genetics: predisposition to cancer Flashcards
what do disease associated mutations do to DNA?
alter protein function:
- functional
- non-functional or missing
- reduced function
how much breast cancer is hereditary
5-10%
how much ovarian cancer is hereditary?
5-10%
causes of hereditary susceptibility to colorectal cancer
familial
HNPCC (hereditary nonpolyposis colorectal cancer)
familial adenomatous polyposis (FAP)
rare CRC syndromes
what is hereditary nonpolyposis colorectal cancer also known as
lynch syndrome
stages in the cell cycle
M (mitosis)
G1 (cell growth)
G0 (resting)
S (synthesis)
G2
where do oncogenes act in the cell cycle
1st part of cell cycle
G1-G0
(cell growth)
where do tumour suppressor genes act in the cell cycle?
2nd part of cell cycle
G0-S
(synthesis)
where do DNA repair genes act in the cell cycle?
second part of cell cycle
S-G2
(synthesis)
what are tumours?
clonal expansions
what do cancers arise from?
gene mutations
features of germline mutations?
- mutation in egg or sperm
- heritable
- cause cancer family syndromes
features of somatic mutations
- nongermline tissues eg breast
- nonheritable
roles of oncogene in cancer development
normal genes regulate cell growth
a single mutation in an oncogene leads to an accelerated cell division
what oncogene is implicated in leukaemia?
oncogene ABL
coding for BCR-ABL fusion protein
role of tumour suppressor genes in cancer development
normal genes prevent cancer
first mutation makes you a susceptible carrier
second mutation leads to cancer
using colon cancer, give an example of multi-step carcinogenesis.
normal epithelium proliferates to become an adenoma
adenoma becomes more dysplastic with the accumulation of genetic events
develops into a carcinoma which can then metastasize
DNA mismatch repair
main mechanism for familial cancer
accumulation of unprepared DNA can be a trigger for cancer
hereditary non-polyposis colon cancer (Lynch Syndrome)
mutation in mismatch repair genes leads to adenoma-carcinoma sequence for polyp formation
early but variable age at CRC diagnosis (~45 years)
tumour site in proximal colon predominates
what cancers are BRCA1 and BRCA2 associated with?
breast cancer (60-80%)
ovarian cancer (20-25%)
males: prostate, breast (BRCA2)
autosomal dominant inheritance
each child has 50% chance of inheriting the mutation
no “skipped generations”
equally transmitted by men and women
when to suspect a hereditary cancer syndrome?
family: cancer in >2 close relatives, autosomal dominant transmission evidence
tumours: multiple, characteristic pattern
diagnosis: early age, bilateral or multiple rare cancers
breast cancer surveillance options
early clinical surveillance 5 years before the age of the 1st cancer in family
- annual or clinical breast exams
- mammography
- MR screening those at highest risk
features of prophylactic mastectomy
removes most but not all breast tissue
reduces breast cancer risk in women with a family history
features of prophylactic oophorectomy
eliminates risk of primary ovarian cancer
induces surgical menopause
surveillance for CRC?
colonoscopy
- high risk 2 yearly from 25 years old
- moderate risk: 55 years old
surveillance for endometrial cancer?
symptom awareness: PMB
surgery
benefits of genetic testing?
identifies
- highest risk
- non-carriers in families with a known mutation
- early detection and prevention strategies
relieves anxiety
risks and limitations of genetic testing
- does not detect all mutations
- continued risk of sporadic cancer
- efficacy of interventions variable
what is the future of genetic testing
polygenic risk scores: decide screening in families without a highly penetrant mutation
increasing role of germline and tumour genetic profile in determining treatment of cancer
