Invasive breast carcinoma - IARC

detectable distant metastasis displayed
significantly fewer chromosomal aberrations
than primary tumours or cells from
patients with manifest metastasis, and
their aberrations appeared to be randomly
generated {2560}. In contrast, primary
tumours and disseminated cancer
cells from patients with manifest metastasis
harboured different and characteristic
c h romosomal imbalances. Thus, contrary
to the widely held view that the precursors
of metastasis are derived from
the most advanced clone within the primary
tumour, these data suggest that
breast tumour cells may disseminate in a
far less progressed genomic state than
previously thought, and that they acquire
genomic aberrations typical of metastatic
cells thereafter. These findings have
two major clinical implications. First, all
adjuvant therapies that do not target
genetic or epigenetic events occurring
early during tumourigenesis are unlikely
to eradicate minimal residual disease,
because disseminated cancer cells may
not uniformly share mutations that are
acquired later on. Second, because disseminated
cells progress independently
from the primary tumour, a simple extrapolation
from primary tumour data to disseminated
cancer cells is impossible.
Genetic susceptibility: familial
risk of breast cancer
Fig. 1.69 Hierarchical clustering of 115 tumour tissues and 7 nonmalignant tissues using gene expression
profiling. Experimental dendrogram showing the clustering of the tumours into five subgroups (top
panel). Gene clusters associated with the ERBB2 oncogene, luminal subtype B, basal subtype, normal
breast-like group, luminal subtype A with high estrogen receptor expression. Scale bar represents fold
change for any given gene relative to the median level of expression across all samples. From T. Sorlie
et al. {2757}.
erogeneity is often present in their cognate
lymph node metastases, suggesting
that the generation of DNA ploidy
diversity has taken place prior to metastasis
{197}. LOH analysis of these DNA
ploidy stemlines showed that all allelic
imbalances observed in the diploid
clones recurred in the cognate aneuploid
clones, but were, in the latter, accompanied
by additional allelic imbalances at
other loci and/or chromosome arm s
{313}. This indicates that the majority of
allelic imbalances in breast carcinomas
a re established during generation of
DNA ploidy diversity. Identical allelic
imbalances in both the diploid and aneuploid
clones of a tumour suggests linear
tumour progression. But the simultaneous
presence of early diploid and
advanced aneuploid clones in both primary
and metastatic tumour sites suggested
that acquisition of metastatic
propensity can be an early event in the
genetic progression of breast cancer.
Intriguingly, single disseminated cancer
cells have been detected in the bone
marrow of 36% of breast cancer patients
{339}. Using single-cell CGH, it was
demonstrated that disseminated cells
f rom patients without a clinically
Fig. 1.70 Axillary lymph node. The nodal architecture
is destroyed by massive metastatic ductal
c a r c i n o m a .
Introduction
Breast cancer has been recognized for
over 100 years as having a familial component
{349}. Epidemiological investigations
have attempted to quantify the risks
associated with a positive family history
and to examine whether the pattern of
related individuals is consistent with the
effects of a single gene of large effect,
s h a red environmental effects, many
genes acting in an additive manner, or
most likely, a combination of two or more
of these. In addition a number of specific
genes have been identified as playing a
role. The most important ones are
BRCA1 and BRCA2 which are discussed
in Chapter 8. However, these two genes
account for only about a fifth of overall
familial breast cancer {107,592,2230}
and explain less than half of all high risk,
site-specific breast cancer families {898,
2631}.
Familial risk of breast cancer
Vi rtually every study has found significantly
elevated relative risks of bre a s t
cancer for female relatives of bre a s t
cancer patients. However, the magnitude
has varied according to the number
and type of affected relatives, age at
diagnosis of the proband(s), laterality,
and the overall study design. Most studies
have found relative risks between
2 and 3 for first-degree relatives selected
without re g a rd to age at diagnosis
or laterality. A comprehensive study,
using the Utah Population Database, of
54 Tumours of the breast