Invasive breast carcinoma - IARC

1 6 q 2 2 : C D H 1. The cell-cell adhesion
molecule E-cadherin acts as a strong
invasion suppressor in experimental
tumour cell systems. Frequent inactivating
mutations have been identified in
CDH1 in over 60% of infiltrating lobular
breast cancers, but not in ductal carcinomas
{261}. Most mutations cause translational
frame shifting, and are predicted to
yield secreted truncated E-cadherin fragments.
Most mutations occur in combination
with LOH, so that no E-cadherin
expression is detectable immunohistochemically.
This offers a molecular explanation
for the typical scattered tumour
cell growth in infiltrative lobular breast
cancer. Lobular carcinoma in situ (LCIS)
has also been found to contain CDH1
mutations {3034}.
17p13: TP53 encodes a nuclear protein
of 53 kD, which binds to DNA as a
tetramer and is involved in the regulation
of transcription and DNA re p l i c a t i o n .
Normal p53 may induce cell cycle arrest
or apoptosis, depending on the cellular
e n v i ronment {3147}. Mutations, which
inactivate or alter either one of these
functions, are found in appro x i m a t e l y
20% of breast carcinomas {2237}. Most
of these are missense changes in the
DNA-binding domain of the protein; a
small proportion (~20%) are frame shifting.
The large majority of these mutations
are accompanied by loss of the wildtype
allele (LOH). Missense mutations in TP53
can be detected immunohistochemically
because mutated p53 fails to activate
expression of MDM2. The MDM2 protein
normally targets p53 for ubiquitin-mediated
degradation, constituting a feedback
loop to maintain low levels of p53
protein in the cell.
genes have not yet been detected in
breast cancer.
Gene expression patterns
Expression profiling is expression-analysis
of thousands of genes simultaneously
using microarrays {69,1072,1171,
2218,2756,3104}. Tumours show great
multidimensional variation in gene exp
ression, with many diff e rent sets of
genes showing independent patterns of
variation. These sets of genes relate to
biological processes such as proliferation
or cell signalling. Despite this variation,
there are also striking similarities
between tumours, providing new opportunities
for tumour classification. ER-positive
and ER-negative cancers show distinct
expression profiles {1072,2986,
3104}. Breast cancers arising in women
carrying a BRCA1 mutation could be distinguished
from sporadic cases, and
from those that developed in BRCA2 carriers
{1171,2986}. Although this field is
still in its infancy, 5 distinct gene expression
patterns were discerned among 115
tumours {2218,2756,2757}, one basallike,
one ERBB2-overe x p ressing, two
luminal-like, and one normal breast tissue-like
subgroup. Approximately 25% of
the tumours did not fit any of these classifications.
The luminal-like tumours
express keratins 8 and 18, and show
strong expression of the estrogen receptor
cluster of genes. The tumours of the
other groups were mainly ER-negative.
The basal-like group is characterized
by high expression of keratins 5/6 and
17 and laminin. The ERBB2-group also
expresses several other genes in the
ERBB2 amplicon, such as GRB7. The
normal breast-like group shows a high
e x p ression of genes characteristic of
adipose tissue and other non-epithelial
cell types. Cluster analyses of 2 published,
independent data sets representing
different patient cohorts from different
laboratories, uncovered the same breast
cancer subtypes {2757}.
Somatic genetics of breast cancer
metastases
According to the present view, metastasis
marks the end in a sequence of
genomic changes underlying the progression
of an epithelial cell to a lethal
cancer. Not surprisingly, therefore, lymph
node metastases and distant metastases
in general contain more genomic aberrations
than their cognate primary tumours
{1117,2028}. Flow cytometric DNA content
measurements have demonstrated
extensive DNA ploidy heterogeneity in
primary breast carcinomas, with the concurrent
presence of diploid and multiple
aneuploid DNA stemlines. Identical het-
Microsatellite instability
Microsatellite instability (MSI) is a genetic
defect caused by mutations in mismatch
repair genes (M L H 1, M S H 2,
MSH6, PMS1, and PMS2), reflected by
the presence of multiple alleles at loci
consisting of small tandem repeats or
mononucleotide runs. MSI in breast cancer
is negligible, with the possible
exception of breast cancer arising in the
context of the HNPCC inherited colon
cancer syndrome. The most convincing
study is probably that of Anbazhagan et
al., who have analysed 267 breast carcinomas
at 104 microsatellite loci {85}; not
one single case of MSI was detected.
Somatic mutations in the mismatch repair
Fig. 1.68 Allelotyping of breast cancer. The percentage LOH is calculated as the ratio between the number
of tumours with loss of an allele at a given chromosome arm and the total number of cases informative (i.e.
heterozygous) for the analysis. Red bars: p-arm; green bars: q-arm.
Invasive breast carcinoma
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