Invasive breast carcinoma - IARC

quality metaphase spreads from an individual
tumour. However, it may also relate
to the genetic complexity of this tumour.
Nonetheless, several hundred primary
tumours have been karyotyped to date,
allowing some general patterns to be
discerned {1879}. An increased modal
chromosome number is the most conspicuous
characteristic in many tumours,
in keeping with the finding that approximately
two-thirds of all breast cancers
have a hyperploid DNA-content in flowcytometric
analysis. Unbalanced translocations
are most often seen as recurrent
changes, with the i(1)(q10) and the
der(1;16)(q10;p10) the most prominent.
For the latter, it is not clear whether loss
of 16q or gain of 1q is the selective
change, or whether both are. Other conspicuous
changes are i(8)(q10), and
subchromosomal deletions on chromosomes
1 (bands p13, p22, q12, q42), 3
(p12-p14), and 6 (q21). No specific
genes have been associated with any of
these changes.
DNA amplification
Classic cytogenetic analysis had already
indicated that double minute chromosomes
and homogeneously staining
regions, are a frequent occurrence in
breast cancer. These regions were later
shown to contain amplified oncogenes
(see below). Comparative genomic
hybridization (CGH) has identified over
20 chromosomal subregions with
increased DNA-sequence copy-number,
including 1q31-q32, 8q24, 11q13,
16p13, 17q12, 17q22-q24 and 20q13.
For many of these regions, the critically
amplified genes are not precisely known.
C h romosomal regions with incre a s e d
copy-number often span tens of
megabases, suggesting the involvement
of more than one gene. Loss of chromosomal
material is also detected by CGH,
and this pattern is largely, though not
completely, in agreement with loss of heterozygosity
data (see below).
Oncogenes
A number of known oncogenes were initially
found to be amplified in subsets of
breast cancer by Southern blot analyses
and fluorescent in situ hybridization.
Subsequently, a number of genes have
been identified as critical targets for
DNA amplifications by a combination of
CGH and gene expression analysis.
Oncogenic activation by point-mutation
seems to be rare in breast tumours.
Listed by chromosome region, the following
(onco)gene amplifications seem to
be involved in the progression of breast
cancer.
1p13-21: DAM1 has been found amplified
in two breast cancer cell lines, but it
is not certain whether this gene is driving
the amplification {1962}.
7 p 1 3 : The epidermal growth factor
receptor gene (EGFR), encoding a cell
membrane localized growth factor
receptor, is amplified in less than 3% of
breast carcinomas.
8p12: The fibroblast growth factor receptor
1 gene (FGFR1; formerly called FLG)
encoding a cell membrane located
receptor for fibroblast growth factor, is
amplified in approximately 10% of breast
carcinomas {41}.
8q24: MYC encodes a nuclear protein
involved in regulation of growth and
apoptosis. MYC amplification is found in
approximately 20% of breast {250,596}.
The MYC protein has a very short halflife,
precluding the assessment of protein
Fig. 1.65 Invasive ductal carcinoma. Summary of comparative genome hybridization analysis of 80 cases. The chromosome numbers are in black. The red curves
depict the average ratio profiles between tumour-derived and normal-derived fluorescence signals. Of the three lines to the right of each chromosome, the middle
represents a ratio of 1.0; deviations of the curve to the left or right indicate loss or gain of chromosomal material, respectively. Average ratios were computed from
"n" single chromosomes from different metaphases. Data were retrieved from the Online CGH Tumour Database (http://amba.charite.de/~ksch/cghdatabase/
index.htm). For details on methodology see F. Richard et al. {2366}.
50 Tumours of the breast