Cancer Genetics Flashcards
Driver mutation
Mutations that are causally implicated in oncogenesis. They are the mutations responsible for the growth of the cancer. They may not be required for the maintenance of the final cancer, but many times are.
Passenger mutations
These mutations are not responsible for cancer development and growth but are within cancer genomes as inert somatic mutations and are present in the final cancer.
HER2/NEU
Oncogene that is upregulated in certain types of breast cancer. A mutation in HER2/NEU gives a worse prognosis. Testing for HER2/NEU is now standard of care to allow for better treatment options for breast cancer patients = Herceptin
Herceptin
Drug used in the treatment of breast cancer patients with HER2/NEU mutation.
Categories of associated with cancer predisposition
- Tumor supressor genes: normally function to halt tumor growth. When they are mutated cancers can develop.
- Oncogenes: necessary for life and are very highly regulated. When regulation is disrupted they are stuck in “on” mode and can result in oncogenesis
- DNA damage-response genes: genes that produce proteins responsible for DNA repair. When these genes are mutated, DNA repair is disrupted which leads to accumulations of mutations in DNA and cancer development.
Gain of function mutation in cancer
Gene amplifications, point mutations, promoter muations that turn one allele of a proto-oncogene into an oncogene.
Loss of function mutation in cancer
One or both allese of a tumor supressor gene are mutated and repression mechanisms for cancer development are lost
Chromosome translocations in cancer
Cause mis-expression of genes or fusion of genes that confer novel functional proerties that can lead to cancers.
What kind of inheritance pattern do familial cancer syndromes caused by mutations in tumor supressor genes follow?
Autosomal Dominant
What kind of penetrance expression do autosomal dominant disorders usually express?
Reduced Penetrance/Incomplete penetrance
What kind of penetrance do autosomal recessive disorders usually exhibit
Complete Penetrance
Complete penetrance
All individuals who have the alleles express the phenotype of the disease
Reduced or incomplete penetrance
Some individuals who have the genotype fail to express the trait even though they carry the gene.
List the factors affecting cancer penetrance
- Modifier genes/noncoding genes (familial gene)
- Carcinogens
- Hormonal & Reproductive factors
- Response to DNA damage
Neurofibromatosis-1
Autosomal dominant disorder with variable expressivity. Severe cases can have many benign neurofibromas all over their bodies while more mild cases will have numerous characteristic cafe-au-lait spots.
Most cancer susceptibility genes follow a(n) _________________ inheritance pattern.
Autosomal dominant with reduced penetrance.
Mutations in what type of gene are most common in familial cancer?
Mutations in tumor supressor genes.
What is the two hit hypothesis?
Described as one “hit” or mutation being inherited in germline cells. This makes an individual a susceptible carrier for cancer. Then, sometime during life, the individual will have a second “hit” acquiring another mutation. There is an 80-90% chance a person will receive a second hit once they have the first. This is because there are several ways a 2nd hit can be obtained.
Two main hallmark’s of familial cancer syndromes.
- Early onset
2. Bilaterality (i.e. bilateral breast tumors, bilateral retinoblastomas)
Li-Fraumeni Syndrome
Autosomal dominant syndrome caused by germline mutations in TP53 on chromosome 17. Characterized by early onset cancer (50% risk of cancer by 35) and 90% lifetime risk of cancer for women, 70% lifetime cancer risk for men.
TP53
Gene located on chromosome 17 that when mutated can lead to Li-Fraumeni Syndrome
Holding’s rule
For any isolated affected individual in a pedigree, there is a 1/3 chance their condition is caused by a new mutation.
How many mutations are necessary for tumor development from oncogenes?
1
