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Biology of Cancer and Omics
Etienne GC Brain, MD PhD
Institut Curie
Saint-Cloud, France
www.siog.org
etienne.brain@curie.fr 1
Tumour tissue vs normal tissue
2
*
Premalignant cells
Dysplasia
Adenoma
Cancer cells
Carcinoma
Invasive carcinoma
Normal cells
La carcinogenèse est un processus multi-étapes
*
*
*
Cell growth w/ increased proliferation and decreased apoptosis
Division = Apoptosis Division >> Apoptosis
1 g tumour = 212 cells = 10 years
3
Molecular abnormality
• Any modification of structure, function,
conformation or expression of a cellular
molecule
– DNA, RNA, proteins, lipids, saccharides
4
DNA
• Base
– Point mutation
– Methylation
• DNA sequence
– Insertion/deletion
– Repetition
– Fusion
• Chromosomes
– Fusion
– Deletion
– Modification of copy number 5
Proteins
• Expression
• Function (activation, inhibition or new function)
• Post translational
• Conformation (3D structure)
• Fusion
6
Somatic vs germinal
• Importance to make a distinction between
– Somatic mutation: acquired on tumour DNA only in specific
cells
– Germinal mutation: any detectable and heritable variation in the
lineage of germ cells in each cell
• BRCA 1 & 2: predisposition to breast & ovarian cancer
• DPD: pharmacogenomic and metabolism of 5-FU
• Cancer = genetic disease
– Succession of genome alterations 7
Passenger versus Driver Mutations
• Passenger no effect (genetic instability).
• Driver selection (proliferation, survival)
– Targetable: by a pharmacological agent
– Actionable: predicting sensitivity or resistance to
pharmacological agent
8
Type of Mutations
Meyerson Nat Rev Genet 2010 9
Hanahan & Weinberg Cell 201
IMMUNITY
ANGIOGENESIS
METABOLISM
MIGRATION
SURVIVAL
GENETIC INSTABILITY
TRANSDUCTION PATHWAYS
CELL CYLE
INFLAMMATION
IMMORTALITY
10
NGS Tools
Simon and Roychowdhury Nature Rev Drug Disc 2013 11
Mutations frequency vary across and within cancer types
Low mutational burden High mutational burden
12
Oncogenes & tumour suppressor genes
• Activation of cell growth
+ proliferation
- apoptosis
• Inhibition of cell growth
- proliferation
+ apoptosis
• Abnormal activation of activating
proteins
– Oncoproteins
• Abnormal inactivation of inhibitory
proteins
– Oncosuppressive proteins
• Oncogene activation
– Mutation
– Gene amplification
– Chromosome translocation
– Viral oncogene expression
≥ 1 event (dominant)
• Tumour suppressor gene
inactivation
– Double deletion
– Mutation and gene deletion
– Loss of gene expression
– Interaction w/ activated cell or virus
oncogene
≥ 2 events (recessive)
13
Definitions
• Oncogenes
– Signal transduction
• Tumour suppressor genes
– DNA repair (caretakers)
– Cell cycle control (gatekeepers)
14
Inactivation of tumour suppressor genes
& genetic predisposition Sporadic Inherited
Mut 1
Mut 2 Loss of
second allel
Constitutional
Germinal
mutation
Mut 2 Loss of
second allel
Somatic event
affecting
1 cell at the
origin of cancer
15
Accumulation of genetic alterations
Some yield selective advantage on growth 16
17
18
Pro-tumour effect Anti-tumour effect
Th1
Treg
Th17
T CD8+
Natural Killer T Lym
ph
oid
ce
lls
Myeloid derived
suppressor cells
Macrophage M2
Macrophage M1
Mye
loid
ce
lls
Carriani 2012 19
Alsaab Frontiers Pharmacol 2017 20
Alsaab Frontiers Pharmacol 2017 21
At least 6 Immune Subtypes In Cancer
Thorsson Cell 2018 22
Heterogeneity is multifactorial
1. Elderly – 75 yo vs 90 yo
– No comorbidity vs dementia
2. Cancers – Kidney cancer curative surgery
– M+ colorectal cancer surgery + chemotherapy
– High grade NHL intensive chemotherapy
3. An early stage breast tumour – ER- surgery + XRT + chemotherapy
