Abstract P2-08-04: Subtype specific chromosomal aberrations in breast cancer

Abstract

Abstract Background: Breast cancer is a heterogeneous disease and divided into five distinct groups (Luminal A, Luminal B, HER2-enriched, Basal-like, and Claudin-low subtypes). DNA copy number studies have suggested that chromosomal aberrations are different among subtypes. Basal-like, and Claudin-low subtypes are mainly ER-, PR- and HER2- (triple negative: TN). Recent study reported that the basal-like subtype was the most distinct with common losses of the regions containing tumor suppressor genes such as RB1, BRCA1, INPP4B, and the greatest overall genomic instability. On the other hand, Claudin-low tumors showed few copy number changes. Luminal A tumors show fewer chromosomal copy number changes than Luminal B and HER2-enriched subtypes. Aims: To investigate the extent of the chromosomal aberrations and to evaluate the relationships between chromosomal aberrations and breast cancer subtypes and other clinicopathological characteristics and prognosis. Methods: Specimens were obtained from 363 invasive breast cancer patients who underwent surgery in our department between 1994 and 2011. Four breast cancer subtypes were determined by the immunohistochemical analysis of ER, PR and HER2; hormone receptor (HR; ER and/or PR)+/HER2-, HR+/HER2+, HR-/HER2+(HER2) and TN. Loss of heterozygosity (LOH) at the tumor suppressor gene (TSGs), BRCA1, BRCA2, TP53, RB1, PTEN and INPP4B, was investigated with microsatellite markers using our microsatellite analysis system. Copy number aberrations (CNAs) were analyzed by SNP-CGH array (Illumina, HumanOmni2.5-8).% Defects, which represents the percent of genome region containing chromosomal aberration, was determined by Karyostudio Software v1.4 (Illumina). Results: The incidence of LOH at BRCA, BRCA2, TP53, RB1, PTEN and INPP4B locus was 37.4, 34.0, 57.1, 41.9, 25.8 and 18.0%, respectively. The incidence of LOH was lowest in hormone receptor (HR)+/HER2- subtype, and higher in HER2 and triple negative (TN) subtypes. LOH at INPP4B locus was significantly associated with TN subtype. The LOH at BRCA1 and TP53 loci was highest in HER2 subtype. The LOH at BRCA1, TP53 and INPP4B loci was significantly associated with poor prognosis in all cases; however, the impact of LOH at these TSGs on the prognosis was different among subtypes. Coexistence of LOH at both BRCA1 and TP53 loci was significantly associated with aggressive phenotype and chromosomal aberrations.%Defect was highest in the tumors with LOH at both BRCA1 and TP53 loci. Coexistence of LOH at both BRCA1 and TP53 loci was significantly associated with poor prognosis, especially in HR+/HER2- subtype. Many cases with TN subtype reveal gross chromosomal aberrations, and these tumors were considered to be basal-like. However, there are some cases with few chromosomal alterations in TN, whose prognosis was very poor. These tumors were considered to be Claudin-low subtype. Conclusions: The incidence and biological significance of LOH at TSGs are different among breast cancer subtypes. Coexistence of LOH at both BRCA1 and TP53 loci was associated with gross chromosomal aberrations and poor prognosis. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-08-04.