Seshadri R, Lee C S, Hui R, McCaul K, Horsfall D J, Sutherland R L
Departments of Haematology and Surgery, Flinders Medical Centre, Bedford Park, South Australia 5042.
Clin Cancer Res. 1996 Jul;2(7):1177-84.
Amplification of chromosome 11q13 is frequently observed in human malignancies, including breast cancers. A candidate oncogene at this locus is the CCND1 gene, which encodes the cell cycle regulatory protein cyclin D1. Because published data on the relationship between 11q13 amplification and prognosis in breast cancer have been controversial, we investigated the clinical significance of CCND1 amplification and its association with established clinicopathological features of prognosis in 1014 primary breast cancer patients. Amplification of the CCND1 gene and the INT-2/FGF-3 gene, which also maps to 11q13, was 10% and 17%, respectively. There were no associations between CCND1 or INT-2 amplification and patient age, tumor size, tumor grade, axillary lymph node status, HER/neu amplification, MIB-1 monoclonal antibody to Ki67 antigen count, or p53 expression. CCND1 amplification was predominantly observed in hormone receptor-positive tumors; at a copy number >/=3, CCND1 amplification was significantly correlated with both estrogen receptor (ER; P = 0.036) and progesterone receptor (P = 0.012) positivity. After a median follow-up period of 66 months, CCND1 or INT-2 amplification was not associated with significant increases in relapse or death from breast cancer. However, in the node-negative and ER-positive subgroups, there was a trend for an increased relapse rate in patients with INT-2 or CCND1 amplification. Thus, in this study, assessment of CCND1 or INT-2 amplification at 11q13 by slot-blot hybridization was of little use in determining phenotype or disease outcome in the whole group of patients but had a potential role in identifying a subset of poor-prognosis patients within the node-negative or ER-positive, good-prognosis groups. Because the prevalence of CCND1 amplification is much lower than the reported prevalence of cyclin D1 overexpression, additional studies are required to determine the true prognostic significance of altered cyclin D1 expression in breast cancer.
11号染色体长臂13区（11q13）的扩增在包括乳腺癌在内的人类恶性肿瘤中经常可见。该位点的一个候选癌基因是CCND1基因，它编码细胞周期调节蛋白细胞周期蛋白D1。由于已发表的关于11q13扩增与乳腺癌预后之间关系的数据存在争议，我们调查了1014例原发性乳腺癌患者中CCND1扩增的临床意义及其与已确定的预后临床病理特征的关联。CCND1基因以及同样定位于11q13的INT-2/FGF-3基因的扩增率分别为10%和17%。CCND1或INT-2扩增与患者年龄、肿瘤大小、肿瘤分级、腋窝淋巴结状态、HER/neu扩增、针对Ki67抗原计数的MIB-1单克隆抗体或p53表达之间均无关联。CCND1扩增主要见于激素受体阳性肿瘤；当拷贝数≥3时，CCND1扩增与雌激素受体（ER；P = 0.036）和孕激素受体（P = 0.012）阳性均显著相关。经过66个月的中位随访期后，CCND1或INT-2扩增与乳腺癌复发或死亡的显著增加无关。然而，在淋巴结阴性且ER阳性的亚组中，INT-2或CCND1扩增的患者有复发率增加的趋势。因此，在本研究中，通过狭缝印迹杂交评估11q13处的CCND1或INT-2扩增对确定整个患者群体的表型或疾病转归作用不大，但在识别淋巴结阴性或ER阳性、预后良好群体中预后不良的患者亚组方面具有潜在作用。由于CCND1扩增的发生率远低于所报道的细胞周期蛋白D1过表达的发生率，因此需要进一步研究以确定细胞周期蛋白D1表达改变在乳腺癌中的真正预后意义。
