genomics applications in gastrointestinal cancers: from
TRANSCRIPT
Genomics Applications in Gastrointestinal Cancers: from
Screening to Therapy
Isabella Tai, MD PhDUniversity of British Columbia.
Genome Sciences Centre,Vancouver, Canada
AAPM 2020 Virtual Annual Meeting July 15, 2020
DISCLOSURE:
NO COMMERCIAL CONFLICT
Cancer is a leading cause of death worldwide: an estimated 9.6 million deaths (2018)
The most common cancers are:
The most common causes of cancer death are cancers of:
Lung - 2.09 million cases Breast - 2.09 million cases Colorectal - 1.80 million
cases) Prostate - 1.28 million
cases Skin cancer non-
melanoma - 1.04 million cases
Stomach - 1.03 million cases
Lung - 1.76 million deaths
Colorectal - 862 000 deaths
Stomach - 783 000 deaths
Liver - 782 000 deaths
Breast - 627 000 deaths
https://www.who.int/news-room/fact-sheets/detail/cancer
Cancer Survival
Screening/Early Detection
Improvements in TherapyScreening/Early Detection
Therapy
SCREENING FOR COLORECTAL CANCER
Stool Fecal Immunohistochemical Test (Stool FIT)
Colonoscopy
MediciNet
Adenoma Colorectal cancer
SCREENING FOR COLORECTAL CANCER
Stool FIT Stool DNA
Test performance: sDNA vs FIT
Imperiale et al, 2014
Modeling of the effect of screening strategies
Berger et al, 2016
Cancer Survival
Screening/Early Detection
Improvements in TherapyScreening/Early Detection
Therapy
Predictive/Prognostic Markers
Prognostic Markers in Early Colorectal Cancer - MSI
Modified from Diesntmann et al, 2015
Prognostic Markers in Early Colorectal Cancer - BRAF
Modified from Diesntmann et al, 2015
Modified from Diesntmann et al, 2015
Prognostic Markers in Early Colorectal Cancer - KRAS
Cancer Survival
Screening/Early Detection
Improvements in TherapyScreening/Early Detection
Therapy
1975
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2010
2015
Modified from Akkad et al, Langenbecks Arch Surg (2015)
5-Fluorouracil Irinotecan
Capecitabine
Oxaliplatin
CANCER DRUGS
2020
Cancer as a Genomic Disease -> Precision Medicine
Colorectal Cancer
GIST Tumor
Lung Cancer
Breast Cancer
KIT Gene Mutation
ERBB2 Amplification
EGFR Mutation
Cetuximab, panitunimabRAS/RAFmut
PIK3CA and RAS/RAFmut
Imatinib
Erlotinib, gefitinib
Lapatinib, trastuzumab
1975
198
0
198
5
199
0
199
5
200
0
200
5
2010
2015
Modified from Akkad et al, Langenbecks Arch Surg (2015)
5-Fluorouracil Irinotecan
Capecitabine
Oxaliplatin
CANCER DRUGS
Bevacizumab(VEGF)
Cetuximab(EGFR) Panitumumab
(EGFR)
Trastuzumab(Her-2)
Lapatinib(Her2/EGFR)
Erlotinib(EGFR)
Imatinib(Bcr-Abltyrosine kinaseinhibitor)
Gefitinib(EGFR)
Nivolumab(PD-1)
pembrolizumab(PD-1)
Atezolizumab(PD-1)
2020
Anti-EGFR treatment – Kras/Nras status
Tran et al, 2015
Anti-EGFR treatment – Braf status
Tran et al, 2015
Anti-EGFR therapy and mutational status
MUTATION Anti-EGFR Therapy
Kras (exons 2, 3, 4) Not indicated
Nras (exons 2, 3, 4) Not indicated
Braf (V600E) Not indicated
PIK3CA >2-line therapy
All wildtype indicated
Tran et al, 2015
Anti-PD-1 antibody
PD1
Tumor
MHC
TCR
PD-L1/PD-L2
PD1
MSS tumor
Tumor
Anti-PD-1 antibody
PD1
Poorresponse
MSI-H/dMMR tumor
Tumor
neoantigen
TCR
PD-L1/PD-L2
PD1
Tumor
Goodresponse
mutation
T cellT cell
T cell T cell
Anti-PD1 Therapy
Modified from Eso et al, 2020
RAS wt 50%
Anti-EGFR antibodies+ chemotherapy
BRAF mut8%
BRAF inhibition + MEK inhibitors
HER2+ 5%
anti-HER2 therapy
MSI5%
Anti-PD1 antibodies
RAS mut50%
No targeted therapy
Potential Combinations of Molecularly Targeted Treatments
Cancer Survival
Screening/Early Detection
Improvements in TherapyScreening/Early Detection
Personalized Therapy?
DNA sequencing costs
24MacConaill JCO 2013 31 (15) 1815 – 1824
Onco-omics→ Precision Cancer Treatment
Personalized Oncogenomics (POG) Project
Project Leaders: Dr. Janessa Laskin (Medical Oncology, BC Cancer)
Dr. Marco Marra (Director, Genome Sciences Centre, BC Cancer)
Whole Genome + Transcriptome Analysis → Inform Treatment Decisions
Personalized Oncogenomics Project:
Patients with advanced, incurable cancer; heavily pre-treated & limited / no treatment options. Consider all cancers.
