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%
