Genetics - Predisposition to cancer Flashcards
What is an oncogene?
Role of tumor suppressor genes?
Mutation in these genes leads to out of control growth in the cell - they stop genes deemed for apoptosis so they can survive.
Normal genes that slow down cell division, repair DNA mistakes, or tell cells when to die (a process known as apoptosis or programmed cell death).
What is a germline mutation?
What is a somatic mutation?
Germline: if parent has a child, the child will have an alteration in every cell in their body - these are heritable, causes cancer family syndromes.
Somatic: Mutation arrising in one cell, doesn’t effect germ line
Please explain DNA mismatch repair.
- Classically seen in lynch syndrome
- DNA is copied, very occasionally a mistake arrises: normally body’s repair protein sorts out but if not correct then there is an additional base on the protein: causing a nonsence mutation = non-functioning protein
What is extragenic DNA?
DNA that has no role in coding: chunks of DNA that is in between DNA which codes for specific things.
What occurs to non-functional or missing protein?
Nonsence mediated decay with premature stop codons - person ends up with half as much protein that they should have.
How much breast and ovarian cancer is hereditary?
1/8 women get breast cancer
1/70 get ovarian cancer
Breast cancer: 5-10% hereditary, 15-20% family clusters
Ovarian cancer: 5-10% hereditary
What are the genes for breast cancer?
- BRCA 1
- BRCA 2
- p53
Colorectal cancer susceptibility: which genes are responsible?
- Familial: 10-30%
- HNPCC (hereditary nonpolyposis colorectal cancer) aka Lynch syndrome: 5%
- FAP (familial adenomatous polyposis): 1%
A child presents with a white pupil on flash photography: what needs to be remembered?
Notice the white pupil, leukochoria: seeing through the pupil a tumour that has arisen in the retina. If the child has a germline mutation then they have a high risk of tumour in their other eye – clinical emergency.
- this is retinoblastoma
Explain Lynch syndrome:
How can lynch syndrome be prevented?
- 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 lynch syndrome?
- Early but variable age at CRC diagnosis (~45 years)
- Tumor site in proximal colon predominates
What is the lifetime risk of BRCA1 and 2?
- Breast cancer: 60-80%
- Second primary breast cancer: 40-60% [prophylactic mastectomy]
- Ovarian cancer 20-50%
- Males have an increased risk of prostate cancer and breast cancer
What is the chance of inheriting risk in autosomal dominant inheritance?
- Each child has 50% chance of inheriting the mutation
- No “skipped generations”
- Equally transmitted by men and women
What is the mendelian risk?
50% risk of carrying mutation,
can only be given when a clear basis of single gene inheritance can be recognized for disorder
When do we suspect hereditary cancer?
- 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
What are the current guidelines for risk estimation?
- All Scottish genetics centres
- Similar to UK National Guidelines
- Recommended use by all doctors
- Screening has support of Scottish Government
- Classify as high, moderate or low
- Low is low genetic risk-
- similar to population average risk
What occurs in the cancer genetics process?
- First, obtain detailed family history
- Confirm diagnosis of cancer
- Do a risk estimation
- Counselling post diagnosis
What is covered in a clinical genetics consulation?
- Go through fam history
- Do a risk estimation
- Explain the basis of risk
- Interventions:
- Increased awareness of SSx
- Lifestyle: diet, smoking, oestrogen use
- screening
- prophylactic surgery
- Genetic testing
What are the breast cancer surveillance options?
- Breast awareness is very important: to promote women to come to the docs if they notice any lumps
- Early clinical surveillance 5yrs before age of 1st cancer in the family
- annual or clinical breast exams (who by?)
- mammography
- Moderate / high: 2 yrly from 35-40, yrly 40 - 50
- MRI screening those at higher risk
What are the benefits 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 benefits and risks of prophylactic oophorectomy?
Benefit
- Eliminates risk of primary ovarian cancer;
- Laparoscopic oophorectomy reduces postsurgical morbidity
Risks
- however, peritoneal carcinomatosis may still occur
- Induces surgical menopause but HRT till 50 does not change BRCA risk
- Risk of subsequent BRCA halved in mutation-positive women
Explain the surveillance for CRC
Intervention:
- Colonoscopy
Recommendation:
- High risk: 2 yrly from 25
- Moderate risk: 35 & 55
Explain the surveillance for endometrial cancer?
Intervention:
- Look for PMB (post-menopausal bleeding)
- Transvaginal ultrasound
- Surgery
Recommendation:
- Debatable
- Not recommended
What are the benefits vs risks of genetic testing?
Benefits:
- Identifies highest risk
- Indentifies non-carriers in families with a known mutation
- Allows early detection and prevention strategies
- May relieve anxiety
Risks:
- Does not detect all mutations
- Continued risk of sporadic cancer
- Efficacy of interventions variable
- May result in psychosocial
or economic harm
What does the future hold for 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
