biology of cancer and omics - geriatric oncology · biology of cancer and omics etienne gc brain,...
TRANSCRIPT
![Page 1: Biology of Cancer and Omics - Geriatric oncology · Biology of Cancer and Omics Etienne GC Brain, MD PhD Institut Curie Saint-Cloud, France ... • Cancer = genetic disease – Succession](https://reader033.vdocuments.mx/reader033/viewer/2022042216/5ebed58b14e9855856654872/html5/thumbnails/1.jpg)
Biology of Cancer and Omics
Etienne GC Brain, MD PhD
Institut Curie
Saint-Cloud, France
www.siog.org
![Page 2: Biology of Cancer and Omics - Geriatric oncology · Biology of Cancer and Omics Etienne GC Brain, MD PhD Institut Curie Saint-Cloud, France ... • Cancer = genetic disease – Succession](https://reader033.vdocuments.mx/reader033/viewer/2022042216/5ebed58b14e9855856654872/html5/thumbnails/2.jpg)
Tumour tissue vs normal tissue
2
![Page 3: Biology of Cancer and Omics - Geriatric oncology · Biology of Cancer and Omics Etienne GC Brain, MD PhD Institut Curie Saint-Cloud, France ... • Cancer = genetic disease – Succession](https://reader033.vdocuments.mx/reader033/viewer/2022042216/5ebed58b14e9855856654872/html5/thumbnails/3.jpg)
*
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
![Page 4: Biology of Cancer and Omics - Geriatric oncology · Biology of Cancer and Omics Etienne GC Brain, MD PhD Institut Curie Saint-Cloud, France ... • Cancer = genetic disease – Succession](https://reader033.vdocuments.mx/reader033/viewer/2022042216/5ebed58b14e9855856654872/html5/thumbnails/4.jpg)
Molecular abnormality
• Any modification of structure, function,
conformation or expression of a cellular
molecule
– DNA, RNA, proteins, lipids, saccharides
4
![Page 5: Biology of Cancer and Omics - Geriatric oncology · Biology of Cancer and Omics Etienne GC Brain, MD PhD Institut Curie Saint-Cloud, France ... • Cancer = genetic disease – Succession](https://reader033.vdocuments.mx/reader033/viewer/2022042216/5ebed58b14e9855856654872/html5/thumbnails/5.jpg)
DNA
• Base
– Point mutation
– Methylation
• DNA sequence
– Insertion/deletion
– Repetition
– Fusion
• Chromosomes
– Fusion
– Deletion
– Modification of copy number 5
![Page 6: Biology of Cancer and Omics - Geriatric oncology · Biology of Cancer and Omics Etienne GC Brain, MD PhD Institut Curie Saint-Cloud, France ... • Cancer = genetic disease – Succession](https://reader033.vdocuments.mx/reader033/viewer/2022042216/5ebed58b14e9855856654872/html5/thumbnails/6.jpg)
Proteins
• Expression
• Function (activation, inhibition or new function)
• Post translational
• Conformation (3D structure)
• Fusion
6
![Page 7: Biology of Cancer and Omics - Geriatric oncology · Biology of Cancer and Omics Etienne GC Brain, MD PhD Institut Curie Saint-Cloud, France ... • Cancer = genetic disease – Succession](https://reader033.vdocuments.mx/reader033/viewer/2022042216/5ebed58b14e9855856654872/html5/thumbnails/7.jpg)
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
![Page 8: Biology of Cancer and Omics - Geriatric oncology · Biology of Cancer and Omics Etienne GC Brain, MD PhD Institut Curie Saint-Cloud, France ... • Cancer = genetic disease – Succession](https://reader033.vdocuments.mx/reader033/viewer/2022042216/5ebed58b14e9855856654872/html5/thumbnails/8.jpg)
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
![Page 9: Biology of Cancer and Omics - Geriatric oncology · Biology of Cancer and Omics Etienne GC Brain, MD PhD Institut Curie Saint-Cloud, France ... • Cancer = genetic disease – Succession](https://reader033.vdocuments.mx/reader033/viewer/2022042216/5ebed58b14e9855856654872/html5/thumbnails/9.jpg)
