Cancer Genetics

Question 1

Driver mutation

Answer 1

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.

Question 2

Passenger mutations

Answer 2

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.

Question 3

HER2/NEU

Answer 3

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

Question 4

Herceptin

Answer 4

Drug used in the treatment of breast cancer patients with HER2/NEU mutation.

Question 5

Categories of associated with cancer predisposition

Answer 5

1. Tumor supressor genes: normally function to halt tumor growth. When they are mutated cancers can develop.
2. Oncogenes: necessary for life and are very highly regulated. When regulation is disrupted they are stuck in “on” mode and can result in oncogenesis
3. 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.

Question 6

Gain of function mutation in cancer

Answer 6

Gene amplifications, point mutations, promoter muations that turn one allele of a proto-oncogene into an oncogene.

Question 7

Loss of function mutation in cancer

Answer 7

One or both allese of a tumor supressor gene are mutated and repression mechanisms for cancer development are lost

Question 8

Chromosome translocations in cancer

Answer 8

Cause mis-expression of genes or fusion of genes that confer novel functional proerties that can lead to cancers.

Question 9

What kind of inheritance pattern do familial cancer syndromes caused by mutations in tumor supressor genes follow?

Answer 9

Autosomal Dominant

Question 10

What kind of penetrance expression do autosomal dominant disorders usually express?

Answer 10

Reduced Penetrance/Incomplete penetrance

Question 11

What kind of penetrance do autosomal recessive disorders usually exhibit

Answer 11

Complete Penetrance

Question 12

Complete penetrance

Answer 12

All individuals who have the alleles express the phenotype of the disease

Question 13

Reduced or incomplete penetrance

Answer 13

Some individuals who have the genotype fail to express the trait even though they carry the gene.

Question 14

List the factors affecting cancer penetrance

Answer 14

1. Modifier genes/noncoding genes (familial gene)
2. Carcinogens
3. Hormonal & Reproductive factors
4. Response to DNA damage

Question 15

Neurofibromatosis-1

Answer 15

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.

Question 16

Most cancer susceptibility genes follow a(n) _________________ inheritance pattern.

Answer 16

Autosomal dominant with reduced penetrance.

Question 17

Mutations in what type of gene are most common in familial cancer?

Answer 17

Mutations in tumor supressor genes.

Question 18

What is the two hit hypothesis?

Answer 18

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.

Question 19

Two main hallmark’s of familial cancer syndromes.

Answer 19

1. Early onset

2. Bilaterality (i.e. bilateral breast tumors, bilateral retinoblastomas)

Question 20

Li-Fraumeni Syndrome

Answer 20

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.

Question 21

TP53

Answer 21

Gene located on chromosome 17 that when mutated can lead to Li-Fraumeni Syndrome

Question 22

Holding’s rule

Answer 22

For any isolated affected individual in a pedigree, there is a 1/3 chance their condition is caused by a new mutation.

Question 23

How many mutations are necessary for tumor development from oncogenes?

Answer 23

1