The Many Faces of Personalized Health
Care: Pediatric and Medical Oncology
Joshua D. Schiffman, MD
Edward B. Clark, MD Chair in Pediatric Research
Associate Professor, Pediatric Hematology/Oncology
University of Utah School of Medicine
April 01, 2014
The Cancer Challenge
• Second leading cause of death worldwide
• 8 million deaths per year worldwide
• 15 people die from cancer every minute
• 1/2 of all men and 1/3 of all women will get cancer
• Relapse is leading cause of cancer-related death
Translational Oncology Core
Pilot Study
Huntsman Cancer Institute
ARUP Laboratories
Translational Oncology Core
Pilot Study
• Enroll RELAPSED cancer patients (N=200)
• Pre- and post-test survey to clinician
• Sequenom Panel (OncoCarta Custom)
– 277 mutation in 25 genes
– Return report to clinician
• OncoScan Array V3.0 (N=48)
– Genome-wide Copy Number/LOH
– 74 Mutations in 9 Genes
Translational Oncology Core
Pilot Study
• Sequenom:
– ABL1, AKT1, AKT2, BRAF, CDK4, CTNNB1,
EGFR, ERBB2, FGFR1, FGFR3, FLT3, HRAS,
JAK2, JAK3, KIT, KRAS, MET, MYC, NRAS,
PDGFRA, PIK3CA, PTEN, RB1, RET, VHL
• OncoScan (Affy):
– BRAF, KRAS, EGFR, IDH1, IDH2, PTEN,
PIK3CA, NRAS, TP53
…So what did we find?
Huntsman Cancer Institute:
Molecular Diagnostic/Translational
Oncology Core (TOC) Pilot Study
• Positive Mutation Frequency
48 out of 137 specimens were
positive for ≥1 mutation (35%)
Huntsman Cancer Institute:
Molecular Diagnostic/Translational
Oncology Core (TOC) Pilot Study
Tumor Types Analyzed by
OncoScan (N=48)
15 ovarian/endometrial
15 colorectal tumors
12 melanoma
4 lung tumor
1 brain tumor
1 thyroid tumor
Clinically actionable/relevant
copy number genes (N=100)
ABL1, AKT1, AKT2, ALK, APC, AR, ARID1A, ASXL1, ATM,
AURKA, BAP, BAP1, BCL2L11, BCR, BRAF, BRCA1, BRCA2,
CCND1, CCND2, CCND3, CCNE1, CDH1, CDK4, CDK6,
CDK8, CDKN1A, CDKN1B, CDKN2A, CDKN2B, CEBPA,
CTNNB1, DDR2, DNMT3A, E2F3, EGFR, EML4, EPHB2,
ERBB2, ERBB3, ESR1, EWSR1, FBXW7, FGF4, FGFR1,
FGFR2, FGFR3, FLT3, FRS2, HIF1A, HRAS, IDH1, IDH2,
IGF1R, JAK2, KDM6A, KDR, KIF5B, KIT, KRAS, LRP1B,
MAP2K1, MAP2k4, MCL1, MDM2, MDM4, MET, MGMT,
MLL, MPL, MSH6, MTOR, MYC, NF1, NF2, NKX2-1,
NOTCH1, NPM, NRAS, PDGFRA, PIK3CA, PIK3R1, PML,
PTEN, PTPRD, RARA, RB1, RET, RICTOR, ROS1, RPTOR,
RUNX1, SMAD4, SMARCA4, SOX2, STK11, TET2, TP53,
TSC1, TSC2, VHL
Ciriello et al., Nat Genet. (2013) / Frampton et al., Nat Biotechnol. (2013)
Pritchard et al., J Mol Diagn. (2014) / Andre et al., Lancet Oncol. (2014)
TOC Colorectal Adenocarcinoma
OncoScan Results (N=15)
Genome view
(Nexus, BioDiscovery, Inc.)
