Genetics: Predisposition to Cancer Flashcards
What is the human genome?
23 pairs of chromosomes made of 6,000 million base pairs forming 22,000 genes
How is extragenic DNA composed?
- Repetitive sequences
- Control regions
- Spacer DNA between genes
- Function mostly unknown
What do disease associated mutations do to DNA?
Alter protein function (protein is non-functional or missing)
How much breast cancer is hereditary
- Family clusters= 15-20%
- Hereditary= 5-10%
How much ovarian cancer is hereditary?
5-10%
What are the causes of hereditary susceptibility to colorectal cancer?
- Familial (10-30%)
- Hereditary nonpolyposis colorectal cancer (5%)
- Familial adenomatous polyposis (1%)
- Rare CRC syndromes (<0.1%)
What are the stages in the cell cycle?
- Mitosis
- G1 (cell growth)
- G0 (resting)
- Synthesis
- G2
Where do oncogenes act in the cell cycle
G1-G0
Where do tumour suppressor genes act in the cell cycle?
G0-S
Where do DNA repair genes act in the cell cycle?
S-G2
What are tumours?
Clonal expansions
What do cancers arise from?
Gene mutations
What are the features of germline mutations?
- Mutation occurs in egg or sperm an affects all cells in the offspring
- Are heritable
- Cause cancer family syndromes
What are the features of somatic mutations?
- Occur in nongermline tissues
- Are nonheritable
What role do oncogenes play in cancer development?
- Normal genes (regulate cell growth)
- Mutation in 1 gene leads to accelerated cell division
- 1 mutation sufficient for role in cancer development
What oncogene is implicated in leukaemia?
Oncogene ABL coding for BCR-ABL fusion protein
What role do tumour suppressor genes play in cancer development?
- Normal genes prevent cancer
- 1st mutation makes you a susceptible carrier
- 2nd mutation/loss leads to cancer
Using colon cancer, give an example of multi-step carcinogenesis.
Normal epithelium LOSS OF APC >Hyper-proliferative epithelium >Early adenoma ACTIVATION OF KRAS >Intermediate adenoma LOSS OF 18Q >Later adenoma LOSS OF TP53 >Carcinoma OTHER ALTERNATIONS >Metastasis
What is DNA mismatch repair?
- Sometimes there is a base pair mismatch i.e. A+G
- Normal DNA repair will lead to A+T
- Mutations can be introduced by unrepaired DNA
What are the features of Hereditary Non-Polyposis Colon Cancer (Lynch Syndrome)?
- Mutation in mismatch repair genes
- Excess of colorectal, endometrial, urinary tract, ovarian and gastric cancers
- Adenoma- carcinoma sequence for polyp formation
- Great opportunity for prevention by colonoscopy
What are the clinical features of HNPCC?
- Early but variable age at CRC diagnosis (~45 years)
- Tumour site in proximal colon predominates
What cancers and BRCA1+2 associated with?
- Breast cancer 60%-80% (often early age at onset)
- Second primary breast cancer 40%-60%
- Ovarian cancer 20%-25% (1>2)
- Males: increased risk of prostate cancer and breast cancer especially BRCA2
What are the features of autosomal dominant inheritance?
- Each child has 50% chance of inheriting the mutation
- No “skipped generations”
- Equally transmitted by men and women
When should you suspect a hereditary cancer syndrome?
- Cancer in 2 or more close relatives (on same side of family)
- Early age at diagnosis
- Multiple primary tumors
- Bilateral or multiple rare cancers
- Characteristic pattern of tumours (e.g. breast and ovary)
- Evidence of autosomal dominant transmission
The cancer family history is the key to…
-Accurate risk assessment
-Effective genetic counselling
0Appropriate medical follow-up
What is involved in the cancer genetics process?
- Obtain a detailed family history
- Confirm diagnoses of cancer
- Risk estimation
- Explanation of basis of risk
- Interventions
- Counselling
- Genetic testing considered if high risk
How can surveillance for breast cancer be carried out?
Early clinical surveillance 5 years before the age of the 1st cancer in family
- Annual or clinical breast exams
- Mammography: (moderate-high 2 yearly 35-40 and yearly 40-50) (high 18 monthly 50-64)
- MR screening those at highest risk
What are the features of prophylactic mastectomy?
- Removes most but not all breast tissue
- Significantly reduces breast cancer risk in women with a family history
- Total (simple) mastectomy removes more breast tissue than subcutaneous mastectomy
- BRCA1 mutation-positive women breast cancer incidence reduced to 5%
What are the features of prophylactic oophorectomy?
- Eliminates risk of primary ovarian cancer; however, peritoneal carcinomatosis may still occur
- Laparoscopic oophorectomy reduces postsurgical morbidity
- Induces surgical menopause but HRT till 50 does not change BRCA risk
- Risk of subsequent BRCA halved in mutation-positive women
What is the surveillance for CRC?
Colonoscopy
- High risk 2 yearly from 25
- Moderate risk: at age 35 and 55
What is the surveillance for endometrial cancer?
- Look for PMB
- Transvaginal ultrasound
- Surgery
- Debatable but not recommended
What are the benefits of genetic testing?
- Identifies highest risk
- Identifies non-carriers in families with a known mutation
- Allows early detection and prevention strategies
- May relieve anxiety
What are the risks and limitations of genetic testing?
- Does not detect all mutations
- Continued risk of sporadic cancer
- Efficacy of interventions variable
- May result in psychosocial or economic harm
What is the future of genetic testing?
- Polygenic risk scores to decide on screening in families without a highly penetrant mutation
- Increasing role of germline and tumour genetic profile in determining treatment of cancer
