-polyposis colon cancer aka Lynch syndrome- CRC &/or endometrial cancer
Give 3 example of polyposis syndromes.
- Familial adenomatous polyposis- severe colonic polyposis
- attenuated FAP- less severe colonic polyposis
- MYH associated polyposis- varying degrees of colonic polyposis
What are the clinical features of HNPCC?
- early but variable age at CRC diagnosis
- tumour site throughout colon
- extra colonic cancers: endometrium, ovary, stomach, urinary tract, small bowel, bile ducts, sebaceous skin tumours
What are the clinical features of FAP?
- estimated penetrance for adenomas >90%
- risk of extra colonic tumours (upper GI, desmoid, osteoma, thyroid, brain, othere)
- CHRPE may be present (congenital hypertrophy of retinal pigment epithelium)
- 100% risk of cancer if untreated
What are the clinical features of AFAP?
- later onset
- few colonic adenomas
- not associated with CHRPE
- upper GI lesions
- associated with mutations at 5’ and 3’ ends of APC gene
What are the clinical features of MYH polyposis?
- similar clinical GI features to AFAP
- common mutations in mut-MYH gene
- recessive inheritance
What may multiple modifier genes of lower genetic risk explain?
- families with history of cancer and no identified mutation
- differences in cancer penetrance in families with same mutation
How can cancer risk in adenomatous polyposis syndromes be managed?
- surveillance
- surgery
- chemoprevention
