To investigate the clinical value of somatic TP53 mutations in breast cancer, we assembled clinical and molecular data on 1,794 women with primary breast cancer with long-term follow-up and whose tumor has been screened for mutation in exons 5 to 8 of TP53 by gene sequencing. TP53 mutations were more frequent in tumors of ductal and medullar types, aggressive phenotype (high grade, large size, node positive cases, and low hormone receptor content) and in women 10 years; P < 0.0001) compared with patients with no such mutation. The prognostic value of TP53 mutation was independent of tumor size, node status, and hormone receptor content, confirming and reconciling previous findings in smaller series. Moreover, an interaction between TP53 mutation and progesterone receptor (PR) status was revealed, TP53 mutation combined with the absence of progesterone receptor being associated with the worst prognosis. Whereas previous studies have emphasized the fact that missense mutations in the DNA-binding motifs have a worse prognosis than missense mutations outside these motifs, we show that non-missense mutations have prognostic value similar to missense mutations in DNA-binding motifs. Nonetheless, specific missense mutants (codon 179 and R248W) seem to be associated with an even worse prognosis. These results, obtained on the largest series analyzed thus far, show that TP53 mutations identified by gene sequencing have an independent prognostic value in breast cancer and could have potential uses in clinical practice.

We have studied the genomic organization of the c-myc locus (MYC) from 121 human primary breast carcinomas. Two types of alterations were observed: (i) the c-myc protooncogene appeared to be amplified 2- to 15-fold in 38 (32%) of the carcinoma DNAs and (ii) a non-germ-line c-myc-related fragment of variable size was detected in 5 primary breast carcinoma DNAs. With three exceptions, all the tumors containing a genetic alteration of the c-myc locus were invasive ductal carcinomas. A significant correlation (P less than 0.02) was observed between patients more than 50 years old and the presence of a genetically altered c-myc. Enhanced levels of c-myc RNA were observed in 10 of 14 breast carcinomas examined. The c-myc gene was genetically altered in 6 of these 10 tumors. The frequency with which the c-myc gene is altered and its correlation with age suggest that it may play a role in the development of breast carcinomas.

The current histoclinical breast cancer classification is simple but imprecise. Several molecular classifications of breast cancers based on expression profiling have been proposed as alternatives. However, their reliability and clinical utility have been repeatedly questioned, notably because most of them were derived from relatively small initial patient populations. We analyzed the transcriptomes of 537 breast tumors using three unsupervised classification methods. A core subset of 355 tumors was assigned to six clusters by all three methods. These six subgroups overlapped with previously defined molecular classes of breast cancer, but also showed important differences, notably the absence of an ERBB2 subgroup and the division of the large luminal ER+ group into four subgroups, two of them being highly proliferative. Of the six subgroups, four were ER+/PR+/AR+, one was ER−/PR−/AR+ and one was triple negative (AR−/ER−/PR−). ERBB2-amplified tumors were split between the ER−/PR−/AR+ subgroup and the highly proliferative ER+ LumC subgroup. Importantly, each of these six molecular subgroups showed specific copy-number alterations. Gene expression changes were correlated to specific signaling pathways. Each of these six subgroups showed very significant differences in tumor grade, metastatic sites, relapse-free survival or response to chemotherapy. All these findings were validated on large external datasets including more than 3000 tumors. Our data thus indicate that these six molecular subgroups represent well-defined clinico-biological entities of breast cancer. Their identification should facilitate the detection of novel prognostic factors or therapeutical targets in breast cancer.

The somatic loss of heterozygosity for normal alleles occurring in human tumors has suggested the presence of recessive oncogenes. The results presented here demonstrate a loss of heterozygosity of several genes on chromosome 11 in primary breast tumors. Restriction fragment length polymorphism analysis of these DNAs further suggests that the most frequent loss of sequences in breast tumors occurs between the β-globin and parathyroid hormone loci on the short arm of chromosome 11. The loss of heterozygosity for chromosome 11 loci has a significant association with tumors that lack estrogen and progesterone receptors, grade III tumors, and distal metastasis.