Lecture 15: Cancer Predisposition

How does one’s rate of mutation accumulation correlate with cancer risk?

Cancer - genetic disease trigger by mutations in tumor suppressors and oncogenes

If a person accumulates somatic mutations at a faster rate, cancer risk will be higher

Where would a somatic mutation have to occur in a parent to produce a child with a germline mutation?

In the ovaries or testes of their parent → produces an egg or sperm that carries the mutation

What is the main difference in the tumor micro-environment of a person with neurofibromatosis type 1 compared to a person without neurofibromatosis type 1?

tumor micro-environment: non-tumor cells and extraceullular matrix that surrounds tumors

neurofibromatosis - all cells in micro-environment are haploinsufficient for NF1

What two cell types can be transformed into cancer by mutations in NF1? Do you expect that these mutations are loss of function mutations or gain of function mutations?

Melanocytes and Schwann cells

Loss of function mutations - NF1 is a tumor suppressor

Would the function of a protein encoded by a tumor suppressor gene be to stimulate cell proliferation? Why or why not?

No, tumor suppressors are cellular brakes - slow or pause cell proliferation

Hereditary cancer syndrome usually are caused by mutations in tumor suppressors, not oncogenes. Propose a reason why.

Oncogenic mutations are GOF, would likely act in dominant fashion - disrupt many essential processes related to proliferation and survival

• decreased survival rate

Tumor suppressor mutations are usually LOF, act in a hereditary fashion

• hereditary cancer syndromes are inherited as heterozygous mutations → one good copy to carry out normal functions

What component of the MAPK goes into the nucleus to bind DNA?

ERK when it is phosphorylated

What are four ways to make the MAPK pathway send more signals to the nucleus?

1. Increase expression of ligand that binds to receptor on cell surface

2. Loss of function mutation in NF1

3. Gain of function mutation in RAS that makes it less able to hydrolyze GTP back to GDP

4. Gain of function mutation in RAF in the auto-inhibitory domain

Answer the following questions about the below figure of somatic mutations that were found in various uveal melanoma tumors

1. What gene is the most frequently mutated in uveal melanomas?

   GNAQ

2. What information about the BAP1 gene suggests that it is a tumor suppressor?

   Truncations and splice site mutations usually produce LOF

3. Is it likely that a uveal melanoma tumor will have a mutation in both the GNAQ and GNA11 genes?

   No, there are no cases of overlap in the table

4. Can a uveal melanoma tumor have both a GNA11 and an EIF1AX?

   Yes, there is one sample like this in the above table

Using the following information acquired from deep sequencing of various tissues to look for somatic mutations, indicate on the diagram when each detected mutation (A, B, C…) must have arisen during the development of this child

1. Skin sample (ectoderm): ABCDE

2. Kidney sample (intermediate mesoderm): DEFGHIJ

3. Blood sample (lateral mesoderm): DEFGLMN