Evolutionary Pathways in BRCAl-Associated Breast Tumors
Abstract
BRCAl-associated breast tumors display loss of BRCA1 and frequent somatic mutations of PTEN and TP53.
Here we describe the analysis of BRCA1, PTEN, and p53 at the single
cell level in 55 BRCA1-associated breast tumors and computational
methods to predict the relative temporal order of
somatic events, on the basis of the frequency of cells with single or
combined
alterations. Although there is no obligatory order
of events, we found that loss of PTEN is the most common first event and
is associated with basal-like subtype, whereas in
the majority of luminal tumors, mutation of TP53 occurs first and mutant PIK3CA is rarely detected. We also observed intratumor heterogeneity for the loss of wild-type BRCA1 and increased cell proliferation
and centrosome amplification in the normal breast epithelium of BRCA1 mutation carriers. Our results have important implications for the design of chemopreventive and therapeutic interventions
in this high-risk patient population.
SIGNIFICANCE: Defining
the temporal order of tumor-driving somatic events is critical for early
detection, risk stratification, and the
design of chemopreventive therapies. Our combined
experimental and computational approach reveal that the loss of
wild-type
BRCA1 may not be the first event in the majority of
BRCA1-associated breast tumors and may not be present in all cancer
cells
within tumors.
Cancer Discov; 2(6); 1–9. ©2012 AACR.
