Isola J, Chu L, DeVries S, Matsumura K, Chew K, Ljung B M, Waldman F M
Laboratory of Cancer Genetics, University and University Hospital of Tampere, Finland.
Clin Cancer Res. 1999 Dec;5(12):4140-5.
Amplification of the ERBB2 oncogene has recently received attention as a target for antibody-based therapies and as a predictor of response to adjuvant chemotherapy. Modification of treatment strategies based on ERBB2 status has led to further interest in the genetic alterations that accompany ERBB2 gene amplification or overexpression. In this study, chromosome alterations that are associated with ERBB2 amplification were defined by comparative genomic hybridization (CGH). Additionally, fluorescence in situ hybridization (FISH) was used to validate gene amplification, and protein expression was detected immunohistochemically. ERBB2-amplified tumors as detected by FISH, immunohistochemistry (IHC), or CGH had twice as many CGH-defined chromosomal alterations (means of 11.8, 11.0, and 12.7, respectively) as the nonamplified tumors (means of 6.8, 7.0, and 5.6, respectively). ERBB2 positivity correlated with the total number of genetic events. A wide spectrum of copy number gains and losses was seen by CGH in all of the tumors. An increased number of losses of 18q and gains of 20q was found in ERBB2-positive tumors. Other common aberrations for all of the tumors were copy number gains of 1q (58%), 8q (52%), 20q (30%), and losses of 18q (39%), 13q (39%), and 3p (33%). A high degree of concordance was observed among the three methods in 33 primary breast cancers. The concurrence for ERBB2 detection between FISH and IHC was 90%, between FISH and CGH was 82%, and between IHC and CGH was 84%. This study shows that breast tumors showing erbB2 overexpression or gene amplification are genetically distinct from erbB2-negative tumors. These differences may relate to the mechanisms underlying altered response to adjuvant therapies and may define the responsiveness to erbB2-directed immunotherapy.
ERBB2癌基因的扩增最近作为基于抗体治疗的靶点以及辅助化疗反应的预测指标受到关注。基于ERBB2状态修改治疗策略引发了人们对伴随ERBB2基因扩增或过表达的基因改变的进一步兴趣。在本研究中，通过比较基因组杂交（CGH）确定了与ERBB2扩增相关的染色体改变。此外，荧光原位杂交（FISH）用于验证基因扩增，免疫组织化学检测蛋白质表达。通过FISH、免疫组织化学（IHC）或CGH检测到的ERBB2扩增肿瘤的CGH定义的染色体改变数量（分别为11.8、11.0和12.7）是非扩增肿瘤（分别为6.8、7.0和5.6）的两倍。ERBB2阳性与基因事件总数相关。通过CGH在所有肿瘤中都观察到广泛的拷贝数增加和减少。在ERBB2阳性肿瘤中发现18q缺失和20q增加的数量增多。所有肿瘤的其他常见畸变是1q（58%）、8q（52%）、20q（30%）的拷贝数增加以及18q（39%）、13q（39%）和3p（33%）的缺失。在33例原发性乳腺癌中，三种方法之间观察到高度一致性。FISH和IHC之间ERBB2检测的一致性为90%，FISH和CGH之间为82%，IHC和CGH之间为84%。本研究表明，显示erbB2过表达或基因扩增的乳腺肿瘤在基因上与erbB2阴性肿瘤不同。这些差异可能与辅助治疗反应改变的潜在机制有关，并可能确定对erbB2导向免疫治疗的反应性。