Determine the feasibility of approach in a tertiary cancer care centre.
genomes (tumor, normal) + transcriptome
Bottlenecks?
Analytic pipelines?
Can the biopsy and subsequent analyses be completed in a timely fashion?
What is the frequency of “actionable” results?
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POG case – Colorectal Cancer
67 year old
Initially presented in May 2010 Stage III colon cancer T3N1 1/18 nodes positive (0.1 mm tumour deposit) moderately differentiated adenocarcinoma
Genetic testing: MLH1 deleted / BRAF wild type (IHC)
Family History: Mother - pancreatic cancer, sister - brain tumor, brother - prostate
cancer 11 brothers and sisters
2014: metastasis Enrolled to POG in Sept 2014
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Pre-treatment PET/CT (Nov 2014)
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METASTASIS
CTTNB1
[4%]
Fold Change: Colon Percentile: COAD
Tumour Sup.Drug Target
Driver Fusion Gene
WNTs
FZDs
PLK
[80%]
APC
[LoF]
activation
inhibition
indirectUP Down
Expression (Fold change)
Copy # relative PLOIDY
Copy Number Change(‘n’ # copy change)
Gain
Loss
GoF: gain of function
LoF: loss of function
VUS: uncertain sig.
hom: homozygous
het: heterozygous
sc: subclonal
[%]: high percentile
[%]: low percentile
[HomD]: homozygous deln
WNTPathway
MLH1
LoF [2]
CYCLINS
[50-80%]
CDK6
[98%]
CDKN2B
VUS [2]
CDKN1B
VUS [1]
Cell Cycle
POG 130 Pathway Analysis
BCCA Confidential - For Research Purposes Only 30
PIK3CA
[GoF]
PI3K-AKT
Pathway
PTEN
[LoF]
mTOR
[60%]
Invasion and Metastasis
Survival and Proliferation
DNA Repair
POLN
VUS [2]
TCF
GSK3A
[95%]
PIK3R1
[GoF]
Gene regulation
MLH3
LoF [2]
MSH3
LoF [2]
MSH6
LoF[1]
ATM
LoF [1]
FANCM
VUS [2]
Mismatch-repair defective
PI3K-Akt not highly deregulated
DHH
PTCH1
SMO
[27%]
HHogPathway
GLI
[75%]
[70%]
[51%]
FOXO1
[20%]
NFKB2
[88%]
CREB3L1
[95%]
JUN
[100%]
FOS
[98%]
AP1 complex
GNAS
[GoF]
PKCPathway
Gene regulation
FBXW7
LoF*
TP53
VUS[1]
BAX
VUS[1]
EP300
VUS[1]
Apoptosis
E2Fs
[90%]
Gene regulation
JUN
[100%]
FOS
[98%]
AP1 complex
Mechanism?
31
http://www.nature.com/ki/journal/v77/n2/fig_tab/ki2009349f2.html
Drug
HMGA1
[99%]AP-1 complex regulates itself
in a positive feedback
mechanism
GNAS
[5%]GoF
PRKCD
[57%]
NFKB2
[88%]
PLK2--4
[>80%]
Gene Regulation
AGTR1
[40%]
MAP3K1
[11%]
MAPK3
[46%]
Downstream transcriptional targets of the AP-1 complex are upregulated
POG-CRC pathway analysis
MAP2K2
[88%]
MAPK8
[7%]
SPINE MET
Post-treatment (4 Weeks)
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Personalized medicine•Prevention•Precision treatment•Early intervention strategies
Disease mechanisms•Origin•Transition•Resistance
Drug discovery•Efficacy•Resistance
Diagnostics•Patient stratification•Early detective
Signatures & new biomarkers•Pre-cancer lesions•Metastatic makers•Drug resistance makers
Interactions•Molecular•Cellular•Spatial
Modified from Rozenblatt-Rosen et al, Cell 2020
Advances in “omics” and Potential Impact on Cancer Management
Thank you!
ACKNOWLEDGEMENTS
CIHR TEAM IN CRC SCREENING
Andy ColdmanHaishan ZhengCalum MacaulayMark ElwoodStuart Peacock
Vancouver General HospitalDavid Owen David SchaefferAlan WeissMichael ByrnePeter KwanNazira ChaturCharles ScudamoreAndrew BuckowskiStephen Chung
Genome Sciences CentreSharon GorskiGregg MorinMarco MarraSteven JonesSimon Chan
BC Cancer Margaret SutcliffeLorena BarclayNhu LeLinlea Armstrong Sharlene GillHagen KenneckeHoward LimJanessa Laskin
FRANCE Virginie Dangles-MarieIvan Bièche
Tai LABORATORYZainab Bazzi
Peter Zhang
Louis-Bastien Weiswald
Angel Yu
Yi-Jye Chern
Jianhua Ren
Hye-Lim Ju
Rubayet Hasan
Mahbuba Hasan
Clarissa Pasilio
Chaoyang Jin
Krithika Selverajan
Jieun Kim
Mi Zhao
Annie Chan
Justin Chan
Farnaz Taghizadeh
Shirley Ho
Winnie So
Young Kim