Heinrich & Corless Laboratories
GIST Research Updates: May 2011
Genotyping for Clinical Trials• Regorafenib (Bayer) – phase II trial
– Tyrosine kinase inhibitor– 3rd/4th line therapy for resistant GISTs– Initial results will be reported at ASCO– FDA has put the drug on fast-track for review– Phase III trial is getting underway
• Synta– HSP90 inhibitor (intravenous)– Phase II trial ongoing
Genotyping for Clinical Trials• PERSIST trial
– Ron DeMatteo’s trial of 5 years of adjuvant imatinib
– More than 50% enrolled• ImClone
– Antibody against PDGFRA– Phase II trial for KIT-mutant or PDGFRA-mutant
tumors resistant to imatinib & sunitinib• Phase I/II trial for a new drug that Mike will
talk about
‘Next Generation’ DNA Sequencing• Traditional DNA sequencing is limited to
just one part of one gene at a time• Second-generation DNA sequencers are
now available and have begun to revolutionize cancer research by generating information on thousands of genes simultaneously
• Starting last summer, we have been using this new technology to study GISTs
Sequencing Data
• Human genome consists of 3.2 billion letters (A, C, T, G)
• Genes comprise only ~2% of our DNA (about 64 million letters)
• We ‘pre-select’ the genes, so that only the 64 million letters of interest get sequenced
• Cost: $3,000 per sample
Sequencing Data
• First experiment: 8/2010• Illumina GAIIX~1,000,000,000 letters per experiment
• Most recent experiment: 4/2011• Illumina HiSeq
~10,000,000,000 letters per experiment
Sequencing GIST Tumors
Source Status Genotypes Source
OHSU Completed 3 tumors; 1 KIT & 2 PDGFRA D842V Primary
Debiec-
Rychter
Completed 6 tumors; KIT exon 9 or 11; some with
resistance mutations
Primary &
Metastatic
Fletcher Data analysis in
progress
5 tumors; KIT exon 9 with varying
resistance mutations
Metastatic
Bauer Pending 9 tumors; KIT exon 9 or 11; some with
resistance mutations
Primary &
Metastatic
Confirmed Mutations
Patient Gene AA Change # exons Exon affected Chr
Sequence
confirmed?
1
PDGFRA D842V 23 18 4q11-q13 yes
HNRNPA2B1 S36G 12 3 7p15 yes
2
PDGFRA D842V 23 18 4q11-q13 yes
TP53 C135G 11 5 17p13.1 yes
MDN1 E661K 102 14 6q15 yes
KEL T421M 19 11 7q33 yes
TACR3 S435N 5 5 4q25 yes
CTNND2 N1211S 21 21 5p15.2 yes
INSR S995A 22 16 19p13.3-p13.2 yes
KIT V559D 21 11 4q11-q12 yes
LAS1L Q634L 14 12 Xq12-q13 yes
ODZ1 R1519C 31 24 Xq25 yes
TP53 L348S 11 10 17p13.1 yes
COL1A2 G430E 52 23 7q22.1 yes
TP53 G245C 11 7 17p13.1 yes
DDEF1/ASAP1 W18C 29 1 8q24.1-q24.2 yes
SAT1 H53Q 3 3 Xp22.1 yes
Patient Gene AA Change # exons Exon affected Chr
Sequence
confirmed? Gene function
4
BAZ2B S554F 37 9 2q23-q24 pendingbromodomain adjacent to zinc finger
domain
FAM134A V296M 9 8 2q35 pending
Possible relationship with lung
ca metastasis?
TNFRSF11B I312T 5 5 8q24 pending
osteoblast-secreted decoy receptor that
functions as a negative regulator of bone
resorption. This protein specifically binds to
its ligand, osteoprotegerin ligand
SERINC2 T245N 10 6 1p35.1 pending Nothing known
SHBG A210V 8 5 17p13-p12 pending Steroid binding globulin
C10orf82 L149M 4 5 10q25.3 pending Nothing known
IFNGR1 N433Y 7 7 6q23-q24 pending interferon gamma receptor 1
PCDHB16 P390H 1 1 5q31 pending Ca++ Cell adhesion
KIT D816G 21 17 4q11-q12 yes
LASS2 L45M 11 2 1q21.2 pending
Growth regulation; sphingolipid
synthesis
FAM176A V12M 4 3 2p12 pending Apoptosis/autophagy
AAAS A167T 16 6 12q13 pending
COL1A2 A683D 52 34 7q22.1 pending
KIT Y823D 21 17 4q11-q12 yes
LASS2 L45M 11 2 12q13 pending
Growth regulation; sphingolipid
synthesis
FAM176A V12M 4 3 2p12 pending Apoptosis/autophagy
GIPC2 L206P 6 4 1p31.1 pending PDZ-containing protein
PRAMEF2 E83K 4 2 1p36.21 pending Nothing known
10(B)KIT INS_AY502-503 21 9 4q11-q12 yes
KIT D816H 21 17 4q11-q12 yes
TP53 G245S 11 7 17p13.1 pending
KIT INS_AY502-503 21 9 4q11-q12 yes
KIT D820E 21 17 4q11-q12 pending
TP53 G245S 11 7 17p13.1 pending
Knight Diagnostic Laboratories• The Corless laboratory has recently been
integrated into the new Knight Diagnostic Laboratories
• These Labs are now operating independent from OHSU Hospital
• Mandate from Dr. Druker:– Offer the most advanced genotyping in the
country– Expand outreach to serve as many cancer patients
as possible