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New Paradigms in Serous Ovarian New Paradigms in Serous Ovarian Cancer
- Dr. Patricia Shaw
New Paradigms in Serous Ovarian New Paradigms in Serous Ovarian - - PowerPoint PPT Presentation
New Paradigms in Serous Ovarian New Paradigms in Serous Ovarian - - PowerPoint PPT Presentation
New Paradigms in Serous Ovarian New Paradigms in Serous Ovarian Cancer Dr. Patricia Shaw Dept of Pathology PMH/UHN PMH/UHN Toronto Ovarian Tissue Bank and Database 1996 2007 Serous Carcinoma, grade 3 Serous Carcinoma, grade 3 Serous
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Serous Carcinoma, grade 3 Serous Carcinoma, grade 3 Serous Carcinoma, grade 1 Serous Carcinoma, grade 1
Silverberg Grading System
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High Grade Serous Carcinoma High Grade Serous Carcinoma Low Grade Serous Carcinoma Low Grade Serous Carcinoma (Micropapillary Micropapillary) )
- Previous abnormal ultrasound
- Stage I at diagnosis
- May have previous normal
ultrasound
- Stage I at diagnosis
- Frequent mutations of
KRAS/BRAF
- Relative chromosomal
ultrasound
- Advanced stage at diagnosis
- p53 mutations over 80%
- Relative chromosomal
stability
- Few DNA copy number gains
- Chemoresistant
- Marked chromosomal
instability
- Chemosensitive
Chemoresistant
- Assoc with LMP tumours
- Assoc with BRCA1/2 germline
mutations
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MODEL OF LOW GRADE SEROUS ONCOGENESIS MODEL OF LOW GRADE SEROUS ONCOGENESIS
OSE
Ovarian Surface Epithelium Epithelial Inclusions Serous Tumor of LMP Low Grade Serous Carcinoma Serous Tumor of LMP with MP Features
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Significant Genes and Pathways Involved in Low Grade Ovarian Carcinogenesis
Protocol:
- Histology review
- LCM
- cDNA amplification
- Affymetrix U133
- Affymetrix U133
Plus 2.0 LMP LMP-MP LGSC May et al 2008
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Am J Path, 164(5): 1511‐1518, 2004
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OCCULT CANCERS IN PROPHYLACTIC SALPINGO OCCULT CANCERS IN PROPHYLACTIC SALPINGO‐ OOPHORECTOMY SPECIMENS OOPHORECTOMY SPECIMENS OOPHORECTOMY SPECIMENS OOPHORECTOMY SPECIMENS
159 patients: BRCA1 BRCA2 (94) (64) (94) (64) Cancer diagnosis at surgery
6 (6 4%) 1 (1 6%)
at surgery
6 (6.4%) 1 (1.6%)
Mean age t di i 49 5 53 at diagnosis 49.5 yr. 53 yr. Cancer Type Serous gr 3 Serous gr 3 Cancer site 5/6 tube Peritoneum 3/6 ovary & tube 1/6 l 1/6 ovary only
Finch et al 2006
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Ovary Fimbria OSE FTE
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Tubal Fimbria
TIC TIC
Ovarian Stroma OSE
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Fallopian Tube and Ovarian Serous Carcinomas Exhibit Fallopian Tube and Ovarian Serous Carcinomas Exhibit Indistinguishable Gene Expression Profiles Indistinguishable Gene Expression Profiles Indistinguishable Gene Expression Profiles Indistinguishable Gene Expression Profiles
- Serous carcinoma specimens
cluster together irrespective
- f presumed origin or
mutation status
- No differentially expressed
genes between tubal and i S C ld b
- varian SerCa could be
identified by SAM
- 10 genes at 77% FDR
- Supports postulate that
tubal and ovarian SerCa may f ll i il follow a similar pathogenesis
Tone et al 2008
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Mucosal epithelial proliferation and p53 overexpression
- f fallopian tube epithelium are frequent in women
- f fallopian tube epithelium are frequent in women
with BRCA mutations. p53
Shaw et al 2004
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p53 Signature Hyperplasia p53 signature p53 Signature p53 neg TIC p53 TIC
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p53 signature p53 Ki67 p53 Ki67
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Tubal Intramucosal Intramucosal Carcinoma p53 Ki67 p
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Overall BRCA1/2 Control
N(%) N(%) N(%) p53 signature 31 (13%) 19 (11%) 12 (19%) “Pre” TIC 4 (2%) 3 (2%) 1 (2%) TIC 17 (7%) 15 (8%) 2 (3%)
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TIC
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TIC
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TIC
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Metastatic Serous Carcinoma OSE Ovarian Cortex
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- Candidate cancer precursor lesions (Pre‐TIC + TIC) :
- Tubal fimbria and distal tube*
- 10% BRCA1/2 mutation carriers
- Not all TIC overexpress p53 by IHC
- All distal, but not all fimbrial – implications for
h l ti prophylactic surgery
- Rarely may be associated with identified
metastasis* metastasis
- No known “recurrences”**
- Role of FTE in serous carcinogenesis:
Role of FTE in serous carcinogenesis:
- Significance of p53 signature uncertain
- Likely cell of origin of High Grade Serous
y g g Carcinoma
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A New Model for High Grade Serous A New Model for High Grade Serous Tumorigenesis Tumorigenesis
Normal p53 Signature TIC HGSCa
?
BRCA1/2
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Differential Impact of the Ovarian Cycle in Differential Impact of the Ovarian Cycle in BRCA BRCA‐Mutation Mutation Carriers Carriers
- The number of differentially expressed genes between the
luteal and follicular phases is far greater in mutation carriers p g relative to normal controls (9.8% FDR)
- Suggests that hormonal influences on the FTE may be greater or
Suggests that hormonal influences on the FTE may be greater or altered as a result of functional BRCA levels
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DAB2 Protein is Preferentially Lost from DAB2 Protein is Preferentially Lost from Secretory Secretory Epithelial Epithelial Cells During the Cells During the Luteal Luteal Phase Phase g
Ciliated (‐) Secretory (+) Ciliated (‐)
FTEb follicular
Secretory (‐) ( )
FTEb luteal High grade SerCa
Tone et al 2008
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TP53 TP53 BR BRCA1 CA1 p2 p21 WEE1 WEE1 SMAD4 SMAD4 CDC2 CDC2 SMAD4 SMAD4 TG TGFBR1 SMAD3 SMAD3
SKIL SKIL
TG TGFBR2 TG TGFBR1 SMAD3 SMAD3 SMAD2 SMAD2
DA DAB2
TG TGFBR2 SMAD2 SMAD2
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TP53 TP53 BR BRCA1 CA1 p2 p21 WEE1 WEE1 SMAD4 SMAD4 CDC2 CDC2 SMAD4 SMAD4 TG TGFBR1 SMAD3 SMAD3
SKIL SKIL
TG TGFBR2 TG TGFBR1 SMAD3 SMAD3 SMAD2 SMAD2
DA DAB2
TG TGFBR2 SMAD2 SMAD2
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TP53 TP53 BR BRCA1 CA1 p2 p21 WEE1 WEE1 SMAD4 SMAD4 CDC2 CDC2 SMAD4 SMAD4 TG TGFBR1 SMAD3 SMAD3
SKIL SKIL
TG TGFBR2 TG TGFBR1 SMAD3 SMAD3 SMAD2 SMAD2
DA DAB2
TG TGF-β-induced
- induced
gr growth inhibition th inhibition
TG TGFBR2 SMAD2 SMAD2
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