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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
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.
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
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
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 - ??
• 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
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
Co
ind
re e
t a
l. C
an
ce
r. 2
00
1; 9
1(1
0):
19
14
-26
.
FNCLCC Grading
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
Nature. 2013;499(7457):214-8
*
Science. 2013;399(6127):-1546-58
*
Nature. 2013;499(7457):214-8
Nature. 2013;499(7457):214-8
Science. 2013;399(6127):-1546-58
Science. 2013;399(6127):-1546-58
Science. 2013;399(6127):-1546-58
19
TCGA – Integrative Analysis
Modified from The Cancer Genome Atlas Pan-Cancer analysis project
20
Pan-Cancer 33 Effort
22
TCGA Sarcoma Case Selection
23
Tumor Map – Josh Stuart, UCSC
24
Tumor Map
25
Unbalanced Copy Number
26
Unbalanced copy alterations vs somatic mutations
27
COSMIC Mutational Signatures in Sarcoma
28
Mutations in Sarcoma
29
Specific Mutations in SMGs
30
Sarcoma SMGs are tumor suppressors
31
Sarcomas have low and high CNV states
32
Image Analysis & Mutational Signatures
34
Immune Microenvironment
35
Immune Microenvironment
36
UPS: pre-tx and at 20 weeks
Radiology courtesy of Scott Schuetze MD/PhD
37
Leiomyosarcoma
38
Leiomyosarcoma
39
Leiomyosarcoma
40
Leiomyosarcoma
41
Leiomyosarcoma -RPPA
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
Clonal
Tumor
Tumor
Absent Markedly Reduced
Mildly Reduced Normal/Increased
PTEN IHC on FFPE Melanoma
Intensity relative to internal (+)ive controls
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
Anders
on N
D,
et al. S
cie
nce,
2018.
Anderson ND, et al. Science, 2018.
Pihan GA, Frontiers in Oncol, 2013.
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
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!
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
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
Thanks!