Genetic Predisposition to Cancer Flashcards
How does disease-associated mutations alter protein function?
Results in non-functional or missing protein
Protein with reduced function
How much is breast and ovarian cancer hereditary?
5-10%
In breast cancer 15-20% is family clusters
What are the causes of hereditary susceptibility to colorectal cancer?
Sporadic
Familial
Rare CRC syndromes
Lynch syndrome
Familial adenomatous
What are germline mutations?
Inherited from single alteration in egg or sperm
Are heritable
Cause cancer family syndromes
What are somatic mutations?
Occur in non-germline tissues
Are non-heritable
What is involved in the cell cycle?
G0
S -synthesis
G2
M -mitosis
G1 - cell growth
Oncogenes, tumour suppressor genes and DNA repair genes
What is an ocogene?
A gene with the potential to cause cancer
1st mutation leads to accelerated cell division
How can tumour suppressor genes?
Normal genes prevent cancer
1st mutation is a susceptible carrier
2nd mutation or loss - leads to cancer
Describe multi-step carcinogenesis
Normal epithelium - hyper-proliferative epithelium - early adenoma - inter-mediate adenoma - late adenoma - carcinoma - metastasis
Describe Lynch syndrome/ HNPCC (hereditary non-polyposis colon cancer)
Mutation in mismatch repair genes
Excess colorectal, endometrial, urinary tract, ovarian and gastric cancers
Adenoma - carcinoma sequence for polyp formation
What are the clinical features of HNPCC?
Early but variable age of CRC diagnosis
Tumour site is proximal colon predominates
What are the BRCA1 and 2 associated cancers?
Breast cancer
Secondary primary breast cancer
Ovarian cancer
Males - prostate cancer and breast cancer
What is mendelian risk?
Dominant
High penetrance syndrome
When is hereditary cancer syndrome suspected?
Cancer in 2 or more close relatives, early age at diagnosis, multiple primary tumours, bilateral or rare cancer, characteristic pattern and evidence of autosomal dominant transmission
What is the cancer genetic process?
Obtain detailed FH
Confirm diagnosis of cancer
Risk estimation
Counselling
What are the breast counselling surveillance options?
Breast awareness
Early clinical surveillance every 5 years
Annual or clinical breast exams
Mammography
MR screening is very high risk
Describe prophylactic mastectomy
Removes most but not all breast tissue
Significantly reduced breast cancer risk in women
BRCA1 mutation positive women - breast cancer incidence reduced to 5%
Describe prophylactic oophorectomy
Eliminates risk of primary ovarian cancer - peritoneal carcinomatosis may still occur
Induces surgical menopause
Risk of subsequent BRCA halved
Describe genetic testing for Lynch syndrome
IHC for mismatch repair gene proteins or microsatellite instability testing
Determine if gene is implicated
Recommended for CRC management
What are the benefits of genetic testing?
Identifies highest risk, non-carriers in families, allows early detection and prevention strategies
What are the risks and limitations of genetic testing?
Does not detect all mutations, continued risk of sporadic cancer, efficacy of interventions variable and may result in psychosocial or economic harm
