Biology of Cancer and Omics - PowerPoint Presentation

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Biology of Cancer and

Omics

Etienne GC Brain, MD PhDInstitut CurieSaint-Cloud, France

www.siog.org

etienne.brain@curie.fr

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Cancer paradox

… is frequentTotal life risk:

1/2 for men 1/3 for women1st cause of deathNew cases / y : 1,270,000Deaths / y : 550,000 80 % of cancers arise after 55 yCost: 180 billions

$Statistics US (280 millions - 2001)

… is

rareIf

one considers :

the number of cells in humans (1013-14)

the number of mitosis during life (1016)

the life expectancy (80 years)3

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Tumour tissue vs normal tissue

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Abnormal cells with

proliferation advantage

invasive properties

morphologic abnormalities

differentiation abnormalities

clonal selection

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Premalignant

cellsDysplasia

Adenoma

Cancer

cells

Carcinoma

Invasive

carcinomaNormal

cellsCell

growth

w/

increased

proliferation

and

decreased

apoptosis

Division =

Apoptosis

Monoclonal or

polyclonal

Division >>

Apoptosis

1 g

tumour

= 2

12

cells

= 10 years

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Cells

with

drivers

genomics

alterations

Cells with passenger / private genomic alterations

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Chambers, A, Nature Cancer Reviews, 2002, 2, 563

Overgrowth

disruption of homeostasis control

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Cancer and molecular

abnormalityCancer = genetic diseaseSuccession of genome alterationsMolecular abnormalityAny modification of structure,

function, conformation or expression of a cellular moleculeDNA, RNA, proteins, lipids, saccharides7

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DNA

BasePoint mutationMethylationDNA sequenceInsertion/deletion

RepetitionFusionChromosomesDeletionFusionModification of copy number8

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Type of Mutations

Meyerson

Nat

Rev

Genet 2010

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Somatic vs germinal

Importance to make a distinction betweenSomatic mutation: acquired on tumour DNA

 only in specific cellsGerminal mutation: any detectable and heritable variation in the lineage of germ cells  in each cell BRCA 1 & 2: predisposition to breast & ovarian cancerDPD: pharmacogenomic and metabolism

of 5-FU10

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Passenger versus d

river mutationsPassenger  no

effect (genetic instability)Driver  selection (proliferation, survival)Targetable: by a pharmacological agent

Actionable: predicting sensitivity or resistance to pharmacological agent

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Oncogenes & tumour suppressor

genesOncogenesSignal transduction

≥ 1 event (dominant)CMYC, RAS, ERBB2, ABL, EGFR,RET, BRAF

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Tumour

suppressor

genes

(TSG)DNA repair (caretakers

)Cell cycle control (gatekeepers)Inactivation = loss of function

≥

2

events

(

recessive

)

p53, p16, RB1, BRCA1, MLH1

Normal

cell

Tumour

cell

"Normal"

cell

Normal

cell

Tumour

cell

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M1

M2

Mx-1

Mx

s

omatic

mutations = genetic alteration acquired

Normal

Tissue

Cancer

tissue

TSG

(A1

)

TSG

(A2)

Sporadic

cancer

M2

My-1

My

genetic alteration acquired

Germline

genetic

alterations

(

inherited

)

TSG

(

A1

)

TSG

(A2)

Hereditary

cancer

"Normal"

Tissue

Cancer

tissue

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Examples

Gene amplificationHER2 and breast cancer 20%N-MYC and neuroblastoma (20-30,%)Ponctual mutations

RAS oncogenes (KRAS, HRAS, NRAS) and GI tumours, melanomasp53 (50% tumours)TranslocationsBCR and CML (fusion gene), BurkittVirusRNA (retrovirus), DNA (HPV, EBV, HHVB, HBV, HCV), endogene sequences (ALU, HERV)Deletions: RB1Epigenetic modifications: BRCA1, p16, VHL, MLH1

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Nik-Zainal

Nature 2016

Very

few mutations are frequent

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Somatic mutations occur in all cells

of the body throughout

life

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Accumulation of

genetic

alterationsSome yield selective advantage on growth

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Cancer is a multi-step disease

in vivo

transformation requires several events

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Mutations

frequency

vary across and within cancer types

Low

mutational

burden

High mutational burden

18Prevalence of somatic mutations among cancers range from 0.01

to

> 400/Mb

Some



translation

of novel peptide epitopes or

neoantigens



enhance tumour immunogenicity

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Most cancers may be due to ageing?

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Alexandrov et al., Nature (2013)

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Sanger



10 exons  5 oncogenes  FFPE

100 ng DNA

"

predefined

NGS"



1000 exons



80

oncogenes

+ 20

TSG



FFPE



10

ng

DNA

100

genes

NGS:

Next

Generation

Sequencing

Technologies & mutations

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What is

NGS?Look for specific mutations in a tumor biopsy  potential important

target for specific treatmentsDifferent types of cancer w/ same important mutationSame organ cancer with different target mutationsTesting for a single specific mutation  NGS: testing many genes of a cancer simultaneously (biopsy, specimen, ctDNA in blood)PROSChance to test many genes simultaneously, potentially saving time, money, and tissue if many markers neededProvide results not only for the mutations specifically needed, but also can identify new markers that may offer additional treatment

options, and accelerate research.CONS2-3 weeks for results (vs ≤ 1 week for individual tests)Cost (typically several thousand

€)Difficult interpretations and treatment decisionsHigh interest for patients who have a cancer in which there are several identified molecular targets that are commonly seen

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Illumina

Life Technologies

Old technologies(Sanger)

Cost

Readout

2Mb/

day

400Mb/

day

500€/Mb

Devices

3€/Mb

C

T

C

A

T

C

G

C

T

A

G

C

A

G

T

-

+

NGS

:

Next

Generation

Sequencing

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Gènes codant

des protéines

Protéines

20 000

500 000 - 1 000

000



Post

translational

modifications

ARNs

100 000



Alternative

splicing

Genes

coding

proteins

Proteins

RNAs

Transcription

Translation

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500 €

WES

(

Whole

Exome

sequencing)

3 000 €

Cost

Mutations exons

Amplifications?

