Cancer Genomics

Question 1

“The Hallmarks of Cancer”

Answer 1

• 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

Question 2

Cancer caused by

Answer 2

combination of inherited genetics, somatic mutation, and the environment

Question 3

example of inherited variation in cancer

Answer 3

brca1/2, rb

Question 4

example of somatic mutation in cancer

Answer 4

p53, MYC, RAS

Question 5

environmental causes

Answer 5

carcinogens: UV, tobacco smoke
- ->lead to mutagenesis
viruses: HPV

Question 6

Cancer genes

Answer 6

certain genes, when mutated, can lead to tumorigenesis
oncogenes
tumor suppressor genes

Question 7

oncogenes

Answer 7

genes that function in cell growth and profile ration. Hit by gain of function mutations can lead to uncontrolled cell division Eg., Ras, MYC

Question 8

tumor suppressor genes

Answer 8

genes that normally protect a cell from tumorigenesis. Hit by loss of function mutations such as Rb

Question 9

Gain of function

Answer 9

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

Question 10

Loss of function

Answer 10

mutation leads to decreased activity of the gene

many ways to break a gene, particular mutations often not reccurrent

Question 11

Classes of mutation type

Answer 11

• point mutations
• translocations and rearrangements
• amplifications and deletions
• viral insertions

Question 12

Point mutations in cancer

Answer 12

-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

Question 13

Transolocation in cancer

Answer 13

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

Question 14

Philadelphia Chromosome

Answer 14

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

Question 15

Amplification and deletions in cancer

Answer 15

-another mechanism to produce gain or loss of function mutations

Question 16

common amplifications

Answer 16

BrCa: MYC, HER2, FGFR1/2
Colon: H/kras, myb
Glioblastoma EGFR

Question 17

Genomic technologies for mutation detection

Answer 17

• 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

Question 18

Large scale genome projects

Answer 18

TCGA
International Cancer Genome Consortium
COSMIC

Question 19

TCGA

Answer 19

The cancer genomes atlas
$220 m from NIH
20+ tumor types
WGS, WES, SNP chips, RNAseq

Question 20

International Cancer Genome Consortium

Answer 20

50 tumor types

500 samples each

Question 21

COSMIC

Answer 21

Catalog of Somatic Mutations in Cancer

curated database of mutations reported in the literature

Question 22

HRAS

Answer 22

one of the first and best characterized oncogenes

>95% of somatic mutations occur at 3 residues and these mutations lead to constitutive activity

Question 23

TP53

Answer 23

One of the first and best characterized tumor suppressor gene
broad patters of mutations and LOF

Question 24

Drivers vs Passengers

Answer 24

Vast majority of mutations identified in tumors have no functional consequence
Drivers = adaptative somatic mutations
passengers = neutral hitchhikers

Question 25

How do we identify drivers?

Answer 25

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

Question 26

Lawrence 2013

Answer 26

Mutation rate heterogeneity across tumor types
whole exome sequencing
mutation rates varied both between and within cell types

Question 27

mutation spectra

Answer 27

focusing on what types of mutation observed rather than how much
c–>a
c–>t
tumors have different types of mutations

Question 28

tumors

Answer 28

evolve rapidly
different muttation, uniqe to tumors
hetergenous mixes of clones

Question 29

Gerlinger 2012

Answer 29

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

Question 30

Nik-Zainal 2012

Answer 30

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

Question 31

gene expression profiling in cancer

Answer 31

sorlie 2001
many tumor collections gene expression profiled
many tumor types (breast) often cluster into distinct subtypes have very distinct gene expression profiles

Question 32

Large scale meta-analyses

Answer 32

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