Graeme Finlay 2

Question 1

What are the two main methods through which RNA viruses can cause tumours?

Answer 1

Insertional mutagenesis where the viruses integrates adjacent to cellular genes that regulate proliferation and activating them
Oncogene transduction where acutely transforming retroviruses had viral sequences replaced by cellular sequences the cell gene is then damaged causing a chimaeric or truncated protein to be expressed and transform the host cell

Question 2

What are the genetic alterations causing gain of function mutants?

Answer 2

Amplification, Deletion affecting activity, Translocation affecting transcription, translocation disrupting protein structure, point mutations
These changes generate oncogenes

Question 3

How can an amplification mutation generate an oncogene?

Answer 3

Many tumours possess extra chromatin in the form of double minute chromosomes or homogenously-staining regions.
Increased copies of Myc are foundin breast and small cell lung cancer and ERB1 in squamous carcinoma and glioblastoma

Question 4

How can a deletion affecting activity generate an oncogene?

Answer 4

In glioblastomas and many other carcinomas there are deletions of ERB1 gene which remove only exons 2-7 causing the ER1 protein to lack a negative regulatory domain and generate excessive activity

Question 5

How can a translocation affecting transcription generate an oncogene?

Answer 5

Many tumour types have mutations which contain specific chromosomal rearrangements. Burkitts lymphoma has one of three translocations t(8:14), t(2:8), t(8:22) these put the MYC gene under control of the one of the three IgH loci regulated by IgH enhancers

Question 6

How can a point mutation generate an oncogene?

Answer 6

Mutations in the RAS family can occur in codons 12,13 or 61 to transform fibroblasts

Question 7

How can a translocation disrupting protein structure generate an oncogene?

Answer 7

In chronic myelogenous leukaemia there is a t(9:22) where the ABL protooncogene is broken with an intron and replaced by some of the BCR gene. This hybrid protein then replaces the normal protein

Question 8

How can genetic alterations causing loss of function mutants lead to cancer?

Answer 8

They act on tumour suppressor genes which normally restrain proliferation and promote differentiation. Recessive mechanisms require the loss of two alleles while dominant mechanisms require the loss of only one allele

Question 9

What are the two mechanisms that can cause loss of function mutants?

Answer 9

Genetic mechanisms which is any mutation which destroys gene function with a typical pattern being a point mutation followed by a loss of chromosome material
Epigenetic mechanisms where genes may be inappropriately turned off by DNA methylation in CpG islands