Exam 4.1 Genetics of Cancer: Oncogenes and Tumor Suppressors

Genetic and epigenetic

Cancer develops from accumulation of _____ and ____ changes that disrupt normal cell growth and regulation

What are the 2 types of mutations?

Inherited (germline) mutation and Somatic mutation

Present in egg or sperm, passed on to offspring

Inherited (Germline) Mutation

Occurs after birth in body cell; not inherited

Somatic Mutation

True or False

Most inherited mutations do not directly cause cancer, but predispose on a person to an increased risk of developing cancer

True

What are some of the traits of cancer?

- Multiple genetic mutation

- Environmental factors

- Gene-environment interactions

This type of tumor is an excessive growth that stays within the basal lamina

Benign tumor

This type of tumor is an excess growth leaked out of basal lamina

Malignant tumor

Tumor growth and progression involves multiple roads of ____ and ___ changes

Genetic and epigenetic

Each ____ gives the cell growth or survival advantage

Hit

Cancer develops after accumulating _______ key genetic "hits" in a single cell

2-8

_______ is a mutation in DNA sequence that causes permanent changes

Genetic changes

Genetic changes affect key genes such as what?

- Oncogenes

- Tumor suppressor genes

- DNA repair genes

True or False

Genetic changes cannot be inherited or acquired

False

______ does not alter DNA sequence, but does affect gene expression

Epigenetic changes

Epigenetic changes includes:

- DNA Methylation

- Histone modification

- MicroRNA dysregulation

Normal cell division and Normal apoptosis leads to _____

Hemeostasis

Increase cell division and normal apoptosis leads to:

Tumor

Normal cell division and Decreased apoptosis leads to:

Also tumor

Cancer can be classified based on ____ or _____

Tissue or cell type they originate from

This type of cancer arise from epithelial cells

Carcinoma

This type of cancer arise from connective tissue and muscle.cells

Sarcomas

This type of cancer arise from white blood cells and their precursors (hematopoietic cells)

Leukemias

This type of cancer arise from lymphatic tissue

Lymphomas

This type of cancer arise from glial cells of the CNS

Gliomas

This gene regulates cell growth and division. They also prevent uncontrolled cell proliferation. However, they become mutated or inactive in cancer and becomes cancer-related gene

Tumor suppressor genes

This cancer-related gene promote cell growth and division, it also causes uncontrolled cell proliferation. This is the mutated version of proto-oncogene

Oncogenes

This cancer-related genes help repair DNA damages

DNA Repair DNA damages

Tumor suppressor genes does the following:

- Anti-oncogenes

- Slow down cell division

- Repair DNA damage

- Triggers apoptosis

What happens when tumor suppressor genes don't work?

- Cell grows uncontrollably

- DNA damage accumulates

- Abnormal cells survive and divide

- Leads to cancer development

Tumor suppressor genes causes cancer when they are inactivated by what?

- Mutation

- Deletion

- Methylation

The following are examples of what?

- Rb gene (RB1) for retinoblastoma

- p16 (CDKN2A) for melanoma and pancreatic cancer

- p53 gene (TP53) for many cancers

Methylation

Oncogenes is a mutated _____

Proto-oncogenes

What does proto-oncogene do?

Control cell growth and division

Oncogene causes what?

Uncontrolled cell growth and division, leads to cancer development

What is the mechanism of Oncogenes?

- Activation of gain of function mutation

- One mutated copy of allele is not often enough to promote cancer

What are some examples of proto-oncogenes?

- RAS

- MYC

- EGFR

This is a type of eye cancer in children

Retinoblastoma

What does Rb protein do?

- Universal cell cycle regulator

- Function as a brake on cell cycle progression

Cancer occurs when ____ is mutated

2 Rb genes

What are the other tumor suppressor genes that follow 2-hit behavior?

- TP53

- BRCA1/2

What are the 2 types of Retinoblastoma?

- Hereditary retinoblastoma

- Sporadic retinoblastoma

Which type of retinoblastoma is being described?

- First mutation is inherited (germline)

- Second mutation is somatic

- Appears early

- Often affects both eyes (bilateral)

Hereditary retinoblastoma

Which type of retinoblastoma is being described?

- Both mutations appears somatically

- Appears later

- Usually affect only one eye (unilateral)

Sporadic retinoblastoma

These are tumor suppressor genes that work together to regulate the G1-to-S phase transition of the cell cycle. Which are they?

p16 and Rb genes

This gene is a transcriptional corepressor that forms complexes with E2F transcription factors to inhibit cell proliferation. What is it?

Rb genes

______ inhibits E2F which prevents G1-to-S transmission

Active Rb

_____ is a CDK inhibitor that blocks Cdk4/6 activity

p16 gene

What does the inactivation of the p16 gene do?

Activates cyclin D-Cdk4/6 complex, which phosphorylates Rb to release E2F

What do active E2F do?

It drives G1-to-S phase transition

What happens when either the p16 or the Rb genes are inactive?

The cell cycle runs unchecked which leads to cancer development

This protein is a tumor suppressor encoded by the TP53 gene. What is it?

p53 protein

p53 protein is also known as the ____

Guardian of the genome

What are some of the functions of p53 proteins?

- Arrest the cell cycle to allow DNA repair

- Trigger apoptosis if damage is irreparable

- Trigger cellular senescence (permanent cell-cycle arrest)

- Prevent propagation of damaged DNA to daughter cells

A mutation of this is found in most tumor types. What gene is it?

TP53 (tumor suppressor gene)

These are responsible for 12-20% of human cancers worldwide.

Viruses

What are the 2 types of viruses?

DNA and RNA

This type of virus is also known as Retroviruses

RNA viruses

What is an example of an RNA virus?

Hep C, which leads to liver cancer

What is an example of a DNA virus?

Human papillomavirus (HPV), which leads to cervical and throat cancer

HPV is a type of DNA virus that causes cancer. It produces 2 key oncoproteins. What are they?

E6 and E7

What do E6 and E7 oncoproteins do?

They disrupt normal cell-cycle control and promote cancer development

Which oncoprotein binds to and promotes the degradation of p53, leading to loss of p53 function, which impairs DNA repair and inhibits apoptosis, allowing damaged cells to survive and divide, and leading to cancer development?

HPV E6 oncoprotein

Which oncoprotein binds and inhibits the retinoblastoma (pRb) protein (tumor suppressor) and activates E2F to drive transcription of genes required for S-phase entry, leading to uncontrolled cell proliferation?

HPV E7 oncoprotein

This type of virus leads to cervical and oropharyngeal (head and neck) cancers. What is it?

HPV (Human papillomavirus)