Genetic Predisposition to cancer Flashcards
Where do somatic mutations occur
In non-germline tissues so are non-heritable
Where are germline mutations found
In eggs or sperm so they are heritable and can cause cancer family syndromes
Which genetic processes are associated with cancer
Oncogenes
Tumour suppressor genes
DNA damage-response genes
What are tumours considered to be
Clonal expansions
What are proto-oncogenes
A normal gene that codes for proteins to regulate cell growth and differentiation
What can cause a proto-oncogene to become an oncogene
Mutations
What does one mutation in an oncogene do
Accelerate cell division
What are tumour suppressor genes
The cell’s brakes for cell growth
What are benign tumours
Tumours which are unable to metastasise
They rarely or never become cancerous but can still cause negative health effects due to pressure on other organs
What are the risk factors for breast cancer
Nulliparity Estrogen use Dietary factors (e.g. alcohol) Lack of exercise Ageing Family history Early menarche Late menopause
Which genes can cause hereditary cancer
BRCA1
BRCA2
TP53
PTEN
What are the risk factors of colorectal cancer
Ageing Personal history of CRC or adenomas High-fat, low-fibre diet Inflammatory bowel disease Family history of CRC
What are adenomas seen as in colorectal cancer
Dysplastic
Which genes are associated with cancer
Oncogenes
Tumour suppressor genes
DNA damage-response genes
How many mutations are required in an oncogene for cancer development
1
How do tumour supressor genes act as a cell’s brakes
They inhibt the cell cycle or promote apoptosis or both
When does cancer arise in regards to tumour supressor genes
When BOTH breaks fail
How many mutations are required in tumour supressor genes for cancer development
2
What are DNA damage response genes
The repair mechanics for DNA
How many mutations are required in DNA damage response genes for cancer development
2
What happens when both genes fail in DNA damage response genes
It speeds the accumulation of mutations in other critical genes
What is HNPCC
Hereditary nonpolyposis colorectal cancer
How does HNPCC arise
From the failure of mismatch repair (MMR) genes
So a base pair mismatch will not undergo DNA repair causing another base to be inserted (so 2 wrong bases present)
What does mismatch repair failure lead to
Microsatellite instability (MSI)
What occurs in microsatellite instability (MSI)
Novel Microsatellite fragments (simple sequence repeats - SSRs) are created
What do mismatch repair (MMR) genes do
Correct errors that spontaneously occur during DNA replication like single base mismatches or short insertions and deletions
What is phenotypic evidence that MMR is not functioning normally
The presence of MSI
What are dysplastic cells
Cells that show abnormalities of appearance & cell maturation
The are benign but could progress to malignancy so are known as pre-malignat
What are malignant tumours
Tumours which can metastasise
Give an example of an oncogene
RET
Give an example of a cancer syndrome an oncogene can cause
MEN2 (Multiple endocrine neoplasia)
Familial medullary thyroid cancer
Give an example of a tumour suppressor gene
BRCA1, BRCA2
APC
P53
RB
Give an example of a cancer syndrome a tumour suppressor gene can cause
Breast/ovarian cancer
Li-Fraumeni syndrome
Retinoblastoma
Give an example of a DNA repair gene
MLH1, MSH2, MSH6, PMS1, PMS2
Give an example of a cancer syndrome a DNA repair gene can cause
HNPCC
Lynch Syndrome
What are the other causes of cancer
Autosomal recessive syndromes (e.g. MYH polyposis)
Where do de novo mutations occur
In the germ cell of a parent that has no family history of hereditary cancer syndrome
Where are de novo mutations common
Familial adenomatous polyposis
Multiple endocrine neoplasia 2B
Hereditary retinoblastoma
Why do most cancer susceptibility genes , which are dominant show incomplete penetrance
The individuals inherit altered cancer susceptibility gene not cancer
What is retinoblastoma
The most common eye tumor in children that can occur in heritable and nonheritable forms
Identifying at-risk infants substantially reduces morbidity and mortality
Describe the features of inherited retinoblastoma
Tumour: Usually bilateral
Average age at diagnosis: Under
Increased risk of second primaries: Osteosarcoma, other sarcomas, melanoma, others
How many mutations are required for colorectal cancer to occur
Multiple
How many adenomas occur in non-polyposis hereditary CRC syndromes
few to none
How many adenomas occur in polyposis hereditary CRC syndromes
Multiple
Give examples of polyposis hereditary CRC syndromes
FAP – severe colonic polyposis +/- CRC
AFAP - less severe colonic polyposis +/-CRC
MAP – varying degrees of colonic polyposis +/- CRC
What is FAP, AFAP and MAP
FAP – familial adenomatous polyposis
AFAP – attenuated FAP
MAP – MYH associated polyposis
What are the clinical features of HNPCC
Early but variable age at CRC diagnosis ( about 45 years)
Tumor site throughout colon rather than descending colon
Extracolonic cancers: ovary, stomach, urinary tract
What are the clinical features of FAP
Risk of extracolonic tumors (upper GI, desmoid, osteoma, thyroid, brain, other)
CHRPE may be present
What are the clinical features of FAP
Risk of extracolonic tumors (upper GI, desmoid, osteoma, thyroid, brain, other)
CHRPE (Congenital Hypertrophy of the Retinal Pigment Epithelium) may be present
What are the clinical features of attenuated FAP
Later onset (CRC about age 50) Few colonic adenomas Not associated with CHRPE Upper GI lesions Associated with mutations at 5' and 3' ends of APC gene
What are the clinical features of attenuated FAP
Later onset (CRC about age 50) Few colonic adenomas Not associated with CHRPE Upper GI lesions Associated with mutations at 5' and 3' ends of APC gene
What are the meatures of MYH polyposis
Upper GI lesions (similar to attenuated FAP)
Common mutations in mut- MYH gene
Recessive inheritance
How is cancer managed in adenomatous polyposis syndromes
Through:
Surveillance
Surgery
Chemoprevention
Polymorphisms, mutations and variants of unknown significance may
Have no difference or have a huge difference
What advances in technology are helping in cancer studies
Exome sequencing - looks for misprints in exons
Genome sequencing - looks for misprints in the whole genome
What do inherited mutations cause
An increased predisposition to cancer
Only a small proportion of cancers are due to inherited mutations
