Reclassifying cancer
Tumor site and outcome
Location, location, location
Provides prognostic and predictive
information
Anatomical position important in
surgical management
Provides some biological information,
including lineage dependencies eg.
hormonal
But how well does anatomical position
capture biological diversity?
Conventional classification of ovarian cancer
6
10
12
15
60
Serous
Mucinous
Endometrioid
Clear cell
Other
OSE
Thought to arise from ovarian surface
epithelium or ovarian inclusion cysts
Pelvic
Ovarian cancer
Mucinous - Most mucinous invasive tumours are secondary GI
malignancies
NOT 15% - Primary invasive mucinous cancers represent only 2.3%
of cancers in the AOCS series.
Pelvic
Ovarian cancer
Endometrioid - Endometriosis
Clear cell - Endometriosis
Wiegand et al NEJM 2010
Pelvic
Ovarian cancer
TIC - Tubal intraepithelial
carcinoma
Serous cancers – derived from secretory
cells of the distal fallopian tube
•Intensely positive p53 foci in FT
•TP53 mutations are an early event
•Matching TP53 mutations found in FT and tumour
•Majority of tumours have TIC in the FT
•FT epithelium gene expression more closely resembles
serous cancers than ovarian surface epithelium
Lee et al (2007) J Pathol
Ovarian cancer is series of molecularly distinct diseases
that share an anatomical location
8
8
10
2.3
serous
74
Type I
•Progress from premalignant cancers
•Generally low grade
•Frequent Ras pathway mutations
•BRCA wild type
•Generally p53 wild type
•Chromosomally stable
•Chemo-resistant
Type II
•De novo invasive tumours in fallopian tube
•High grade
•Ras wild type
•BRCA dysfunction
•~100% p53 mutant
•Widespread DNA copy number change
•Platinum sensitive
High grade serous cancer and triple negative breast
cancer are related
8
8
10
2.3
serous
74
*Triple negative breast cancer
Type II
•De novo invasive tumours in fallopian tube
•High grade*
•Ras wild type
•BRCA dysfunction*
•~100% p53 mutant*
•Widespread DNA copy number change*
•Platinum sensitive*
A model for the evolution of high grade (Type II)
serous cancers
Type II
•De novo invasive tumours in fallopian tube
•High grade
•Ras wild type
•BRCA dysfunction
•~100% p53 mutant
•Widespread DNA copy number change
•Platinum sensitive
Bowtell (2010) Nature Reviews Cancer
Platinum response in high grade serous cancers drives
chemotherapy in ovarian cancer as a whole
8
8
10
2.3
serous
74
Type II
•De novo invasive tumours in fallopian tube
•High grade
•Ras wild type
•BRCA dysfunction
•~100% p53 mutant
•Widespread DNA copy number change
•Platinum sensitive
Sub-classification of high grade serous cancers
serous
Serous
Type II
Microarray gene expression reveals four novel
molecular subtypes of high-grade serous cancer
C1
C2
C4
C5
Class 1 (C1), C2, C4, C5 = high grade subtypes
C3, C6 = low grade subtypes
Clinical Cancer Research (2008)
Richard
Tothill
Anna
Tinker
Molecular subtypes of high-grade serous cancer with
distinct clinical outcomes
N=939
Helland et al PLoS One (2011) in press
TCGA Consortium Nature 2011 (in press)
MYCN, LIN28B, Let-7, HMGA2 pathway
activation in C5 tumours
C1
C2
C4
C5
Helland et al PLoS One (2011) in press
Unraveling ‘ovarian’ cancer
Conventional
6
8
10
8
10
12
15
Current
2.3
60
Serous
Mucinous
Endometrioid
Clear cell
Other
74
Molecular
subtypes
Clear cell and serous cancers are unrelated
Serous
Proliferation
Clear Cell
Xenobiotic metabolism
UDP‐Glucosyltransferases
Receptors
HNF1b
Transmembrane transporters
c‐Met
Immune
IL‐6
EPAS1 (Hif2a)
Lyn
Stromal
Mesenchymal
Anglesio et al Clinical Cancer Research (2011)
Ovarian clear cell cancer resemble renal clear
cell cancer
Serous
Proliferation
Clear Cell
Xenobiotic metabolism
UDP‐Glucosyltransferases
Receptors
HNF1b
Transmembrane transporters
c‐Met
Immune
IL‐6
EPAS1 (Hif2a)
Lyn
TGFb
IL6
Hypercalcemia
of malignancy
PTHrP
Thrombosis
STAT3
Stromal
Mesenchymal
HIF1a
VEGF
HIF2a
Anglesio et al Clinical Cancer Research (2011)
Pseudo-hypoxic drive
Angiogenesis
Defective protein turnover
Striking response to VEGFR inhibitor sunitinib
in OCCC
Anglesio et al Clinical Cancer Research (2011)
Molecular subtypes of breast cancer and glioma
Perou (2000) Nature
Verhaak et al (2010) Cancer Cell
One disease
Ovarian cancer
Many diseases
Fragmentation
Ovarian cancer
Convergence
Breast cancer
Renal cancer
At a fork in the road for cancer classification?
25,000 cancer genomes
Limited consideration
of individual variation
Treatment based on
experience with thousands
of previous patients
Tissue of origin
Cancer
Molecular subtype
information layered
over site of origin
Treatment decision
explicitly incorporates
molecular data
Cancers eventually
seen as #32 or #26,
not breast or ovarian
cancer