Chapter 27 -- Breast Cancer Genomics, Section VI, Pathology and Biological Markers of Invasive Breast Cancer Page: 4 of 30
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Nearly 10% of all human genes in these discovery efforts harbored mutations in the discovery screen.
This seems extraordinarily high but the background mutation rate of the tumors is roughly one mutation
per megabase of genomic DNA (which corresponds to about 3,000 random mutations in the genome)
that it is not wholly unexpected. The validation phase, however proved truly remarkable; 167 genes
harbored mutations in both the discovery and validation phases, which is approximately 1% of all human
genes. Beyond the large numbers of genes observed to be mutated, two key observations emerge from
this analysis: first, many recurrent mutations occur in genes that are not obviously related to cancer (i.e.,
the glycosylase GALNT5 and the transglutaminase TGM3); second and more importantly, many of the
mutations appear to be clustered in pathways. For example, at least seven biological pathways,
including ATM signaling and apoptosis induction, show significant levels of mutation (17) (Table 27.2).
The observation that particular pathways are significantly mutated provides a framework in which to
understand their functional significance, and further suggests that a few key pathways may be especially
critical for the development of oncogenesis.
The next step, which is still in its infancy, is to relate the patterns of mutation to clinical outcome and
treatment. For genes previously known to drive breast cancer when mutated, such as TP53, PIK3CA, and
PTEN, the relationship between mutation and outcome for breast cancer has been examined and shown
to be significant (18-20). In fact, conditional analysis of the activating mutation of PIK3CA (the catalytic
subunit of P13-kinase) or inactivating events of its negative regulator PTEN, provided better
discrimination of outcome than mutation of either gene alone (Fig. 27.2).
STRUCTURAL ANALYSIS OF THE CANCER GENOME
Metaphase Chromosome Analysis
One of the most methodologically challenging questions in breast carcinomas is to understand the
structural organization of a tumor genome. This is a critical area of research, which can easily be
evidenced by the large number of chromosomal fusion events that drive malignancies in the leukemias
and lymphomas. Recurrent mutations have become even more interesting since the recent
identification of recurrent gene fusion events including TMPRSS-ERG in prostate cancer (21). Analyses of
metaphase chromosome spreads from cultures of human tumors using classic banding techniques
provided the first views of the extent of structural rearrangements that exist in human breast cancers.
The catalogue by Mitelman et al. (22) provides a comprehensive assessment of breast cancer
chromosome changes discovered using this approach. The general structural and numerical chaos is
clear from these studies, but the approach is difficult because of the difficulty of preparing metaphase
spreads of sufficiently high-quality metaphase chromosome preparations to allow identification of
rearrangements with confidence.
The introduction of fluorescence in situ hybridization (FISH) with whole chromosome probes (23, 24)
and the subsequent development of combinatorial multicolor labeling and analysis (25-27) substantially
simplified the identification interpretation of these complex karyotypic rearrangements. Molecular
cytogenetic analyses using whole chromosome analysis techniques are, however, limited in resolution to
a few million base pairs by the complex organization of DNA along chromosomes. FISH, with multiple,
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Spellman, Paul T.; Heiser, Laura & Gray, Joe W. Chapter 27 -- Breast Cancer Genomics, Section VI, Pathology and Biological Markers of Invasive Breast Cancer, book, June 18, 2009; Berkeley, California. (digital.library.unt.edu/ark:/67531/metadc843844/m1/4/: accessed November 15, 2018), University of North Texas Libraries, Digital Library, digital.library.unt.edu; crediting UNT Libraries Government Documents Department.