Genetics - Predisposition to Cancer Flashcards
what % of DNA is entragenic and can therefore code for proteins
2%
what is nonsense mediated decay of DNA?
premature stop codon resulting in a shorter protein than expected
what % of breast ca is hereditary?
5-10%
what % of ovarian ca is hereditary?
5-10%
genes linked to breast ca
BRCA 1 + 2
P53
germline mutations
o Present in egg or sperm
o Are heritable
o Cause cancer family syndromes
somatic mutations in cancer
o Occur in nongermline tissues
o Are nonheritable
oncogenes and cancer
1st mutation leads to accelerated cell division.
Leukemias – oncogene ABL, BCR-ABL fusion protein. This switches on the BCR which creates and oncogene causing increased cell division.
tumour suppressor genes in cancer
When the first mutation happens, the person becomes susceptible to cancer but the 2nd loss or mutation leads to cancer.
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
- Early but variable age at CRC diagnosis (approx. 45)
- Tumour site in proximal colon predominat
life time risk of cancer in BRCA 1 + 2 related cancers
o Breast cancer – 60-80% often at early age
o Second primary breast cancer 40-60%
o Ovarian cancer BRCA 1 50%, BRCA 2 20%
o Males have an increases risk of prostate cancer and breast cancer esp. BRCA2
when to suspect hereditary cancer syndrome
- Cancer in 2 or more close relatives on same side of family
- Early age at diagnosis
- Multiple primary tumours
- Bilateral or multiple rare cancers
- Characteristic pattern of tumours (e.g. breast and ovary)
- Evidence of autosomal dominant transmission
cancer genetics process
• Obtain detailed family Hx Figure 8 Inheritance • Confirm diagnoses of cancer • Risk estimation • Counselling
clinical genetics consultation
• Go through family history • Risk estimation • Explanation of basis of risk • Intervention o Increased awareness of symptoms/signs o Lifestyle – diet, smoking, oestrogen use o Screening o Prophylactic surgery • Genetic testing – consider in high risk
breast cancer surveillance syndromes
• Breast awareness
• Early clinical surveillance 5yr < age 1st Ca in cancer
o Annual or clinical breast exams
o Mammography
§ Moderate/high: 2 yearly from 35-40, yearly 40-50
§ High only 18 monthly 50 – 64
o MR screening those at highest risk
prophylactic mastectomy for hereditary breast ca
• Removes most but not all breast tissue
• Significantly reduces breast cancer risk in woman with a family history
• Total (simple) mastectomy removes more breast tissue than SC mastectomy (leave nipples)
Figure 9 Always Double Check Family History
• BRCA1 positive women mastectomy reduces incidence to 5%
prophylactic mastectomy for hereditary ovarian cancer
• Eliminates risk of primary ovarian cancer; however, peritoneal carcinomatosis may still occur
o Embryonic remnants
• Laparoscopic oophorectomy reduces postsurgical morbidity
• Induces surgical menopause but HRT till 50 does not change breast cancer risk (as body would
have had it anyway)
• Risk of subsequent breast Ca halved in mutation positive women
surveillance for CRC
• Colorectal cancer o Colonoscopy o High risk 2 yearly from 25 o Moderate risk 35-55 • Endometrial o Only for women with Lynch syndrome mutations o Look for PMB o Transvaginal USS o Surgery o Screening not recommended
benefits of genetic testing
o Identifies highest risk
o Identifies non-carriers in families with a known mutation
o Allows early detection and prevention strategies
o May relieve anxiety
risks and limitations of genetic testing
o Does not detect all mutations
o Continued risk of sporadic cancer
o Efficacy of interventions variable
o May result in psychosocial or economic harm
