Grushko Tatyana A, Dignam James J, Das Soma, Blackwood Anne M, Perou Charles M, Ridderstråle Karin K, Anderson Kristin N, Wei Min-Jie, Adams April J, Hagos Fitsum G, Sveen Lise, Lynch Henry T, Weber Barbara L, Olopade Olufunmilayo I
Section of Hematology/Oncology, Department of Medicine, Committees on Genetics and Cancer Biology, University of Chicago, Chicago, Illinois 60637-1463, USA.
Clin Cancer Res. 2004 Jan 15;10(2):499-507. doi: 10.1158/1078-0432.ccr-0976-03.
Germ-line mutations in the BRCA1 tumor suppressor gene predispose to early onset breast cancers with a distinct phenotype characterized by high tumor grade, aneuploidy, high proliferation rate, and estrogen receptor-negativity. The molecular mechanisms and cooperative oncogenes contributing to multistep tumor progression in cells lacking BRCA1 are not well defined. To examine whether C-MYC (MYC), a transforming oncogene associated with genetic instability, contributes to multistep tumor progression in BRCA1-associated breast cancer, we have analyzed tumors from women with hereditary BRCA1-mutated and sporadic breast cancers.
We performed fluorescence in situ hybridization using a MYC:CEP8 assay on formalin-fixed paraffin-embedded tumor tissues from 40 women with known deleterious germ-line BRCA1 mutations and 62 sporadic cases, including 20 cases with hypermethylation of the BRCA1 gene promoter.
We observed a MYC:CEP8 amplification ratio >/=2 in 21 of 40 (53%) BRCA1-mutated tumors compared with 14 of 62 (23%) sporadic tumors (P = 0.003). Of the 14 sporadic cases with MYC amplification, 8 (57%) were BRCA1-methylated. In total, MYC amplification was found in a significantly higher proportion of tumors with BRCA1 dysfunction (29 of 60, 48% versus 6 of 42, 14%; P = 0.0003). In a multivariable regression model controlling for age, tumor size, and estrogen receptor status, BRCA1-mutated tumors demonstrated significantly greater mean MYC:CEP8 ratio than sporadic tumors (P = 0.02).
Our data indicate that MYC oncogene amplification contributes to tumor progression in BRCA1-associated breast cancers. Thus, we conclude that the aggressive histopathological features of BRCA1-associated tumors are in part due to dysregulated MYC activity.
BRCA1肿瘤抑制基因的种系突变易导致早发性乳腺癌，其具有独特的表型，特征为肿瘤分级高、非整倍体、增殖率高和雌激素受体阴性。在缺乏BRCA1的细胞中，导致多步骤肿瘤进展的分子机制和协同致癌基因尚未明确。为了研究与基因不稳定相关的转化致癌基因C-MYC（MYC）是否促成BRCA1相关乳腺癌的多步骤肿瘤进展，我们分析了患有遗传性BRCA1突变乳腺癌和散发性乳腺癌女性的肿瘤。
我们使用MYC:CEP8检测法对40名已知有害种系BRCA1突变的女性以及62例散发性病例（包括20例BRCA1基因启动子高甲基化病例）的福尔马林固定石蜡包埋肿瘤组织进行了荧光原位杂交。
我们观察到，40例（53%）BRCA1突变肿瘤中有21例的MYC:CEP8扩增率≥2，而62例散发性肿瘤中只有14例（23%）如此（P = 0.003）。在14例MYC扩增的散发性病例中，8例（57%）为BRCA1甲基化。总体而言，在BRCA1功能障碍的肿瘤中，MYC扩增的比例显著更高（60例中的29例，48%；42例中的6例，14%；P = 0.0003）。在控制年龄、肿瘤大小和雌激素受体状态的多变量回归模型中，BRCA1突变肿瘤的平均MYC:CEP8比率显著高于散发性肿瘤（P = 0.02）。
我们的数据表明，MYC致癌基因扩增促成BRCA1相关乳腺癌的肿瘤进展。因此，我们得出结论，BRCA1相关肿瘤侵袭性的组织病理学特征部分归因于MYC活性失调。
