Genetic Predisposition to Cancer Flashcards
Cancer is a genetic disease of
somatic cells
Most cancers happen by
‘chance’ or due to envinronmental factors
Somatic mutations
- Occur in nongermline tissues
- Are nonheritable
Germline mutations
- Present in egg or sperm
- Are heritable
- Cause cancer family syndromes
- All cells affected in offspring
Different genetic processes associated with Cancer
- Oncogenes
- Tumour suppressor genes
- DNA damage-response genes
Proto-oncogenes =
normal gene that codes for proteins to regulate cell growth and differentiation.
Mutations can change a proto-oncogene into
an oncogene
- Oncogenes can accelerate cell division
- Cancer arises when stuck in “on” mode
Tumour suppressor genes
- The cell’s brakes for cell growth
- Genes inhibit cell cycle or promote apoptosis or both
- Cancer arises when both brakes fail
‘Two – hit’ hypothesis (Knudson 1971)
The Two-Hit Hypothesis example
First hit in germline of child
- Second hit (tumor)
not everyonewho has the gene will develop the cancer but they have a higher risk of having it than someone who doesnt have the first hit.
oncogenes are
dominant genes in effect
tumour suppressor genes are
recessive genes in effect
- second mutation or loss results in cancer
DNA damage-response genes
The repair mechanics for DNA
- Cancer arises when both genes fail, speeding the accumulation of mutations in other critical genes
HNPCC Results From
Failure of Mismatch Repair (MMR) Genes
Mismatch Repair Failure Leads to
Microsatellite Instability (MSI) - addition of nucleotide repeats
MMR corrects errors that
spontaneously occur during DNA replication like single base mismatches or short insertions and deletions
Cells with abnormally functioning MMR tend to
accumulate errors.
Microsatellites (aka Simple Sequence Repeats SSR) are
repeated sequences of DNA, can be made of repeating units of 1 – 6 base pairs
MSI (changes in microsatellite sequences) is the
phenotypic evidence that MMR is not functioning normally – genetic hypermutability
BENIGN =
lacks ability to metastasize. Rarely or never become cancerous.
Can still cause negative health effects due to pressure on other organs.
DYSPLASTIC =
‘benign’ but could progress to malignancy.
Cells show abnormalities of appearance & cell maturation. Sometimes referred to as ‘pre-malignant’.
(NB distinguish from ‘hip dysplasia’ which is macroscopically abnormal but not pre-malignant!)
MALIGNANT =
not ‘benign’. Able to metastasize.
NB distinguish from ‘malignant hypertension’, ‘malignant hyperthermia’
Tumour suppressor genes that are common dominantly inherited cancer syndromes
BRAC1, BRAC2
APC
P53
RB
Mutation of P53 leads to
Li-Fraumeni syndrome
Oncogenes that are common dominantly inherited cancer syndromes
RET
Mutation of RET causes
MEN2 (multiple endocrine neoplasia)
familial medullary thyroid cancer
DNA repair (mis-match repair) that are common dominantly inherited cancer syndromes
MLH1, MSH2, MSH6,
PMS1, PMS2
mutations of MLH1, MSH2, MSH6, PMS1 or PMS2 can lead to
HNPCC/Lynch syndrome
Autosomal recessive syndromes =
both copies of the gene have inherited mutations
- MYH polyposis
New (de novo) mutation occurs in
germ cell of parent
- no family history of hereditary cancer syndrome
de novo mutations are common in:
- Familial adenomatous polyposis
- Multiple endocrine neoplasia 2B
- Hereditary retinoblastoma
How do we look for an inherited cancer predisposition syndrome?
TAKE A FAMILY HISTORY!
Most Cancer Susceptibility Genes Are
Dominant With Incomplete Penetrance.
- May appear to “skip” generations
- Individuals inherit altered cancer susceptibility gene, not cancer
Features of Retinoblastoma
- Most common eye tumor in children
- Occurs in heritable and nonheritable forms
- Identifying at-risk infants substantially reduces morbidity and mortality
Heritable Retinoblastoma is
Usually bilateral
- some in family history
- inccreased risk of osteosarcoma, other sarcoma, melanoma
- less than one years old
Inheritable retinablastoma is
unilateral
- no family history
- no risk of secondary primaries
- around 2 years old
Risk Factors for Breast Cancer
- Ageing
- Dietary factors (eg: alcohol)
- Lack of exercise
- Family history
- Late menopause
- Estrogen use
Genes contributing to familial ovarian cancer
BRCA1 BRCA2 TP53 RAD51C RAD51D Mis-match repair gene
Genes contributing to familial breast cancer
BRCA1 BRCA2 TP53 PALB2 PTEN
BRCA1-Associated Cancers:
Lifetime Risk
likelihood of having secondary breast cancer and ovarian cancer.
- Possible increased risk of other cancers (eg, prostate, colon)
BRCA2-Associated Cancers:
Lifetime Risk
occurs in men too.
Increased risk of prostate, laryngeal, and pancreatic cancers (magnitude unknown)
Risk Factors for Colorectal Cancer (CRC)
- Ageing
- Personal history of CRC or adenomas
- High-fat, low-fibre diet
- Inflammatory bowel disease
- Family history of CRC
Clinical Features of HNPCC
- Early but variable age at CRC diagnosis (~45 years)
- Tumor site throughout colon rather than descending colon
- Extracolonic cancers: endometrium, ovary, stomach, urinary tract, small bowel, bile ducts, sebaceous skin tumors
Untreated polyposis leads to
100% risk of cancer
Attenuated FAP is
Later onset (CRC ~age 50)
- Few colonic adenomas
- Not associated with CHRPE
- Upper GI lesions
- Associated with mutations at 5’ and 3’ ends of APC gene
Attenuated FAP is associated with mutations at
5’ and 3’ ends of APC gene
Recessive MYH polyposis have
Similar clinical GI features to attenuated FAP
Managing cancer risk in Adenomatous Polyposis syndromes can be done through
- Surveillance
- Surgery
- Chemoprevention
Mutation testing is now being carried out routinely on certain cancers, to
identify familial mutations and to target therapies