– ER+ surgery + XRT + endocrine treatment ± chemotherapy
23
• HES stage, LN, immune infiltration
mucinous Poorly differenciation/medullar
TIL Peritumour Cohn-like reaction
CCR & Techniques - 1
24
• IHC
hMLH1 PMS2
hMSH2 hMLH6
HER2
CCR & Techniques - 2
25
CCR
MMR
Treatment strategy
Genetic
Lynch 5-10%
BRAF c.1799T>A (p.Val600Glu)
MSI Lynch Syndrome
26
Tumour DNA
• RAS mutations (KRAS & NRAS) & BRAF
Selection
Macrodissection
27
Illumina (Solexa)
PGM (LifeTech)
> 1 week, complex, compatibility with disease course
Analysis of a large number of sequences
Full or targeted sequencing (predfined genes)
High-depth sequencing to identify undererepresented clones (<10% cells)
High Through Put Sequencing
28
Liquid Biopsy
29
Monitoring Tumour Progression
30
Personalized Medicine
• Stratified/tailored medicine (precision)
Develop drug in a population
defined by a biomarker i.e
companion biomarker
• Personalized medicine Each patient is unique
• Precision & Personalized medicine
- Way 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 31
Targets Targeted theapy Tumour type Biomarker
EGFR Erlotinib/Gefitinib Cetuximab/Panitumumab
Cetuximab
Lung Colon
H&N
Mutation EGFR Mutation KRAS
-
HER-2 Trastuzumab/TDM-1 Lapatinib/Pertuzumab
Trastuzumab
Breast Breast
Stomach
Amplification HER2 Amplification HER2
Amplification HER2
mTOR Temsirolimus/Everolimus Everolimus
Kidney Endocrine tumours
- -
c-Kit Imatinib GIST Over expression c-Kit
SMO Vismodegib Basocellular carcinoma -
VEGF(R) Bevacizumab Sunitinib
Sorafenib
Breast, kidney, colon, lung Kidney, endocrine tumours
Kidney, hepatocarcinoma
- -
-
HDAC Vorinostat Cutaneous lymphoa -
NF-κB Bortezomib Multiple myeloma -
CTLA4 Ipilumumab Melanoma -
RAF Vemurafenib Melanoma Mutation V600E BRAF
ALK Crizotinib Lung Translocation ALK
RET Vandetanib/Cabozantinib Thyroid medullary carcinoma - 32
> ?
Le Tourneau Lancet Oncol 2015 33
Cibles Altérations moléculaires Thérapies ciblées
KIT, ABL1/2, RET Mutation/Amplification Imatinib
PI3KCA, AKT1
AKT2/3, mTOR, RICTOR, RAPTOR
PTEN
STK11
INPP4B
Mutation/Amplification
Amplification
Délétion homozygote
Délétion Hétérozygote + mutation ou IHC
Délétion homozygote
Délétion Hétérozygote + mutation
Délétion homozygote
Everolimus
BRAF Mutation/Amplification Vemurafenib
PDGFRA/B, FLT3 Mutation/Amplification Sorafenib
EGFR Mutation/Amplification Erlotinib
HER-2 Mutation/Amplification Lapatinib + Trastuzumab
SRC
EPHA2, LCK, YES1
Mutation/Amplification
Amplification Dasatinib
RO, RP Expression protéique >10% en IHC Tamoxifen ou Letrozole
RA Expression protéique >10% en IHC Abiraterone
3 molecular pathways (hormone receptor, PI3K/AKT/mTOR, RAF/MEK)
Le Tourneau Lancet Oncol 2015 34
Oct 2012 to July 2014: 741 pts w/ any tumour type 293 (40%) pts w/ ≥ 1 molecular alteration matching 1 of 10 available regimens
Median FU 11.3 mo
Grade 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 35
Schematic representation of the five omics technologies, focusing on the accessed element (blue) and the methods used (orange).
Genomics: access to DNA sequences using gDNA-sequencing and bioinformatics for annotation. Transcriptomics: access to mRNA
sequence and level of expression using microarray hybridization or RNA-sequencing. Proteomics: access to protein sequence thanks to
liquid chromatography and mass spectrometry. Epigenomics: access to DNA methylation and histone modification (two of the most
characterized epigenetic modifications) using ChIP-sequencing or bisulfite sequencing. Cistromics: access to the genomic repertoire of
the binding sequences of a transcriptome factor (TF), using ChIP-sequencing.
5 Major Omics Technologies
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