TP53 mutation status and gene expression profiles are powerful prognostic markers of breast cancer.
BACKGROUND
Gene expression profiling of breast carcinomas has increased our understanding of the heterogeneous biology of this disease and promises to impact clinical care. The aim of this study was to evaluate the prognostic value of gene expression-based classification along with established prognostic markers and mutation status of the TP53 gene (tumour protein p53) in a group of breast cancer patients with long-term (12 to 16 years) follow-up.


METHODS
The clinical and histopathological parameters of 200 breast cancer patients were studied for their effects on clinical outcome using univariate/multivariate Cox regression. The prognostic impact of mutations in the TP53 gene, identified using temporal temperature gradient gel electrophoresis and sequencing, was also evaluated. Eighty of the samples were analyzed for gene expression using 42 K cDNA microarrays and the patients were assigned to five previously defined molecular expression groups. The strength of the gene expression based classification versus standard markers was evaluated by adding this variable to the Cox regression model used to analyze all samples.


RESULTS
Both univariate and multivariate analysis showed that TP53 mutation status, tumor size and lymph node status were the strongest predictors of breast cancer survival for the whole group of patients. Analyses of the patients with gene expression data showed that TP53 mutation status, gene expression based classification, tumor size and lymph node status were significant predictors of survival. Breast cancer cases in the 'basal-like' and 'ERBB2+' gene expression subgroups had a very high mortality the first two years, while the 'highly proliferating luminal' cases developed the disease more slowly, showing highest mortality after 5 to 8 years. The TP53 mutation status showed strong association with the 'basal-like' and 'ERBB2+' subgroups, and tumors with mutation had a characteristic gene expression pattern.


CONCLUSIONS
TP53 mutation status and gene-expression based groups are important survival markers of breast cancer, and these molecular markers may provide prognostic information that complements clinical variables. The study adds experience and knowledge to an ongoing characterization and classification of the disease.
Langerød
Anita
A
Department of Genetics, Institute for Cancer Research, Rikshospitalet-Radiumhospitalet Medical Center, Oslo, Norway N-0310. anita.langerod@medisin.uio.no
Zhao
Hongjuan
H
Borgan
Ørnulf
Ø
Nesland
Jahn M
JM
Bukholm
Ida R K
IR
Ikdahl
Tone
T
Kåresen
Rolf
R
Børresen-Dale
Anne-Lise
AL
Jeffrey
Stefanie S
SS
D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D001943:Breast Neoplasms / Q000453:epidemiology* / Q000235:genetics* / Q000401:mortality; D018567:Breast Neoplasms, Male / Q000235:genetics / Q000401:mortality; D005260:Female; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D018734:Genes, erbB-2; D016158:Genes, p53; D005819:Genetic Markers; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D012044:Regression Analysis; D016019:Survival Analysis; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D005819:Genetic Markers; D016159:Tumor Suppressor Protein p53