Cancer Genomics Flashcards
“The Hallmarks of Cancer”
- Self sufficiency in growth signals, cells will grow with requiring external stimuli
- Insensitivity to antigrowth, ignore stop signals
- Evasion from apoptosis, ignore program cell death
- Limitless replicative potential, divide as many times as they feel like
- sustained angiogenesis, tumor cells get larger
- invasion and metastasis
Cancer caused by
combination of inherited genetics, somatic mutation, and the environment
example of inherited variation in cancer
brca1/2, rb
example of somatic mutation in cancer
p53, MYC, RAS
environmental causes
carcinogens: UV, tobacco smoke
- ->lead to mutagenesis
viruses: HPV
Cancer genes
certain genes, when mutated, can lead to tumorigenesis
oncogenes
tumor suppressor genes
oncogenes
genes that function in cell growth and profile ration. Hit by gain of function mutations can lead to uncontrolled cell division Eg., Ras, MYC
tumor suppressor genes
genes that normally protect a cell from tumorigenesis. Hit by loss of function mutations such as Rb
Gain of function
Mutations that lead to increased activity or a novel activity of the gene
Oncogenetic GOF mutations are recurrent, i.e. you find the same mutation in many tumors
Loss of function
mutation leads to decreased activity of the gene
many ways to break a gene, particular mutations often not reccurrent
Classes of mutation type
- point mutations
- translocations and rearrangements
- amplifications and deletions
- viral insertions
Point mutations in cancer
-missense: amino acid changes lead to GOF or LOF
-stop gain: results in truncated protein, NMD
, typically LOG
-stop loss: results in protein extension
-splice site: alters transcript isoform
TERT promoter mutation recurrent in melanoma
Transolocation in cancer
large scale breakage and/or union of chromosomal segments
often lead to gene fusions
change expression level of gene
remove an ibhinoty domain of protein
this would lead to GOF
Philadelphia Chromosome
found in 95% of chronic myelogenous leukemia(CML) cases
reciprocal translocation between chromosomes 9 and 22
discovered by now eel and hugnerfor at pen/fox chase in 1960
characterized by janet rowly in chicago 13 years later
creates the BCR-ABL fusion a constitutively active tyrosine kinase
Amplification and deletions in cancer
-another mechanism to produce gain or loss of function mutations
common amplifications
BrCa: MYC, HER2, FGFR1/2
Colon: H/kras, myb
Glioblastoma EGFR
Genomic technologies for mutation detection
- point mutations: WGS, WES, targeted sequencing panels, paired tumor and normal sequencing
- amplification and deletions: WGS, SNP chips
- Translocations and rearrangements: RNAseq, large insert WGS, copy number neutral or associated with change in ploidy, precise break points often difficult to delineate
Large scale genome projects
TCGA
International Cancer Genome Consortium
COSMIC
TCGA
The cancer genomes atlas
$220 m from NIH
20+ tumor types
WGS, WES, SNP chips, RNAseq
International Cancer Genome Consortium
50 tumor types
500 samples each
COSMIC
Catalog of Somatic Mutations in Cancer
curated database of mutations reported in the literature
HRAS
one of the first and best characterized oncogenes
>95% of somatic mutations occur at 3 residues and these mutations lead to constitutive activity
TP53
One of the first and best characterized tumor suppressor gene
broad patters of mutations and LOF
Drivers vs Passengers
Vast majority of mutations identified in tumors have no functional consequence
Drivers = adaptative somatic mutations
passengers = neutral hitchhikers
How do we identify drivers?
functional studies are always gold standard but very difficult
rely on statically significant recurrence of mutations at a particular base or gene
more mutations in a gene then we would except by chance
Lawrence 2013
Mutation rate heterogeneity across tumor types
whole exome sequencing
mutation rates varied both between and within cell types
mutation spectra
focusing on what types of mutation observed rather than how much
c–>a
c–>t
tumors have different types of mutations
tumors
evolve rapidly
different muttation, uniqe to tumors
hetergenous mixes of clones
Gerlinger 2012
WES on 8 biopsies of primary tumor and 3 from metastases (kidney cancer)
results: pattern of mutation sharing demonstrated extensive sub clonality , early branching of metastasis
phylogenetic tree comparing tumors
Nik-Zainal 2012
sequence a bunch of different areas of a tumor we will see different clones
used read depth and allele frequency to infer copy # state across the genome
this can make inferences of clusters
and model the evolutionary process based on relatedness between mutational clusters
gene expression profiling in cancer
sorlie 2001
many tumor collections gene expression profiled
many tumor types (breast) often cluster into distinct subtypes have very distinct gene expression profiles
Large scale meta-analyses
Laurie 2012 analyzed SNP-chip genotypes from 50k whole blood samples
detected sub clonal mosaicism that rises rapidly with age
young subjects in gwas have low mosaicism until 50
