Genetic Predisposition to Cancer Flashcards
How much of breast cancer is hereditary?
Sporadic (majority) 70-80%
Family clusters = 15-20%
Hereditary 5-10%
How much of ovarian cancer is hereditary?
Hereditary 5-10%
Sporadic 90-95%
How much of colorectal cancer is due to hereditary susceptibility?
Sporadic 65-85%
Rare CRC syndromes < 0.1%
Familial 10-30%
Familial adenomatous polyposis (FAP) = 1%
Hereditary nonpolyposis colorectal cancer (HNPCC) 5%
The cell cycle involves…
Oncogenes GO - resting Tumour suppressor genes DNA repair genes S (synthesis) G2 M - mitosis G1 - cell growth
What are tumours?
Clonal expansions
What does cancer arise from?
Gene mutations
What kind of gene mutations can cancer arise from?
Germline mutations
Somatic mutations
Features of germline mutations
mutation in egg or sperm of the parent which affects all cells in the offspring
are heritable
cause cancer family syndromes
Features of somatic mutations
e.g. in breast
occur in non germline tissues
are non heritable
Normal gene oncogenes do what?
Regulate cell growth
What does a 1st mutation in an oncogene do?
Leads to accelerated cell division
1 mutation sufficient for role in cancer development
Tumour suppressor genes
Normal genes - prevent cancer
1st mutation - susceptible to cancer
2nd mutation or loss - leads to cancer
DNA base pair mismatch can lead to either…
Normal DNA repair OR
Mutation induced by unrepaired DNA
Pathology of HNPCC / lynch syndrome
Mutation in mismatch repair genes
excess of colorectal, endometrial, urinary tract, ovarian and gastric cancers
What sequence for polyp formation is in HNPCC / lynch syndrome?
Adeno-carcinoma
Clinical features of HNPCC / lymph syndrome
early but variable age at CRC diagnosis (approx. 45 years)
Tumour site in proximal colon predominates
Lifetime associated risks of the BRCA1 and 2 genes
Breast cancer 60-80% (often early age at onset)
Secondary breast cancer 40-60%
Ovarian cancer = 20-50% (1>2)
males ; increased risk of prostate cancer and breast cancer especially in BRCA2
In autosomal dominant inheritance, what chance does the child have of inheriting the mutation?
50%
Features of autosomal dominant inheritance
child has 50% chance of inheriting the mutation
no “skipped” generations
equally transmitted by men and women
Features of Mendelian risk
Dominant, high penetrance syndrome
can have a 25-50% chance of carrying the mutation
When to suspect a hereditary cancer syndrome
cancer in 2 or more close relatives or same side of family
early age at diagnosis
multiple primary tumours
bilateral or multiple rare cancers
characteristic pattern of tumours (breast and ovary)
Evidence of autosomal dominant transmission
Breast cancer surveillance options
breast awareness early clinical surveillance 5yr < age 1st Ca in family - annual clinical breast exams - mammography - MR screening those at highest risk
How often is a mammogram done depending on your risk of breast cancer?
Moderate / high - 2 yearly from 35-40, - yearly from 40-50 High - 18 monthly from 50-64
Effects of a mastectomy on chances of breast cancer
Significantly reduces breast cancer risk in women with FH
BRCA1 mutation positive women breast cancer incidence reduced to 5%
Effects of a prophylactic oophorectomy on chances of ovarian cancer
Eliminates risk of primary ovarian cancer
- however peritoneal carcinomatosis may still occur
Induces surgical menopause but HRT until 50 does not change until BRCA risk
Risk of subsequent BRCA halved in mutation positive women
Surveillance for colorectal cancer
Colonoscopy High risk - 2 yearly from 25 Moderate risk - 35 - 55
Effects of colorectal screening
Reduces risk of colorectal cancer in HNPCC families
Screening for Endometrial cancer
Look for
- PMB
- transvaginal USS
- surgery
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
Risks and limitations of genetic testing
does not detect all mutations
continued risk of sporadic cancer
efficacy of interventions variable
may result in psychological or economic harm
Examples of a 1st degree relative
Sister
Child
Parent
Examples of a 2nd degree relative
Aunt / uncle (on either side)
Grandparent (on either side)
Examples of a 3rd degree relative
First cousin
