High incidence and frequency of LOH are associated with aggressive features of high-grade HER2 and triple-negative breast cancers

Abstract

Background: Basal-like and HER2-overexpressing breast carcinomas are histologically undifferentiated, high-grade tumors with a high proliferation rate and associated with a poor outcome. Most basal-like tumors lack the expression of ER, PR, and HER2 (triple-negative; TN). Loss of heterozygosity (LOH) is thought to reflect random chromosomal instability, and recent studies have shown that DNA-copy number alterations or LOH occur with a high frequency in basal-like and HER2-amplified tumors.

Methods: The levels and patterns of LOH were analyzed by the microsatellite alteration analysis using fluorescence-labeled primers and an automated DNA sequencer at 5 randomly selected loci in 246 Japanese primary breast cancers. Associations between the level of LOH and breast cancer subtypes and tumor aggressiveness were investigated.

Results: The incidence and frequency of LOH was significantly higher in HER2 (56.3, 26.7%) and TN groups (44.4, 27.1%) than in luminal A (ER-positive and/or PR-positive and HER2-negative) groups (32.0, 12.2%). The incidence and frequency of LOH increased as nuclear grade was elevated. There were significantly more grade 3 tumors in the HER2 (80.0%) and TN (68.2%) subgroups (p < 0.0001). Even in HER2 and TN cases, the incidence and frequency of LOH was significantly higher in nuclear grade 3 cases than in grade 1 or 2 cases. Relapse-free survival of patients with LOH was significantly shorter than for those without LOH. In addition, the survival time was shorter as the frequency of LOH elevated. The incidence of LOH was an independent prognostic factor for relapse-free survival by multivariate analysis.

Conclusion: High incidence and frequency of LOH, which indicate increased genetic instability, were found to be associated with the aggressive features of high-grade HER2 and TN breast cancers.