Type of Mutations
Meyerson Nat Rev Genet 2010 9
![Page 10: Biology of Cancer and Omics - Geriatric oncology · Biology of Cancer and Omics Etienne GC Brain, MD PhD Institut Curie Saint-Cloud, France ... • Cancer = genetic disease – Succession](https://reader033.vdocuments.mx/reader033/viewer/2022042216/5ebed58b14e9855856654872/html5/thumbnails/10.jpg)
Hanahan & Weinberg Cell 201
IMMUNITY
ANGIOGENESIS
METABOLISM
MIGRATION
SURVIVAL
GENETIC INSTABILITY
TRANSDUCTION PATHWAYS
CELL CYLE
INFLAMMATION
IMMORTALITY
10
![Page 11: Biology of Cancer and Omics - Geriatric oncology · Biology of Cancer and Omics Etienne GC Brain, MD PhD Institut Curie Saint-Cloud, France ... • Cancer = genetic disease – Succession](https://reader033.vdocuments.mx/reader033/viewer/2022042216/5ebed58b14e9855856654872/html5/thumbnails/11.jpg)
NGS Tools
Simon and Roychowdhury Nature Rev Drug Disc 2013 11
![Page 12: Biology of Cancer and Omics - Geriatric oncology · Biology of Cancer and Omics Etienne GC Brain, MD PhD Institut Curie Saint-Cloud, France ... • Cancer = genetic disease – Succession](https://reader033.vdocuments.mx/reader033/viewer/2022042216/5ebed58b14e9855856654872/html5/thumbnails/12.jpg)
Mutations frequency vary across and within cancer types
Low mutational burden High mutational burden
12
![Page 13: Biology of Cancer and Omics - Geriatric oncology · Biology of Cancer and Omics Etienne GC Brain, MD PhD Institut Curie Saint-Cloud, France ... • Cancer = genetic disease – Succession](https://reader033.vdocuments.mx/reader033/viewer/2022042216/5ebed58b14e9855856654872/html5/thumbnails/13.jpg)
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
![Page 14: Biology of Cancer and Omics - Geriatric oncology · Biology of Cancer and Omics Etienne GC Brain, MD PhD Institut Curie Saint-Cloud, France ... • Cancer = genetic disease – Succession](https://reader033.vdocuments.mx/reader033/viewer/2022042216/5ebed58b14e9855856654872/html5/thumbnails/14.jpg)
Definitions
• Oncogenes
– Signal transduction
• Tumour suppressor genes
– DNA repair (caretakers)
– Cell cycle control (gatekeepers)
14
![Page 15: Biology of Cancer and Omics - Geriatric oncology · Biology of Cancer and Omics Etienne GC Brain, MD PhD Institut Curie Saint-Cloud, France ... • Cancer = genetic disease – Succession](https://reader033.vdocuments.mx/reader033/viewer/2022042216/5ebed58b14e9855856654872/html5/thumbnails/15.jpg)
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
![Page 16: Biology of Cancer and Omics - Geriatric oncology · Biology of Cancer and Omics Etienne GC Brain, MD PhD Institut Curie Saint-Cloud, France ... • Cancer = genetic disease – Succession](https://reader033.vdocuments.mx/reader033/viewer/2022042216/5ebed58b14e9855856654872/html5/thumbnails/16.jpg)
Accumulation of genetic alterations
Some yield selective advantage on growth 16
![Page 17: Biology of Cancer and Omics - Geriatric oncology · Biology of Cancer and Omics Etienne GC Brain, MD PhD Institut Curie Saint-Cloud, France ... • Cancer = genetic disease – Succession](https://reader033.vdocuments.mx/reader033/viewer/2022042216/5ebed58b14e9855856654872/html5/thumbnails/17.jpg)
17
![Page 18: Biology of Cancer and Omics - Geriatric oncology · Biology of Cancer and Omics Etienne GC Brain, MD PhD Institut Curie Saint-Cloud, France ... • Cancer = genetic disease – Succession](https://reader033.vdocuments.mx/reader033/viewer/2022042216/5ebed58b14e9855856654872/html5/thumbnails/18.jpg)
