Target Discovery and Validation Reviews and Protocols

Molecular Profiling of Breast Cancer 109
7. Identification of Novel Markers
Gene signatures identified by whole-genome profiling that are significantly
linked to clinically important parameters are valuable sources for discovering
novel prognostic factors and targets for therapy. Many such markers have been
suggested for breast cancer in the literature, in particular for predicting survival
(23,26,30,33,34,74), with varying degree of success. A striking discovery was
the lack of overlap of the predictive genes in most of these studies. This lack of
overlap could be because of different microarray technologies, patient populations,
study design, and statistical methods, or it could reflect the redundancy
of valid correlations in such data. Recently, this idea was investigated in a study
of one single breast cancer data set and by one statistical method (75), where
the researchers showed that the resulting gene set was not unique and was
strongly influenced by the subset of patients selected for the analysis. Many
equally prognostic gene sets could be produced. This illustrates the consequence
of molecular heterogeneity even within tumor groups that share the
same histomorphology.
Recently, we have identified a subset of 54 marker genes that specifically
capture the luminal A and the basal-like subtypes (13a), which represent two
clinically very different groups of patients. These markers define a set of highly
validated and promising potential prognostic molecular markers for breast cancer,
and further confirmation in larger patient cohorts will be conducted.
8. Conclusion and Future Perspectives
Cancer genomics, as illustrated here by DNA microarray techniques, has
challenged the traditionally used tumor classification schemes by identifying
genetic alterations that can be used to group tumors into novel and clinically
useful categories. In addition to leading to a improved cancer taxonomy, comprehensive
gene profiling of tumors promises to enhance our understanding of
the underlying biological processes and their biological effects. It also offers the
greatest challenge to how clinical trials should be conducted. Designing the
appropriate clinical trials in combination with genomics that use optimal laboratory
methods and advanced statistics that incorporate biological knowledge may
offer the opportunity to explore and understand the mechanisms controlling
tumor behavior in vivo. In time, this approach will likely lead to improved prognostication
and aid in therapy selection.
Fig. 6. (Coninued) maintained in the bottom panel. The 354 genes present on the
microarrays and mapping to chromosome 17, and for which both DNA copy number and
mRNA levels were determined, are ordered by position along the chromosome; selected
genes are indicated in color-coded text. Fluorescence ratios (test/reference) are depicted
by separate log 2 pseudocolor scales (indicated). Adapted from ref. 69.