Expression profiling of breast cancer, influence of tumor genotype and patient genotype

Breast cancers are heterogeneous and consist of several pathologic subtypes with different histological appearances of the malignant cells, different clinical presentations and outcomes, and the patients show a diverse range of responses to a given treatment. Furthermore, breast tumor tissue also shows heterogeneity with respect to its microenvironment including specifically the types and numbers of infiltrating lymphocytes, adipocytes, stromal and endothelial cells. The cellular composition of tumors is a central determinant of both the biological and clinical features of an individual's disease. We have performed expression studies of more than 300 breast carcinomas of different stages and histological subtypes, using high-density cDNA microarrays, aiming at novel tumor classification that can predict survival and treatment response. The expression patterns observed provided a remarkably distinctive molecular portrait of each tumor. The tumors could be classified into five novel subtypes (two luminal epithelial derived estrogen receptor-positive tumor subtypes, a basal epithelial-like, an ERBB2-positive group, and a normal breast-like group). Survival analyses showed significantly different outcome for patients belonging to the various subtypes, including a poor prognosis for the basal-like and a significant difference in outcome for the two luminal/estrogen receptor-positive subtypes. Differences in TP53 mutation frequency between the subtypes indicated an important role for this gene in determining the gene expression pattern in the various tumors. The frequency of the different genotypes of the codon 72 polymorphism of the TP53 genes was significantly different in the five subgroups identified by expression analysis, indicating that the TP53 genotypes also have an impact on the expression profile. Unequal distribution of the different genotypes of the CYP19 gene between the different subgroups was also observed. Cluster analyses of two published, independent data sets representing different patient cohorts from different laboratories, uncovered some of the same breast cancer subtypes. In the one data set that included information on time to development of distant metastasis, subtypes were associated with significant differences in this clinical feature. By including a group of tumors from BRCA1 carriers in the analysis we found that this genotype predisposes to the basal tumor subtype. Our results strongly support the idea that many of these breast tumor subtypes represent biologically distinct disease entities, and that both the patient's genotype and the tumor genotype have a strong influence on the expression pattern developed in a given tumor.