Relating Genotype and Phenotype in Breast Cancer: An Analysis of the Prognostic Significance of Amplification at Eight Different Genes or Loci and of p53 Mutations
2000
Breast cancer heterogeneity can be related directly to its variability
at the genetic level. Thus, tumor genotyping could be a valuable
approach to define breast tumor subtypes. It has been shown that it is
possible to delineate subgroups of breast tumors according to specific
sets of DNA amplifications. The aim of the present work was to study
the prognostic significance of these DNA amplifications. We studied DNA
amplification at eight genes or loci ( AIB1 ,
CCND1 , EMS1 , ERBB2 ,
FGFR1 , MDM2 , MYC , and
RMC20C001 ) as well as p53
mutations in a series of 640 breast cancer patients who had not
received presurgical therapy and analyzed the correlations with
survival. DNA amplification was assessed by Southern blotting and was
scored positive when exceeding three to five copies. Mutations in the
p53 gene were searched by four-color fluorescent
single-strand conformational polymorphism, using an automated
sequencer. Of the nine genetic alterations tested, four
( CCND1 , EMS1 , FGFR1 , and
p53 mutations) showed a significant association with
reduced disease-free (DFS) and/or overall survival (OVS) in the
unselected set of patients by univariate test. Correlations for
p53 were found only when selecting mutations in exons 5
or 7. Analysis of node-negative and -positive subgroups of patients
showed that MDM2 amplification and p53
mutations bore prognostic significance in node-negative patients,
whereas amplification of CCND1 , EMS1 , and
FGFR1 correlated with poor outcome in node-positive
patients. Multivariate analysis on an unselected set of patients
retained significance for the amplification of EMS1 ,
FGFR1 , and MDM 2 with DFS, of
CCND1 with OVS, and of RMC20C001 with
both DFS and OVS. Interestingly, stratified analysis according to nodal
status confirmed results obtained in the univariate tests: significance
of MDM2 amplification and p53 mutations
in node-negative and that of CCND1 , EMS1 ,
and FGFR1 in node-positive patients. We also observed an
association between the number of genetic alterations observed in a
tumor and poor prognosis. Patients with two or more amplified loci had
a worsened outcome. Strongly correlating coamplifications such as
CCND1 and FGFR1 , as well as
ERBB2 and MY C, were associated with a
significant reduction of patient survival, thus indicating cooperative
effects. Our data support the idea that genetic alterations in breast
cancer are not only helpful for phenotyping purposes, but can also
represent powerful prognostic indicators in the clinical practice.
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