Copy number aberrations in 15
colorectal adenocarcinoma cases
BMP-039
Metastatic tumor (left ovary)
90% tumor content by Sequenom
KRAS G12S mutation
BMP-039
Metastatic tumor (left ovary)
90% tumor content by Sequenom
KRAS G12S mutation
Focal CCND1 gain (4 copies) in LOH
region in case BMP-18
Metastatic CRC (liver and bile duct)
50% tumor content by Sequenom
KRAS G12D mutation
Focal CDK6 gain (7 copies) in BMP-46
Metastatic CRC (right colon)
30% tumor content by Sequenom
KRAS G12C mutation
Next Study Design:
360 Degree Profiling
Mutation Panel
Genome-wide copy number
Genome-wide transcriptome
Genome-wide methylation
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•
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•
Relapsed Pediatric Tumors
Relapsed Colorectal Cancer
Relapsed Ovarian/Endometrial
Relapsed Melanoma
Relapsed Sarcoma
Utah and Pediatric Cancer
Tumors found by early screening (Utah)
9 yo boy
(TP53)
Grade II Glioma
Grade III AA
Lung Adenoca.
17 yo girl
24 yo man
41 yo woman
(TP53)
(TP53)
(TP53)
Renal Cell Carcinoma
30 yo man
(SDHB)
Carotid Body
Tumor
Carotid Body
Tumor
Pheochromocytoma
51 yo woman
58 yo man
34 yo man
(SDHB)
(SDHB)
(SDHB)
Screening TP53 mutation carriers
100%
Survival!
8 LFS families
−33 TP53 mut +
−18 surveillance
−12 no surveillance
20% Survival
P=0.0056
Surveillance
− 10 tumors, 7 pts
− All pts alive
No Surveillance
− 12 tumors, 10 pts
− 2 alive (20%)
Villani et al. Lancet Oncology (2011)
Cancer Genetics Study (CGS)
• Familial cancer syndrome global registry and
biospecimen bank
• Enroll children and families at high risk for
cancer
• DNA, cell lines, and tumor samples
• Biology and clinical data linked to family
pedigrees
• Participants linked to UPDB
Bella Johnson, Anne Naumer, Wendy Kohlmann
Cancer Genetics Study
• Data collection
– Cancer history
– Medical history
– Genetic testing
– Cancer screening
– Patient reported family history
– Linked to UPDB genealogy records
• Databases
– CCR, Subject, itBioPath, Progeny
Cancer Genetics Study
• Sample collection
– 1ACD tube for cell lines (limited availability)
– 1 EDTA tube for DNA and plasma
– 1 Red top tube for serum
– 1 PAXgene tube for RNA
– 1 CPT tube for PBMC
– Archived tissue or excess tissue from surgery if
not already in TRAC
PCH Pediatric Cancer Program
• Life Course Health Care Complications and
Costs – Anne Kirchhoff, PhD
• Value-Based Pediatric Clinical Cancer Care –
Richard Lemons, MD PhD
• Advanced Therapeutic Approaches to
Pediatric Cancer – Mike Spigarelli, MD PhD
• Identifying New Genes and Novel Screening
Approaches for Pediatric Cancer –
Joshua Schiffman, MD
DICER1 Family
“I’m not sure that you guys are
really going to be able to find
anything with this study if you are
stupid enough to drive out here in
this weather.”
Summary
1. Precision Oncology is happening now at
University of Utah
2. Early tumor surveillance in patients at
genetic risk for cancer saves lives
3. PCH Pediatric Cancer Program identifying
late effects, toxicities, pharmacodynamics, and genetic risks
4. UGP is finding cancer-associated genes
Questions?