Deletions

?

Alterations

60 Mb (2%)

3 Gb (100%)

DNA

Mutations exons

Amplifications

Deletions

Mutations introns

Mutations

promoters

Mutations

intragenic

Translocations

WGS

(Whole Genome sequencing)

WES versus WGS

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50

€

2020

1000 €

2017

10 000

€

2012

1.5 millions

€

2006

100 millions

€

2002

Geno

-tsunami: cost

of complete

sequencing

of human genome

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NGS Tools

Simon and

Roychowdhury

Nature Rev Drug

Disc 2013

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Gerlinger et al, NEJM 2012, 366:883

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Hanahan

& Weinberg Cell 2011

IMMUNITYANGIOGENESIS

METABOLISMMIGRATION

SURVIVAL

GENETIC INSTABILITY

TRANSDUCTION PATHWAYS

CELL CYLE

INFLAMMATIONIMMORTALITY28

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Pro-tumour

effectAnti-tumour

effect

Th1

Treg

Th17

T CD8+

Natural Killer T

Lymphoid

cells

Myeloid

derived

suppressor

cells

Macrophage M2

Macrophage M1

Myeloid

cells

Carriani

2012

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Alsaab

Frontiers

Pharmacol 201730

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Alsaab

Frontiers

Pharmacol 201731

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At least 6 Immune Subtypes

In Cancer

Thorsson

Cell 2018

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Liquid Biopsy

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Monitoring Tumour Progression

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Personalized Medicine

Stratified/tailored medicine (precision)

Develop

drug in a

population

defined by a biomarker i.e

companion biomarker

Personalized medicine  Each

patient is uniquePrecision & Personalized medicineWay that healthcare is moving in the future

Model customizing healthcare based on the individual's and tumour’s genetics

Main goal = to

make medicine 

predictive

(

precision

),

preventive

,

personalized

 and 

participatory

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Targeted

molecular therapies

Monoclonal

antibodies (mab)Monospecific

Target 1 specific protein of the tumour process

)Heavy molecular weight

InjectionExtracellular actionTyrosine kinase inhibitors

(inib)Mono/multi targetTKR, signal transduction receptors)Low molecular weight

POIntracellular action

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Targets

Targeted theapy

Tumour typeBiomarkerEGFRErlotinib/GefitinibCetuximab/PanitumumabCetuximabLungColonH&N

Mutation EGFRMutation KRAS-HER-2

Trastuzumab/TDM-1Lapatinib/Pertuzumab

TrastuzumabBreast

BreastStomach

Amplification HER2

Amplification HER2Amplification HER2mTORTemsirolimus

/EverolimusEverolimusKidneyEndocrine tumours-

-

c-Kit

Imatinib

GIST

Over expression c-Kit

SMO

Vismodegib

B

asocellular

carcinoma

-

VEGF(R)

Bevacizumab

Sunitinib

Sorafenib

Breast

,

kidney

, colon, lungKidney, endocrine tumoursKidney,

hepatocarcinoma---HDACVorinostat

Cutaneous lymphoa-NF-κBBortezomibMultiple myeloma-CTLA4IpilumumabMelanoma

-

RAFVemurafenib

MelanomaMutation V600E BRAFALK

CrizotinibLung

Translocation ALKRET

Vandetanib/CabozantinibThyroid

medullary carcinoma-

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>

?

Le

Tourneau

Lancet

Oncol

2015

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Basket vs

Umbrella

trials

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Targets

Molecular alterations

Targeted theraîesKIT, ABL1/2, RETMutation/AmplificationImatinibPI3KCA, AKT1AKT2/3, mTOR, RICTOR, RAPTOR

PTENSTK11INPP4B

Mutation/

AmplificationAmplificationH

omozygote deletion

Homozygote

deletion + mutation or IHCH

omozygote deletionHeterozygote deletion

+

mutation

H

omozygote

deletion

Everolimus

BRAF

Mutation

/

Amplification

Vemurafenib

PDGFRA/B, FLT3

Mutation

/

Amplification

Sorafenib

EGFR

Mutation

/

AmplificationErlotinibHER-2

Mutation/AmplificationLapatinib + TrastuzumabSRCEPHA2, LCK, YES1Mutation/AmplificationAmplification

Dasatinib

RO, RPProtein

expression >10% by IHC

Tamoxifen or LetrozoleRA

Protein expression >

10% by IHCAbiraterone

3 molecular pathways (hormone receptor, PI3K/AKT/mTOR, RAF/MEK)

Le

Tourneau Lancet Oncol 2015

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Oct 2012 to July 2014: 741 pts w/

any

tumour type293 (40%) pts w/ ≥ 1 molecular alteration matching 1 of 10 available regimensMedian FU 11.3 moGrade 3-4 AEs 43% vs 35% (p=0.30)Small study (n=195 randomized), heavily pretreated…

Multiple alterations and Rx groups Supports caution

Le Tourneau

Lancet Oncol 2015

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Take

home messages: CancerS

!Frequent disease but rare event considering number of cells

Cancers are genetic diseases (but rarely inherited)

Due to combination of oncogenes and tumor suppressor genes

Both can play a role in inherited cancer predispositions

General rules, but many exceptions, and a lot of unknown!

Cancer genetics is important to clarifying oncogenesis genetic counseling and "patient" care

adapting treatments