Normal breast tissue
Summary: CNA-expression groupings of TNBC
• BASAL, genomically unstable
– ? Constitutive PI3K active impact of phosphatases (several) from differentiation state and somatic deletions – ?? Immune subtype of basal
CLINICAL SUBTYPES
Heterogenous group Non basal Younger patients Fewer therapeutic options Express Basal markers
MOLECULAR SUBTYPES
Eg: IntClust subtypes CNA-expression subytpes
TNBC – a spectrum of different biological subtypes of disease • 15% of the breast cancer population • ‘Orphan’ disease subtype, defined by exclusion (absence of ER+ expression and HER2 amplification) • Not a single disease entity • A proportion are misclassified ER+ cancers • A proportion are misclassified HER2 cancers
No outcomes information
Basal (2 groups) Immune (previously noted) Mesenchymal related (3 groups) Androgen related
Lehmann et al, JCI 2011
Expression relationships, ‘in-cis’ with copy number events (1000 breast cancers)
HER2- ER-
ER~35% ~15 %
HER2+
trastuzumab
ER+ ~65%
Special types
High mitotic rate ER+
Endocrine therapy +/- cytotoxic chemo
HER2- ER+
Low mitotic rate ER+
(Curtis et al, Nature 2012)
in cis, overexpression
in cis, overexpression
in cis, loss of expression
Subtype specific, no CNA association
Approximately 45 ‘hotspot’ regions of the genome are in-cis CNA-expression outliers in breast cancers
TNBC sequence dataset
• Analysed 104 primary TNBC with combination of shotgun genome (Illumina & Solid4), exome (Illumina), transcriptome(Illumina), SNP6.0 • EARLY TNBC – ie early in clinical course (90% pT1 or T2) • 2164 validated SNVs at median of >20,000 fold coverage
PP2A subunits and MAP2K4 emerge as drivers in deletion landscape Curtis et al, Nature 2012
10 subgroups from joint clustering of CNA/expression in 1,000 breast cancers
CNA frequency
Chi-square P-value (subtype test)
= non HER2, 17q subtype = HER2 subtype = GROUP 10 = predominantly basal TN
= genomically quiescent tumours
TNBC
basal
Non-basal
Exons
Shah et al, Nature 2012 & Aparicio, 2012 unpublished. – ex; RNA-seq of 104 TNBC cases
INPP4B long isoform expressed in normal luminal myoepithelium, but not basal
Basal/Non-basal, derived from expression profiling of primary breast cancers
Doesn’t account for what is now known about the mutational landscape
Parker, JCO 2009
INPP4B expression is low in ‘basal’ subtype TNBC
But why?
Gewinner et al, Cancer Cell 2009 Fedele et al, PNAS 2010
INPP4b isoforms are differentially expressed in basal and non-basal TNBC
The clonal and mutational spectrum of marker negative breast cancers (TNBC)
Samuel AJR Aparicio BM BCh PhD FRCPath Nan and Lorraine Robertson Chair, UBC Canada Research Chair, Molecular Oncology BC Cancer Agency/UBC, Vancouver http://molonc.bccrc.ca (postdoc & student oportunities – see website!)
How many subgroups make up TNBC?
1. Expression and CNA-expression studies 2. Somatic mutational spectrum of primary TNBC 3. Clonal evolution spectrum of primary TNBC
In summary TNBC at a glance …
Overlapping biologies suggested by somatic mutations PARK2, ATM translocations Mesenchymal Phenotype? Androgen signaling Wide spectrum of clonal complexity at diagnosis Patient 1 pT1
Shah et al, Nature 2012
Location specific genome aberrations in TNBC
• Modalities exhibiting patterns of recurrence >5% between patients
– Large scale chromosome events (ploidy, whole arm gains/losses) (chr1, 8) – Segmental (copy number gains) and losses – Single mutations/variants (SNV) and small indels (eg p53, PIK3CA)
Basal/gp10 specific
PI3K network
Immune Cell cycle ?PP2A phosphatases
Wnt signaling
Shah et al Nature 2012 Curtis et al, Nature 2012
INPP4b a phosphatase regulator of the PI3K pathway
= novel 11q subtype = 1q, mostly quiescent tumours Curtis et al, Nature 2012
Expression relationships ‘in trans’ – correlated expression with CNA event at another locus
Patient 2 pT1
Cell type(s) of origin?
Rb -
Cell shape motility
Patient 3 pT1
A significant proportion of “actionable” events (~20%)
Biological subtypes of breast cancer
The clonal and mutational evolution of primary triple negative breast cancers • Dr. Aparicio has no relevant financial relationships to disclose.