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TRANSCRIPT
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SY-20 = Soft Tissue and Bone Pathology: Diagnostic molecular pathology of bone and soft tissue tumors: techniques, translation and targets – Genomic insights in sarcomas
31st ECP; Nice, FranceTuesday 10 September 2019; 14:45 – Athena AuditoriumAlexander Lazar MD/PhDProfessorDepartments of Pathology, Genomic Medicine & DermatologySarcoma Research Center
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DISCLOSURE OF RELATIONSHIPS WITH INDUSTRY
Alexander Lazar MD/PhDTuesday 10 September 2019
31st ECP: Nice, France
SY-20 = Soft Tissue and Bone Pathology: Diagnostic molecular pathology of bone and soft tissue tumors: techniques, translation and
targets – Genomic insights in sarcomas
I have the following financial relationships to disclose:
GSK, Novartis, BMS, Pfizer, Loxo / Bayer, AbbVie, Astra-Zeneca / MedImmune, Merck, Roche / Genentech / Ignyta, ArcherDx, Illumina, ThermoFisher, Beta-Cat
Pharmaceuticals / Iterion Therapeutics, Foghorn Therapeutics, Flagship Pioneering, Human Longevity Inc, Nucleai, Elsevier, SpringerNature, USCAP, CAP, AACR, ASCO,
WHO / IARC, various VC, strategic consultancies, & marketing concerns.
(mostly scientific advisory boards, clinical trials, research / travel support and business / financial strategy consulting)
These relationships are NOT relevant to the educational content of this lecture.
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Road Map of the Talk
• Quick sarcoma introduction
• Sarcoma and Cancer Genome introduction
• The Cancer Genome Atlas (TCGA) in a nutshell:
– Sarcoma Biomarker
– Clinical implications of Sarcoma TCGA
– Related sarcoma studies
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Sarcoma Classification
• Can be challenging
• Heterogeneous group of tumors with >50
histological subtypes, each with varying clinical
phenotypes and behavior
• Some tumors are unclassifiable
• Many benign entities (100:1), some of which can be
confused for sarcomas
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Sarcoma Classification:Histogenesis/Line of Differentiation
Osteosarcoma
Chondrosarcoma
Angiosarcoma
UPS
Liposarcoma
Leiomyosarcoma
Rhabdomyosarcoma
MPNST
Synovial Sarcoma - ?? Ewing Sarcoma/PNET - ??
Courtesy of Dr. Brian Rubin, CCF
ASPS - ??
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• Morphologically or by immunohistochemical studies
• Beware of mimics
• Some tumors lack a normal counterpart (i.e. synovial sarcoma)
• Not all tumors with similar differentiation will behave the same
Sarcoma Classification: Line of Differentiation
A-RMS
PLPS
Myogenin
ALT
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FNCLCC Grading
• All three numbers are summated to determine degree of differentiation
Grade 1 : 2-3
Grade 2 : 4-5
Grade 3 : 6-8
• Proven to correlated well with survival
• Mitotic Count. In the most mitotically active area, ten successive high-power fields (at 400x magnification=0.1734 mm2) using a 40x objective.
1 0-9 mitoses per 10 HPFs2 10-19 mitoses per 10 HPFs3 >20 mitoses per 10 HPFs
• Tumor necrosis. Evaluated on gross examination and validated with histological sections
0 No tumor necrosis1 <50% tumor necrosis2 >50% tumor necrosis
• Degree of Differentiation. 1-3
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Co
ind
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t a
l. C
an
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19
14
-26
.
FNCLCC Grading
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Sarcoma Genomic Classification
• Simple karyotype (recurrent)
– Translocation (SS, RMS, DFSP, MLPS, etc)
– Activating Gene Mutations (GIST, desmoid)
• Intermediate (recurrent)
– WD/DD liposarcoma
• Complex karyotype
– TP53, disrupted chromosome management
– UPS, MFS, pleomorphic liposarcoma
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Nature. 2013;499(7457):214-8
*
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Science. 2013;399(6127):-1546-58
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*
Nature. 2013;499(7457):214-8
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Nature. 2013;499(7457):214-8
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Science. 2013;399(6127):-1546-58
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Science. 2013;399(6127):-1546-58
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Science. 2013;399(6127):-1546-58
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TCGA – Integrative Analysis
Modified from The Cancer Genome Atlas Pan-Cancer analysis project
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Pan-Cancer 33 Effort
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TCGA Sarcoma Case Selection
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Tumor Map – Josh Stuart, UCSC
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Tumor Map
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Unbalanced Copy Number
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Unbalanced copy alterations vs somatic mutations
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COSMIC Mutational Signatures in Sarcoma
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Mutations in Sarcoma
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Specific Mutations in SMGs
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Sarcoma SMGs are tumor suppressors
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Sarcomas have low and high CNV states
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Image Analysis & Mutational Signatures
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Immune Microenvironment
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Immune Microenvironment
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UPS: pre-tx and at 20 weeks
Radiology courtesy of Scott Schuetze MD/PhD
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Leiomyosarcoma
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Leiomyosarcoma
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Leiomyosarcoma
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Leiomyosarcoma
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Leiomyosarcoma -RPPA
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PTEN Loss Correlates with AKT Activation
BRAF NRAS WTn=39 n=18 n=37
-2.6 2.1
Ph
osp
ho
-AK
T Th
r30
8
PTEN
Tumors (n=96)
BR
AF
Mu
tati
on
+ P
TEN
Lo
ss
PT
EN L
oss
• RPPA of 96 OCT-embedded melanoma metastases & 58 cell lines
– Y-axis, P-AKT expression; Color ~ PTEN expression
• Compared PI3K-AKT pathway activation to mutation status
Davies, CCR, 2009
AKT
PI3K
PTEN
NRAS
• Loss of PTEN associated with greater activation of PI3K pathway (P-AKT) than NRAS mutations
• ~Results in tumors and cell lines
Supports that PTEN is the critical regulator pathway in melanoma
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Clonal
Tumor
Tumor
Absent Markedly Reduced
Mildly Reduced Normal/Increased
PTEN IHC on FFPE Melanoma
Intensity relative to internal (+)ive controls
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Correlation of PTEN loss in melanoma cells with an immune resistance phenotype.
Weiyi Peng et al. Cancer Discov 2016;6:202-216
©2016 by American Association for Cancer Research
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Anders
on N
D,
et al. S
cie
nce,
2018.
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Anderson ND, et al. Science, 2018.
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Pihan GA, Frontiers in Oncol, 2013.
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de Pagter M.S., Kloosterman W.P. (2015) The Diverse Effects of Complex Chromosome
Rearrangements and Chromothripsis in Cancer Development. In: Ghadimi B., Ried T. (eds)
Chromosomal Instability in Cancer Cells. Recent Results in Cancer Research, vol 200.
Springer, Chamhttp://neuropathologyblog.blogspot.com/2015/10/chromothripsis.html
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A very different picture than in BAF loss-of-function cancer types – this is why
these diseases are different! Different BAF complex mechanisms on
chromatin!
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McBride, Pulice et al., Cancer Cell June 2018
RNAseq reveals distinct SS gene expression signature, consistent with different
chromatin changes between SS18-SSX complexes and LOF (i.e. loss of
SMARCB1/loss of SMARCA4 , etc) BAF complexes
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Conclusions
• Sarcoma genomics is a bit complicated
• Complex karyotype sarcomas are driven by copy number alterations and loss of TSG
• Translocation-associated sarcomas can have complex mechanisms to produce fusions
• Epigenetics is an important component of sarcoma tumor biology
MDACC & PICI confidential - not for
distribution
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Thanks!