Joshua.Schiffman@hci.utah.edu
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Schiffman Lab
– Lisa Abegglen
– Christin Christensen
– Ashley Chan
– Marcus Stucki
– Jamie Gardiner
– Tonya Santoro
– Kristy Lee
– Sharanya Raghunath
– Clint Mason
ARUP
– Sarah South, Xinjie Xu, Erica
Andersen, Reha Toydemir
Nexus (BioDiscovery)
– Soheil Shams, PhD
RESEARCH SUPPORT:
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ASH Scholar Fellowship Award
Curesearch Foundation (Children’s
Oncology Group)
St. Baldrick’s Foundation
Alex’s Lemonade Stand Foundation
SARC Career Development Award
Children’s Health Research Career
Development Award
(5K12HD001410-09)
Damon Runyon Clinical Investigator
Award
Leukemia & Lymphoma Society
1R01CA161780-01 (NCI/NIH)
Colorectal Cancer Mutation Summary
Sample ID
CNA/LOH
Sequenom
OncoScan
BMP-002
+++
No mutations
No mutations
BMP-006
+
KRAS G12D
KRAS G12D (6.59)
BMP-015
+
BRAF V600E
BRAF V600E (9.31)
BMP-017
+++
KRAS G12C
PIK3CA E542K
KRAS G12D/V (8.83)
PIK3CA E542K (41.22)
14/15
(93%)
=
Copy
Number
Present
BMP-018
++
KRAS G12D
KRAS G12D/V (10.21)
+++
KRAS G12D
KRAS G12D/V (12.44)
8/15
(53%)
=
KRAS
mutations
BMP-025
++
No mutations
No mutations
BMP-022
2/15 (13%)
= PIK3CA
mutations
+
KRAS G12V
KRAS G12D/V (11.36)
BMP-033
++
No mutations
No mutations
BMP-036
2/15 (13%)
= BRAF
mutationsKRAS G12D/V (12.47)
++
KRAS G12D
BMP-039
++
KRAS G12S
KRAS G12C/S (46.16)
+++
No mutations
No mutations
BMP-040
BMP-041
1/15 (7%) = JAK3
PTENmutation
K267fs*9
BMP-043
-
PIK3CA C420R
BRAF V600E
PTEN K267fs*9 (128.56)
(not included in panel)
BRAF V600E (57.54)
BMP-046
++
KRAS G12C
KRAS G12C/S (21.45)
BMP-047
++
JAK3 V7221
(not included in panel)
Ovarian and Endometrial Samples (N=15):
Mutation Summary
Sample CNA Sequenom
OncoScan
BMP 1
Yes
No Mutations
No Mutations
BMP 4
Yes
PIK3CA p.E545K
PIK3CA p.E545K
BMP 5
Yes
No Mutations
No Mutations
BMP 8
Yes
No Mutations
TP53 p.R273H/L
Yes
PIK3CA p.R88Q
TP53 p.R248Q/L
Yes
PTEN p.N323fs*2
KRAS p.G12D/V (Score:8.32)
No Mutations Present
Yes (93%)
No Mutations = Copy Number
14/15
BMP12
BMP20
No Mutations
No Mutations
4/15Yes(27%)
= PIK3CA mutations
BMP23
BMP26
No Mutations
No Mutations
2/15Yes(13%)
= PTEN mutations
BMP27
Yes
PIK3CA p.H1047R
PTEN p.R130G
PIK3CA p.H1047R
PTEN p.R130G
BMP42
Yes
No Mutations
No Mutations
BMP44
Yes
PIK3CA p.Q546K
PIK3CA p.Q546K
BMP45
Yes
No Mutations
No Mutations
BMP48
Yes
No Mutations
No Mutations
BMP28
2/15No(13%)
= TP53 mutations
No Mutations
No Mutations
BMP29
Metastatic Melanoma (N=12):
Mutation Summary
Case ID
CNAs
By Sequenom
By OncoScan
BMP-009
Yes
NRAS Q61K Mutation
NRAS Q61K Mutation
12/12 Yes
(100%)
= Copy Number
Present
NRAS G12C Mutation
NRAS G12C Mutation
BMP-010
Yes
No Mutations
No Mutations
BMP-013
V600E Mutation
BRAF V600E Mutation
Yes
4/12 (33%)
=BRAFNRAS
mutations
BMP-014
BMP-019
Yes
No Mutations
No Mutations
Q61R mutation
NRAS Q61R mutation
Yes
2/12 (17%)
=NRAS
BRAF
mutations
BMP-021
BMP-024
Yes
No Mutations
H701Pmutation
mutation
Yes
1/12 (8%)
=PIK3CA
PTEN
BMP-030
BMP-031
No Mutations
No Mutations
Yes
NRAS Q61K Mutation
NRAS Q61K Mutation
BMP-035
Yes
PTEN R130fs*4 mutation
PTEN R130fs*4 mutation
BMP-037
Yes
No Mutations
(CCND1 amplification)
1/12 (8%)
= BRAF
PIK3CA
mutationNo Mutations
K601E Mutation
Yes
BMP-034