18
![Page 19: Biology of Cancer and Omics - Geriatric oncology · Biology of Cancer and Omics Etienne GC Brain, MD PhD Institut Curie Saint-Cloud, France ... • Cancer = genetic disease – Succession](https://reader033.vdocuments.mx/reader033/viewer/2022042216/5ebed58b14e9855856654872/html5/thumbnails/19.jpg)
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
![Page 20: Biology of Cancer and Omics - Geriatric oncology · Biology of Cancer and Omics Etienne GC Brain, MD PhD Institut Curie Saint-Cloud, France ... • Cancer = genetic disease – Succession](https://reader033.vdocuments.mx/reader033/viewer/2022042216/5ebed58b14e9855856654872/html5/thumbnails/20.jpg)
Alsaab Frontiers Pharmacol 2017 20
![Page 21: Biology of Cancer and Omics - Geriatric oncology · Biology of Cancer and Omics Etienne GC Brain, MD PhD Institut Curie Saint-Cloud, France ... • Cancer = genetic disease – Succession](https://reader033.vdocuments.mx/reader033/viewer/2022042216/5ebed58b14e9855856654872/html5/thumbnails/21.jpg)
Alsaab Frontiers Pharmacol 2017 21
![Page 22: Biology of Cancer and Omics - Geriatric oncology · Biology of Cancer and Omics Etienne GC Brain, MD PhD Institut Curie Saint-Cloud, France ... • Cancer = genetic disease – Succession](https://reader033.vdocuments.mx/reader033/viewer/2022042216/5ebed58b14e9855856654872/html5/thumbnails/22.jpg)
At least 6 Immune Subtypes In Cancer
Thorsson Cell 2018 22
![Page 23: Biology of Cancer and Omics - Geriatric oncology · Biology of Cancer and Omics Etienne GC Brain, MD PhD Institut Curie Saint-Cloud, France ... • Cancer = genetic disease – Succession](https://reader033.vdocuments.mx/reader033/viewer/2022042216/5ebed58b14e9855856654872/html5/thumbnails/23.jpg)
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
![Page 24: Biology of Cancer and Omics - Geriatric oncology · Biology of Cancer and Omics Etienne GC Brain, MD PhD Institut Curie Saint-Cloud, France ... • Cancer = genetic disease – Succession](https://reader033.vdocuments.mx/reader033/viewer/2022042216/5ebed58b14e9855856654872/html5/thumbnails/24.jpg)
• HES stage, LN, immune infiltration
mucinous Poorly differenciation/medullar
TIL Peritumour Cohn-like reaction
CCR & Techniques - 1
24
![Page 25: Biology of Cancer and Omics - Geriatric oncology · Biology of Cancer and Omics Etienne GC Brain, MD PhD Institut Curie Saint-Cloud, France ... • Cancer = genetic disease – Succession](https://reader033.vdocuments.mx/reader033/viewer/2022042216/5ebed58b14e9855856654872/html5/thumbnails/25.jpg)
• IHC
hMLH1 PMS2
hMSH2 hMLH6
HER2
CCR & Techniques - 2
25
![Page 26: Biology of Cancer and Omics - Geriatric oncology · Biology of Cancer and Omics Etienne GC Brain, MD PhD Institut Curie Saint-Cloud, France ... • Cancer = genetic disease – Succession](https://reader033.vdocuments.mx/reader033/viewer/2022042216/5ebed58b14e9855856654872/html5/thumbnails/26.jpg)
CCR
MMR
Treatment strategy
Genetic
Lynch 5-10%
BRAF c.1799T>A (p.Val600Glu)
MSI Lynch Syndrome
26
![Page 27: Biology of Cancer and Omics - Geriatric oncology · Biology of Cancer and Omics Etienne GC Brain, MD PhD Institut Curie Saint-Cloud, France ... • Cancer = genetic disease – Succession](https://reader033.vdocuments.mx/reader033/viewer/2022042216/5ebed58b14e9855856654872/html5/thumbnails/27.jpg)
Tumour DNA
• RAS mutations (KRAS & NRAS) & BRAF
Selection
Macrodissection
