Genetic Predisposition to Cancer Flashcards
What are somatic mutations?
Most common form of cancer where cells iwhtin the body, not the germline, develop genetic alterations.
Where do somatic mutations occur?
Occur in nongermline tissues
Are somatic mutations inheritable?
No
Where do germline mutations arise from?
Present in egg or sperm
Are germline mutations inheritable?
Yes and can cause family cancer syndromes.
Describe what is meant by the fact that tumours are clonal expressions.
-A normal cell develops an alteration and then through the daughter cells copying and dividing, more mutations can be acquired.
As more critical mutations arise, you may get a tumour with the potential to metastasise.
Wat are proto-oncogenes?
Normal gene that codes for proteins to regulate cell growth and differentiation.
What changes a proto-oncogene into an oncogene?
Mutations
What can oncogenes do to cell division?
Accelerates the process
How many mutations is sufficient enough for the fomration of cancer?
1
What are Tumour suppressor genes?
The cell’s brakes for cell growth as genes can inhibit the cycle, promote apoptosis or both.
When does cancer occur?
If both Tumour suppressor genes do not function and not not ‘brake’.
How many hits on Tumour suppressor genes does it take for cancer to arise?
2 as two brake mechanisms
(inhibition and apotosis).
What are DNA damage-response genes?
The repair mechanics for DNA
When does cancer arise relating to DNA damage-response genes?
Cancer arises when both genes fail, speeding the accumulation of mutations in other critical genes
What does mismatch repair do?
(
MMR corrects errors that spontaneously occur during DNA replication like single base mismatches or short insertions and deletions
What are microsatellites?
Microsatellites (aka Simple Sequence Repeats SSR) are repeated sequences of DNA, can be made of repeating units of 1 – 6 base pairs
What is MSI?
(Microsatellite instability)
MSI (changes in microsatellite sequences) is the phenotypic evidence that MMR is not functioning normally – genetic hypermutability
Describe benign tumours.
-Lacks ability to metastasize.
-Rarely or never become cancerous.
-Can still cause negative health effects due to pressure on other organs.
Define malignant tumours.
Able to metastasize.
Describe dysplastic tumours.
Benign but could progress to malignancy. Cells show abnormalities of appearance & cell maturation. Sometimes referred to as ‘pre-malignant’.
Give examples of some Dominantly Inherited Cancer Syndromes and then gene process and genes that cause them.
Familial medullary thyroid cancer- RET genes in oncogenes
Breast/ovarian cancer- BRCA1, BRCA2 in tumour suppressor genes
HNPCC / Lynch Syndrome- MLH1, MSH2, MSH6, PMS1, PMS2 in DNA repair/ DNA mismatch repair
What are de novo mutations?
New mutation in an individual present in the germline but not in their parents
What is retinoblastoma?
Most common eye tumour in children
List some of the risk factors of breast cancer.
Ageing
Family history
Early menarche
Late menopause
Nulliparity
Estrogen use
Dietary factors (eg: alcohol)
Lack of exercise
List some of the high risk genes contributing to familial breast cancer.
BRCA1
BRCA2
List some of the moderate risk genes contributing to familial breast cancer.
CHEK2 heterozygous mutation
BRIP1
List some of the high risk genes contributing to familial ovarian cancer.
BRCA1
BRCA2
List some of the moderate risk genes contributing to familial ovarian cancer.
PALB2
BARD1
List some 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
List some clinical features of HNPCC
-Early but variable age at CRC diagnosis (~45 years)
-Tumour site throughout colon rather than descending colon
List some clinical features of HNPCC
-Early but variable age at CRC diagnosis (~45 years)
-Tumour site throughout colon rather than descending colon
Give a few examples pf extracolonic cancers
Extracolonic cancers: endometrium, ovary, stomach, urinary tract, small bowel, bile ducts, sebaceous skin tumors
What does Non-polyposis mean?
Few to no adenomas
What does polyposis mean?
Several adenomas.
List some clinical features of FAP (familial adenomatous polyposis)
Estimated penetrance for adenomas >90%
Risk of extracolonic tumors (upper GI, desmoid, osteoma, thyroid, brain, other)
CHRPE (Congenital hypertrophy of the retinal pigment epithelium) may be present
Untreated polyposis leads to 100% risk of cancer
Describe Attenuated FAP
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
How is cancer risk in Adenomatous Polyposis syndromes managed?
Surveillance
Surgery
Chemoprevention
Those with family history of cancer…
are more likely to get it
Who does genetic counselling?
Clinical geneticist
Genetic counsellor
Hospital doctor
GP
Nurse…
->GP’s and nurses more as beginning to mainstream genetic testing so some is undertaken by these professionals.
