Genetic alterations in ERBB2-amplified breast carcinomas.
Genetic alterations in ERBB2-amplified breast carcinomas.
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发表时间：
1999-12
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通讯作者：
J. Isola;L. Chu;S. Devries;K. Matsumura;K. Chew;B. Ljung;F. Waldman
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作者：
J. Isola;L. Chu;S. Devries;K. Matsumura;K. Chew;B. Ljung;F. Waldman
ERBB2癌基因的扩增作为基于抗体的治疗靶点和辅助化疗反应的预测指标，最近受到了关注。基于ERBB2状态的治疗策略的修改导致了对ERBB2基因扩增或过表达的遗传改变的进一步关注。在这项研究中，通过比较基因组杂交（CGH）定义了与ERBB2扩增相关的染色体改变。此外，采用荧光原位杂交（FISH）验证基因扩增，免疫组织化学检测蛋白表达。通过FISH、免疫组化（IHC）或CGH检测到的erbb2扩增肿瘤，其CGH定义的染色体改变（平均值分别为11.8、11.0和12.7）是非扩增肿瘤（平均值分别为6.8、7.0和5.6）的两倍。ERBB2阳性与遗传事件总数相关。CGH在所有肿瘤中均可见拷贝数增加和减少的广谱谱。在erbb2阳性肿瘤中发现18q缺失和20q增加的数量增加。所有肿瘤的其他常见畸变是拷贝数增加1q（58%）、8q（52%）、20q(30%)，以及丢失18q（39%）、13q（39%）和3p（33%）。在33例原发性乳腺癌中观察到三种方法的高度一致性。FISH和免疫组化检测ERBB2的一致性为90%，FISH和CGH的一致性为82%，免疫组化和CGH的一致性为84%。本研究表明，erbB2过表达或基因扩增的乳腺肿瘤与erbB2阴性肿瘤在遗传上是不同的。这些差异可能与对辅助治疗反应改变的机制有关，并可能定义对erbb2定向免疫治疗的反应性。
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.