lecture 2- cancer genetics

Question 1

Describe how checkpoints in the cell cycle contribute to the genetic fidelity of the process of cell division

Answer 1

Question 2

When would CELL ARREST OR DELAY occur

Answer 2

Growth signals absent or excessive

DNA damage or incomplete

Chromosomes not attached to spindles

Question 3

Outline how oncogenes of viral or host-cell origin may become activated and contribute to dysregulated cell division in cancer

Answer 3

An oncogene can induce a gene to become constitutively activated

Ex:

EGF activated MAPK which activated MYC

VRAS can activate MAPK in the absence of EGF. This is the example of Epstein barr virus- lymphoma

Question 4

What is a proto-oncogene

Answer 4

Proto-oncogene activating mutation that can derive from point mutation or a mutation in the controlling region , or the fusion of another protein that causes its activation

Question 5

Distinguish the main evolutionary stages in the development of a solid tumor, including cellular proliferation in situ, invasion, and metastasis, and outline the dysregulated cellular processes mediated by genetic alterations at each stage

Answer 5

Proliferation-invasion-metastasis

Invasion: can result from a single cell or multiple.

Disrupted epithelium, BM degredation, reactive stromem, stroma fibers realigned

BM perforated, tracks of stroma fibers, invasion mixing of stromal fibers, EMT

Overall: MMPs, abnormal BM, tracking along nerves nd blood vessels

metastisis: dissementation, micrometastisis, and macrometastisis

dissementaion is short term , micro is long term survival and macro is reseeding and tertiary amplification

Question 6

Outline how germline mutation of tumor suppressor genes predisposes to cancer using Rb as specific examples, and describe how further somatic mutation of such genes contributes further to tumor evolution

Answer 6

Rb is tumor suppressor gene

MAPK blocks Rb, RB blocks E2F and the E2F induces cyclins to signal to begin the S phase. So deletion of Rb allos entry into S phase

Question 7

a.Outline how germline mutation of tumor suppressor genes predisposes to cancer using TP53 as specific examples, and describe how further somatic mutation of such genes contributes further to tumor evolution

Answer 7

TP53 is also a tumor suppressor gene

TF respond to cell stress such as DS breaks by causing cell arrest and apoptosis.

Normally the ATM/ATR phorphorylates P53 - P21 - shut down cell cycle and makes it remain in G1

Malfunction leads to genetic instability, damaged cells with DS breaks allowed to enter the S phase

Question 8

a.Outline how germline mutation of tumor suppressor genes predisposes to cancer using BRCA1/2 as specific examples, and describe how further somatic mutation of such genes contributes further to tumor evolution

Answer 8

BRCA1/2 - protein complex recruited to ds breaks.

Most people are heterozygous until tumor formation.

When inactive there re impaired DNA repair processes

Question 9

Outline how genetic alterations that result in the expression of neoantigens by tumor cells render such cells susceptible to immune destruction and how host immune mechanisms may be exploited for therapeutic benefit

Answer 9

Immune surveillance protects against cancer, to amp this up one can take dendritic cells expose them to antigens and present to T cells and then the T cell will produce killer T cells as well as helper T cell aagainst that. Tumors can also use PD-L to bind to PD1 of T cells and make then inactive. Antibodies can bind to either of those to restore recognition