Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan.
Breast Cancer. 2012 Apr;19(2):161-9. doi: 10.1007/s12282-010-0232-7. Epub 2010 Nov 10.
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.
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.
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.
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.
基底样和 HER2 过表达型乳腺癌在组织学上是未分化的、高级别肿瘤，具有高增殖率，并与不良预后相关。大多数基底样肿瘤缺乏 ER、PR 和 HER2 的表达（三阴性；TN）。杂合性缺失（LOH）被认为反映了随机染色体不稳定性，最近的研究表明，DNA 拷贝数改变或 LOH 在基底样和 HER2 扩增型肿瘤中高频发生。
使用荧光标记引物和自动 DNA 测序仪在 246 例日本原发性乳腺癌的 5 个随机选择的基因座上分析 LOH 的水平和模式。研究了 LOH 水平与乳腺癌亚型和肿瘤侵袭性之间的关系。
HER2（56.3%，26.7%）和 TN 组（44.4%，27.1%）的 LOH 发生率和频率显著高于 luminal A 组（ER 阳性和/或 PR 阳性和 HER2 阴性）（32.0%，12.2%）。随着核级升高，LOH 的发生率和频率增加。HER2（80.0%）和 TN（68.2%）亚组中，3 级肿瘤的比例显著更高（p<0.0001）。即使在 HER2 和 TN 病例中，3 级核级病例的 LOH 发生率和频率也显著高于 1 级或 2 级病例。有 LOH 的患者的无复发生存率明显短于无 LOH 的患者。此外，随着 LOH 频率的升高，生存时间缩短。多因素分析显示，LOH 的发生率是无复发生存的独立预后因素。
高发生率和频率的 LOH 表明遗传不稳定性增加，与高级别 HER2 和 TN 乳腺癌的侵袭性特征相关。
