Yeh I-Tien, Martin Mathew A, Robetorye Ryan S, Bolla Aswani R, McCaskill Chris, Shah Rashmi K, Gorre Mercedes E, Mohammed Mansoor S, Gunn Shelly R
Department of Pathology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
Mod Pathol. 2009 Sep;22(9):1169-75. doi: 10.1038/modpathol.2009.78. Epub 2009 May 15.
The HER2 gene is an important prognostic and therapeutic marker in newly diagnosed breast cancer. Currently, HER2 status is most frequently determined by immunohistochemical detection of HER2 protein expression on the cellular membrane surface or by fluorescence in situ hybridization analysis of HER2 gene copy number in fixed tissue using locus-specific probes for the HER2 gene and chromosome 17 centromere. However, these methods are problematic because of issues with intra- and inter-laboratory reproducibility and preanalytic variables, such as fixation time. In addition, the commonly used HER2/chromosome 17 ratio presumes that chromosome 17 polysomy is present when the centromere is amplified, even though analysis of the rest of the chromosome is not included in the assay. In this study, 97 frozen samples of invasive lobular and invasive ductal carcinoma, with known immunohistochemistry and fluorescence in situ hybridization results for HER2, were analyzed by comparative genomic hybridization to a commercially available bacterial artificial chromosome whole-genome array containing 99 probes targeted to chromosome 17 and the HER2/TOP2 amplicon. Results were 97% concordant for HER2 status, meeting the College of American Pathologists/American Society of Clinical Oncology's validation requirements for HER2 testing. Surprisingly, not a single case of complete polysomy 17 was detected even though multiple breast cancer cases showed clear polysomies of other chromosomes. We conclude that array comparative genomic hybridization is an accurate and objective DNA-based alternative for clinical evaluation of HER2 gene copy number, and that polysomy 17 is a rare event in breast cancer.
HER2基因是新诊断乳腺癌中重要的预后和治疗标志物。目前，HER2状态最常通过免疫组织化学检测细胞膜表面HER2蛋白表达或使用针对HER2基因和17号染色体着丝粒的位点特异性探针，对固定组织中HER2基因拷贝数进行荧光原位杂交分析来确定。然而，由于实验室内部和实验室之间的可重复性问题以及分析前变量（如固定时间），这些方法存在问题。此外，常用的HER2/17号染色体比率假定当着丝粒扩增时存在17号染色体多体性，即使该检测未包括对染色体其余部分的分析。在本研究中，通过与一种市售的包含99个针对17号染色体和HER2/TOP2扩增子的探针的细菌人工染色体全基因组阵列进行比较基因组杂交，分析了97份已知HER2免疫组织化学和荧光原位杂交结果的浸润性小叶癌和浸润性导管癌冷冻样本。HER2状态的结果一致性为97%，符合美国病理学家学会/美国临床肿瘤学会对HER2检测的验证要求。令人惊讶的是，即使多例乳腺癌病例显示出其他染色体的明显多体性，也未检测到一例完整的17号染色体多体性。我们得出结论，阵列比较基因组杂交是一种准确、客观的基于DNA的替代方法，可用于临床评估HER2基因拷贝数，并且17号染色体多体性在乳腺癌中是罕见事件。