27
![Page 28: Biology of Cancer and Omics - Geriatric oncology · Biology of Cancer and Omics Etienne GC Brain, MD PhD Institut Curie Saint-Cloud, France ... • Cancer = genetic disease – Succession](https://reader033.vdocuments.mx/reader033/viewer/2022042216/5ebed58b14e9855856654872/html5/thumbnails/28.jpg)
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
![Page 29: Biology of Cancer and Omics - Geriatric oncology · Biology of Cancer and Omics Etienne GC Brain, MD PhD Institut Curie Saint-Cloud, France ... • Cancer = genetic disease – Succession](https://reader033.vdocuments.mx/reader033/viewer/2022042216/5ebed58b14e9855856654872/html5/thumbnails/29.jpg)
Liquid Biopsy
29
![Page 30: Biology of Cancer and Omics - Geriatric oncology · Biology of Cancer and Omics Etienne GC Brain, MD PhD Institut Curie Saint-Cloud, France ... • Cancer = genetic disease – Succession](https://reader033.vdocuments.mx/reader033/viewer/2022042216/5ebed58b14e9855856654872/html5/thumbnails/30.jpg)
Monitoring Tumour Progression
30
![Page 31: Biology of Cancer and Omics - Geriatric oncology · Biology of Cancer and Omics Etienne GC Brain, MD PhD Institut Curie Saint-Cloud, France ... • Cancer = genetic disease – Succession](https://reader033.vdocuments.mx/reader033/viewer/2022042216/5ebed58b14e9855856654872/html5/thumbnails/31.jpg)
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
![Page 32: Biology of Cancer and Omics - Geriatric oncology · Biology of Cancer and Omics Etienne GC Brain, MD PhD Institut Curie Saint-Cloud, France ... • Cancer = genetic disease – Succession](https://reader033.vdocuments.mx/reader033/viewer/2022042216/5ebed58b14e9855856654872/html5/thumbnails/32.jpg)
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
![Page 33: Biology of Cancer and Omics - Geriatric oncology · Biology of Cancer and Omics Etienne GC Brain, MD PhD Institut Curie Saint-Cloud, France ... • Cancer = genetic disease – Succession](https://reader033.vdocuments.mx/reader033/viewer/2022042216/5ebed58b14e9855856654872/html5/thumbnails/33.jpg)
> ?
Le Tourneau Lancet Oncol 2015 33
![Page 34: Biology of Cancer and Omics - Geriatric oncology · Biology of Cancer and Omics Etienne GC Brain, MD PhD Institut Curie Saint-Cloud, France ... • Cancer = genetic disease – Succession](https://reader033.vdocuments.mx/reader033/viewer/2022042216/5ebed58b14e9855856654872/html5/thumbnails/34.jpg)
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
![Page 35: Biology of Cancer and Omics - Geriatric oncology · Biology of Cancer and Omics Etienne GC Brain, MD PhD Institut Curie Saint-Cloud, France ... • Cancer = genetic disease – Succession](https://reader033.vdocuments.mx/reader033/viewer/2022042216/5ebed58b14e9855856654872/html5/thumbnails/35.jpg)
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
![Page 36: Biology of Cancer and Omics - Geriatric oncology · Biology of Cancer and Omics Etienne GC Brain, MD PhD Institut Curie Saint-Cloud, France ... • Cancer = genetic disease – Succession](https://reader033.vdocuments.mx/reader033/viewer/2022042216/5ebed58b14e9855856654872/html5/thumbnails/36.jpg)
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
![Page 37: Biology of Cancer and Omics - Geriatric oncology · Biology of Cancer and Omics Etienne GC Brain, MD PhD Institut Curie Saint-Cloud, France ... • Cancer = genetic disease – Succession](https://reader033.vdocuments.mx/reader033/viewer/2022042216/5ebed58b14e9855856654872/html5/thumbnails/37.jpg)