Genetics Flashcards
How do disease-associated mutations alter protein function?
Can cause it to be non-functional.
Or reduce its function.
What percentage of breast and ovarian cancer is hereditary?
10%
15% for breast family clusters.
What percentage of colorectal cancer is hereditary?
10-30%
Lynch syndrome.
What are Germline mutations?
Mutation in egg or sperm which then affects all cells in the offspring.
Cause cancer family syndromes.
What are somatic mutations?
Occur in nongermline
Nonheritable
If there is a problem with oncogenes what happens?
Accelerated cell division - 1 mutation is sufficient role in cancer development.
Tumour suppressor gene problems what happens?
1st mutation (susceptible carrier) 2nd mutation (leads to cancer)
What is the main mechanism for familial cancer?
Faulty DNA mismatch repair.
Base pair mismatch and then mutation introduced by unrepaired DNA.
What happens in Lynch syndrome?
Mutation is mismatch repair genes.
Excess of colorectal, endometrial, urinary, ovarian and gastric cancers.
Adenoma - carcinoma sequence for polyp formation.
Diagnosis age and site in HNPCC?
Early but variable age at CRC diagnosis ( about 45).
Tumour site in proximal colon predominates.
What can be used as a preventative treatment for Lynch?
Prophylactic Aspirin - for gene carriers.
don’t know dosage
BRCA 1 is associated with what cancers?
Breast (60-80%)
Second primary breast (40-60%)
Ovarian (20%-50%)
What is BRCA2 associated with?
Increased risk of Prostate and Breast in men.
When is hereditary cancer syndrome suspected?
Cancer in 2 or more close relatives.
Early age at onset.
Multiple primary tumours.
Characteristic pattern of tumours. (breast and ovary)
Autosomal dominant transmission evidence.
Cancer family history - what is key?
Accurate risk assessment.
Effective genetic counselling.
Appropriate medical follow up.
What is the process for cancer genetics?
Obtain detailed family history.
Confirm diagnoses of cancer.
Risk estimation.
Counselling.
Breast cancer surveillance options?
Breast awareness.
Early clinical surveillance 5yr Annual or clinical brest exams.
Mammography.
MRI screening those at highest risk.
What does a prophylactic mastectomy do?
Removes most of breast tissue.
Significantly reduces breast cancer risk in women with fam history.
BRCA1 mutation-positive women breast cancer incidence reduced to 5%.
What does a prophylactic oophorectomy do?
Eliminates risk of primary ovarain cancer; however, peritoneal carcinomatosis may still occur.
Induces surgical menopause but HRT till 50 does not change BRCA risk.
Risk of subsequent BRCA halved in mutatrion-positive women.
What are the benefits of genetic testing?
Identifies highest risk.
Non-carriers identified.
Allows early detection.
May relieve anxiety.
What are the risks and limitations to genetic testing?
Does not detect all mutations.
Continued risk of sporadic cancer.
Efficacy of interventions variable.
May result in psychosocial or economic harm.
What are the modes of inheritance in multi-system disorders?
Chromosomal - numerical e.g. trisomy 21. Structural.
Single gene disorders - Autosomal dominant e.g. TS, NF1
Autosomal recessive e.g. CF
X-linked e.g. Duchenne muscular dystrophy.
Multifactorial - polygenic, environment.
Why are multi-systems involved in these mutations?
Several genes with diverse functions are involved (chromosomal).
Single gene widely expressed in different tissues.
Single gene tissue-specific expression but tissue integral part of many different systems.
What are the common problems in multi-system disease?
Variable expression within as well as between families.
Present to a large variety of different specialists.
Family history easily missed.
What is Neurofibromatosis Type 1 (NF1)?
Autosomal dominant
Prevalence 1/2500-3500
What are the NF1 signs and symptoms?
Need 2+ for diagnosis: Cafe au lait spots - 6 or more. Neurofibromas - 2 or more. Axillary freckling Lisch nodules Optic glioma Thinning of long bone cortex Fam History Short stature Macrocephaly Learning difficulties Epilepsy Scoliosis Raised BP Neoplasia (CNS)
Diagnosis and Management of NF1
Clinical diagnosis using diagnostic criteria.
Management:
Annual review of affected individuals and at risk children until diagnosis can be excluded.
- BP
- spine for scoliosis
- tibia for unusual angulation
- Visual acuity and visual fields
- educational assessment
- ask patient to report any unusual symptoms
Genetics of NF1
Autosomal dominant
Variable expression (inter/intra)
Gene identified - 17q - tumour supressor gene.
Mutations different in different families.
50% due to new mutations.
What are the main features of NF2?
Acoustic neuromas Usually bilateral CNS and spinal tumours Few cal spots On chromosome 22
What is Tuberous Sclerosis?
Incidence 1 in 7000 newborns
Classic triad: Epilepsy, Learning difficulties, Skin lesions.
Autosomal dominant
Hamartomas in different organs.
What are the genetics behind TS?
Autosomal dominant
Variable expression
Almost full penetrance
2 genes on different chromosomes both cause TS with identical phenotypes. (TSC1/2)
What are the clinical features of TS?
Multi-system (lung,skin,heart,brain,kidney,other) Variable expression Learning difficulty 40% Seizures 65% Skin lesions (depigmented macules) Kidney (cysts) Phakomas in eye Rhabdomyomas in heart.
Screening of at-risk relatives?
Siblings and parents may be mildly affected.
Surveillance and genetic counselling.
Clinical exam.
Cranial MR scan, renal US, Echocardiogram.
What is myotonic dystrophy?
Signs and symptoms?
Autosomal dominant CTG repeat. Bilateral late-onset cataract. Muscle weakness, stiffness, myotonia. Low motivation, bowel problems, diabetes mellitus. Heart block Death post-anaesthetic risk.
What are the mechanisms of adult onset genetic disease?
Single gene
Chromosomal
Mitochondrial
Multifactorial (genes and environment)
What makes a disease a shared genetic heritage?
Genetic disease affects families, not individuals.
Discovery of a genetic disorder implies a risk for relatives.
What are possible advantages to predictive testing for Huntington’s disease?
Uncertainty of gene status removed.
