Genetic predisposition to Cancer Flashcards
Describe the differences between somatic mutations and germline mutations
Somatic mutations o Occur in non-germline tissues o Are non-heritable Germ line mutations e.g. in sperm or ovum o Present in egg or sperm o Are heritable o Cause cancer family syndromes o Causes all cells in offspring to be effected
Define the important of clonal expansion in the formation of neoplasms
Cells in neoplasms compete for resources, such as oxygen and glucose, as well as space. Thus, a cell that acquires a mutation that increases its fitness will generate more daughter cells than competitor cells that lack that mutation. In this way, a population of mutant cells, called a clone, can expand in the neoplasm. Clonal expansion is the signature of natural selection in cancer.
What are the 3 major genetic mutations associated with cancer development?
- Oncogenes
- Tumour suppressor genes
- DNA damage-response genes
What are proto-oncogenes?
Proto-oncogenes – normal gene that codes for proteins that regulate cell growth and differentiation
Mutations can change a proto-oncogene into an oncogene. Oncogenes can accelerate cell division and play a role in cancer development
What are oncogenes?
Mutated proto-oncogenes, allowing the cells to carry through cell division unchecked.
What are tumour suppressor genes?
A tumor suppressor gene, or antioncogene, is a gene that protects a cell from one step on the path to cancer. When this gene mutates to cause a loss or reduction in its function, the cell can progress to cancer, usually in combination with other genetic changes. The loss of these genes may be even more important than proto-oncogene/oncogene activation for the formation of many kinds of human cancer cells
What are the DNA damage response genes?
The DNA damage gene response involves a network of cellular pathways that sense, signal and repair DNA lesions. Surveillance proteins that monitor DNA integrity can activate cell cycle checkpoints and DNA repair pathways in response to DNA damage, to prevent the generation of potentially deleterious mutations.
What is mismatch repair?
DNA mismatch repair is a system for recognizing and repairing erroneous insertion, deletion, and mis-incorporation of bases that can arise during DNA replication and recombination, as well as repairing some forms of DNA damage. Mismatch repair is strand-specific.
What cancer is associated with errors in mismatch repair?
HNPCC – hereditary non-polyposis colorectal cancer
What does mismatch repair usually result in?
Microsatellite instability
What is microsatellite instability?
Microsatellite instability (MSI) is the condition of genetic hypermutability that results from impaired DNA mismatch repair (MMR). The presence of MSI represents phenotypic evidence that MMR is not functioning normally.
Define a benign tumour
Benign – lacks ability to metastasize. Rarely or never become cancerous. Can still cause negative health effects due to pressure on other organs.
Define a dysplastic tumour
Dysplastic – ‘benign’ but could progress to malignancy. Cells show abnormalities of appearance & cell maturation. Sometimes referred to as ‘pre-malignant’ e.g. bowel polyps
Define a malignant tumour
Malignant – not ‘benign’. Able to metastasize.
Give an example of a cancer inherited dominantly due to a mutation to a proto-oncogene
MEN2 (multiple endocrine neoplasia)
Give examples of a cancer inherited dominantly due to a mutation in a tumour suppressor gene
Breast/ovarian cancer
FAP (familial adenomatous polyposis)
Retinoblastoma
Give examples of a cancer inherited dominantly due to a mutation in mismatch repair
HNPCC
Give an example of a cancer inherited autosomal recessively
MYH polyposis
Define a de nova mutation
De novo mutation, an alteration in a gene that is present for the first time in one family member as a result of a mutation in a germ cell (egg or sperm) of one of the parents or in the fertilized egg itself.
What can lead to the occurrence of a genetically linked cancer when there is no prior family history?
De nova mutations
Name some cancers which are often caused by de nova mutations
FAP (familial adenomatous polyposis)
MEN2 (multiple endocrine neoplasia)
Hereditory retinoblastoma
Describe the factors of both non-heritable and heritable retinoblastoma
Non-heritable - unilateral, no family history, dx ~ 2 yo, no increased risk of secondary cancers
Heritable - bilateral, germ line mutation in RB1 gene, 20% cases have family history, dx < 1 yo,increased risk of secondary cancers e.g. osteosarcoma, sarcomas, melanomas
What mutations causes heritable retinoblastoma?
Germ line mutation in RB1 gene (de nova mutations as well as inherited).
Describe risk factors for breast cancer
- Ageing
- Family history
- Early menarche
- Late menopause
- Nulliparity (no babies)
- Estrogen use
- Dietary factors (eg: alcohol)
- Lack of exercise
Name some genes responsible for hereditary breast cancer
BRCA 1/2 (20-40%/10-30%)
TP53 (<1%)
PTEN (
What are the normal functions of BRCA1 and BRCA2?
BRCA1 functions
o Checkpoint mediator
o DNA damage signalling and repair
o Chromatin remodelling (inactive X chromosome)
o Transcription (not essential for this)
BRCA2 functions
o DNA repair by HR (homologous recombination)
Describe 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
- Genetic mutations due to errors in MMR
Describe the clinical features of HNPCC
- Early but variable age at CRC diagnosis (~45 years)
- Tumor site throughout colon rather than descending colon
- Extra-colonic cancers: endometrium, ovary, stomach, urinary tract, small bowel, bile ducts, sebaceous skin tumors
Describe the clinical features of FAP
- Estimated penetrance for adenomas >90%
- Risk of extracolonic tumors (upper GI, desmoid, osteoma, thyroid, brain, other)
- CHRPE may be present (Congenital Hypertrophy of the Retinal Pigment Epithelium)
- Untreated polyposis leads to 100% risk of cancer
Describe the clinical features of 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
Describe the clinical features of MYH polyposis
- Similar clinical GI features to attenuated FAP
- Common mutations in mut- MYH gene
- Recessive inheritance i.e. need mutations in both copies of the gene.
Whats are the major issues with genetic screening for cancer susceptibility?
Problems of gene variants of unknown significance (VUS)
Moral dilemma of screening children for adult onset cancer
Surveillance or straight in?
