Genomic subtypes of breast cancer identified by array-comparative genomic hybridization display distinct molecular and clinical characteristics

Abstract

IntroductionBreast cancer is a profoundly heterogeneous disease with respect to biologic and clinical behavior. Gene-expression profiling has been used to dissect this complexity and to stratify tumors into intrinsic gene-expression subtypes, associated with distinct biology, patient outcome, and genomic alterations. Additionally, breast tumors occurring in individuals with germline BRCA1 or BRCA2 mutations typically fall into distinct subtypes.MethodsWe applied global DNA copy number and gene-expression profiling in 359 breast tumors. All tumors were classified according to intrinsic gene-expression subtypes and included cases from genetically predisposed women. The Genomic Identification of Significant Targets in Cancer (GISTIC) algorithm was used to identify significant DNA copy-number aberrations and genomic subgroups of breast cancer.ResultsWe identified 31 genomic regions that were highly amplified in > 1% of the 359 breast tumors. Several amplicons were found to co-occur, the 8p12 and 11q13.3 regions being the most frequent combination besides amplicons on the same chromosomal arm. Unsupervised hierarchical clustering with 133 significant GISTIC regions revealed six genomic subtypes, termed 17q12, basal-complex, luminal-simple, luminal-complex, amplifier, and mixed subtypes. Four of them had striking similarity to intrinsic gene-expression subtypes and showed associations to conventional tumor biomarkers and clinical outcome. However, luminal A-classified tumors were distributed in two main genomic subtypes, luminal-simple and luminal-complex, the former group having a better prognosis, whereas the latter group included also luminal B and the majority of BRCA2-mutated tumors. The basal-complex subtype displayed extensive genomic homogeneity and harbored the majority of BRCA1-mutated tumors. The 17q12 subtype comprised mostly HER2-amplified and HER2-enriched subtype tumors and had the worst prognosis. The amplifier and mixed subtypes contained tumors from all gene-expression subtypes, the former being enriched for 8p12-amplified cases, whereas the mixed subtype included many tumors with predominantly DNA copy-number losses and poor prognosis.ConclusionsGlobal DNA copy-number analysis integrated with gene-expression data can be used to dissect the complexity of breast cancer. This revealed six genomic subtypes with different clinical behavior and a striking concordance to the intrinsic subtypes. These genomic subtypes may prove useful for understanding the mechanisms of tumor development and for prognostic and treatment prediction purposes.

BRCA1 interacts with Nrf2 to regulate antioxidant signaling and cell survival

“…Twosided independent Student's t test without equal variance assumption was used to determine p-values (*, P < 0.05; **, P < 0.01). For analysis of gene expression microarray in primary human breast tumors, box plots and dot plots were performed on three publicly available datasets of BRCA1 mutated breast tumors (van 't Veer et al, 2002;Jönsson et al, 2010;Waddell et al, 2010) and on three sporadic breast tumor datasets (Pawitan et al, 2005;Chin et al, 2006;Sabatier et al, 2011), respectively. Tumor subtype classification was determined as described in each study.…”

Combination of the proliferation marker cyclin A, histological grade, and estrogen receptor status in a new variable with high prognostic impact in breast cancer

“…Tumors were classified to a genetic grade signature as described elsewhere [15,23]. In the original study gene expression profiling was performed on 359 tumors.…”

“…Gene expression analysis was performed as previously described [23]. Tumors were classified to a genetic grade signature as described elsewhere [15,23].…”

Calcium-activated chloride channel ANO1 promotes breast cancer progression by activating EGFR and CAMK signaling

“…The 11q13 amplicon is one of the most frequently amplified chromosomal regions in human cancer and correlates with a poor prognosis (3)(4)(5)(6)(7). Although cyclin D1 (CCND1) has been considered to be the main driver of the 11q13 amplicon (8)(9)(10), it is not sufficient for malignant transformation of normal breast cells and lacks predictive value for the survival of head-and-neck squamous cell carcinoma (HNSCC) or breast cancer patients (8,(11)(12)(13)(14).…”