Download Week 2--1/18

Genes altered in cancer typically:
• Have a positive role in cell division
• Have a negative role in cell division
• Have a role in the maintenance of DNA integrity
Protooncogenes  Oncogenes
Too much of a good thing….
Src
Conversion of a Protooncogene  an Oncogene
Change gene Expression / Protein Production
Alter promoter utilization by
METHYLATION
Alter promoter utilization
Alter promoter utilization by POINT MUTATION
Frequency of TERT promoter mutations in human cancers.
Abstract
Reactivation of telomerase has been implicated in human tumorigenesis, but the underlying mechanisms
remain poorly understood. Here we report the presence of recurrent somatic mutations in the TERT promoter
in cancers of the central nervous system (43%), bladder (59%), thyroid (follicular cell-derived, 10%) and skin
(melanoma, 29%). In thyroid cancers, the presence of TERT promoter mutations (when occurring together
with BRAF mutations) is significantly associated with higher TERT mRNA expression, and in glioblastoma we
find a trend for increased telomerase expression in cases harbouring TERT promoter mutations. Both in
thyroid cancers and glioblastoma, TERT promoter mutations are significantly associated with older age of the
patients. Our results show that TERT promoter mutations are relatively frequent in specific types of human
cancers, where they lead to enhanced expression of telomerase.
Nat Commun. 2013;4:2185.
Alter promoter by TRANSLOCATION
Chromosome 14 with
translocation
Chromosome 8 with
translocation
Viral driver
Increase the number of copies of a gene
Increase the number of copies of a gene
Increase the amount of
mRNA
Transcription
Translation
Increase the amount of
mRNA
Increase protein production by::
• Promoter mis-use
•
•
•
•
Decreased Methylation
Point Mutation
Translocation
Viral Expression
• Increase copy number
• In DNA
• Of RNA/Protein
Conversion of a Protooncogene  an Oncogene
Change the function of a gene product
DNA Point Mutation
DNA Deletion / Protein Truncation
Chromosomal
Translocation
Decrease Turnover
Increase protein activity by::
• Advantageous DNA mutation
• Point mutation
• Deletion/truncation
• Creation of a fusion protein
• Decrease protein turnover
• Inhibit destruction