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 Carcinoma, grade 1 Serous Carcinoma, grade 1 Silverberg Grading System

Low Grade Serous Carcinoma Low Grade Serous Carcinoma High Grade Serous Carcinoma High Grade Serous Carcinoma (Micropapillary Micropapillary) ) • Previous abnormal ultrasound • May have previous normal • • Stage I at diagnosis Stage I at diagnosis ultrasound ultrasound • Frequent mutations of • Advanced stage at diagnosis KRAS/BRAF • p53 mutations over 80% • • Relative chromosomal Relative chromosomal • Marked chromosomal stability instability • Few DNA copy number gains • Chemosensitive • Chemoresistant Chemoresistant • Assoc with BRCA1/2 germline • Assoc with LMP tumours mutations

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 Serous Tumor of LMP with Carcinoma MP Features

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

? Am J Path, 164(5): 1511 ‐ 1518, 2004

OCCULT CANCERS IN PROPHYLACTIC SALPINGO ‐ OCCULT CANCERS IN PROPHYLACTIC SALPINGO OOPHORECTOMY SPECIMENS OOPHORECTOMY SPECIMENS OOPHORECTOMY SPECIMENS OOPHORECTOMY SPECIMENS 159 patients: BRCA1 BRCA2 (94) (94) (64) (64) Cancer diagnosis 6 (6.4%) 6 (6 4%) 1 (1.6%) 1 (1 6%) at surgery at surgery Mean age at diagnosis t di i 49 5 49.5 yr. 53 53 yr. Cancer Type Serous gr 3 Serous gr 3 Cancer site 5/6 tube Peritoneum 3/6 ovary & tube 1/6 1/6 ovary only l Finch et al 2006

Ovary Fimbria OSE FTE

Tubal Fimbria TIC TIC Ovarian Stroma OSE

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 of presumed origin or mutation status • No differentially expressed genes between tubal and ovarian SerCa could be i S C ld b identified by SAM • 10 genes at 77% FDR • Supports postulate that tubal and ovarian SerCa may f ll follow a similar i il pathogenesis Tone et al 2008

Mucosal epithelial proliferation and p53 overexpression of fallopian tube epithelium are frequent in women of fallopian tube epithelium are frequent in women with BRCA mutations. p53 Shaw et al 2004

Hyperplasia p53 signature p53 Signature p53 Signature TIC p53 p53 neg TIC

p53 signature p53 p53 Ki67 Ki67

Tubal Intramucosal Intramucosal Carcinoma p53 p Ki67

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%)

TIC

TIC

TIC

Metastatic Serous Carcinoma OSE Ovarian Cortex

• 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 prophylactic surgery h l ti • 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

A New Model for High Grade Serous A New Model for High Grade Serous Tumorigenesis Tumorigenesis Normal p53 Signature TIC HGSCa ? BRCA1/2

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

DAB2 Protein is Preferentially Lost from DAB2 Protein is Preferentially Lost from Secretory Secretory Epithelial Epithelial Cells During the Cells During the Luteal g Luteal Phase Phase Secretory (+) Ciliated ( ‐ ) Ciliated ( ‐ ) FTEb follicular Secretory ( ‐ ) ( ) FTEb luteal High grade SerCa Tone et al 2008

TP53 TP53 BR BRCA1 CA1 p2 p21 WEE1 WEE1 CDC2 CDC2 SMAD4 SMAD4 SMAD4 SMAD4 TG TG TGFBR1 TGFBR1 SMAD3 SMAD3 SMAD3 SMAD3 DA DAB2 SKIL SKIL SMAD2 SMAD2 SMAD2 SMAD2 TGFBR2 TG TG TGFBR2

TP53 TP53 BR BRCA1 CA1 p2 p21 WEE1 WEE1 CDC2 CDC2 SMAD4 SMAD4 SMAD4 SMAD4 TG TG TGFBR1 TGFBR1 SMAD3 SMAD3 SMAD3 SMAD3 DA DAB2 SKIL SKIL SMAD2 SMAD2 SMAD2 SMAD2 TGFBR2 TG TG TGFBR2

TP53 TP53 BR BRCA1 CA1 p2 p21 WEE1 WEE1 CDC2 CDC2 SMAD4 SMAD4 SMAD4 SMAD4 TG TGFBR1 TG TGFBR1 SMAD3 SMAD3 SMAD3 SMAD3 DAB2 DA SKIL SKIL TG TGF- β -induced -induced gr growth inhibition th inhibition SMAD2 SMAD2 SMAD2 SMAD2 TGFBR2 TG TG TGFBR2

Acknowledgements Acknowledgements Students Collaborators Alicia Tone Ted Brown Taymaa May Taymaa May Igor Jurisica Igor Jurisica Jim Greenaway Joan Murphy Barry Rosen Steven Narod John McLaughlin BioBank Microarray Centre Heather Begley Monika Sharma Kelvin So Carl Virtanen Supported by Canary Foundation T Toronto Fashion Show t F hi Sh CIHR DOD