Millikan R, Hulka B, Thor A, Zhang Y, Edgerton S, Zhang X, Pei H, He M, Wold L, Melton L J
Department of Epidemiology, University of North Carolina, Chapel Hill 27599, USA.
J Clin Oncol. 1995 Sep;13(9):2293-300. doi: 10.1200/JCO.1995.13.9.2293.
Patients with benign breast biopsies that exhibit atypical epithelial proliferation or fibroadenoma may be at increased risk for invasive breast cancer. We hypothesized that molecular markers might also be useful to evaluate the malignant potential of nonneoplastic breast tissue.
Study subjects belonged to a cohort of 6,805 women who underwent biopsy for nonmalignant breast disease at the Mayo Clinic and Rochester-affiliated hospitals between 1967 and 1981. As part of a nested case-control study that compared subjects who developed invasive breast cancer with those who did not, we analyzed a sample of 60 benign breast biopsies for the following markers: HER-2/neu and p53 over-expression by immunohistochemistry, HER-2/neu and PRAD-1 amplification using differential polymerase chain reaction (PCR), and p53 mutation using single-strand conformation analysis (SSCA) and direct DNA sequencing by asymmetric PCR.
None of 60 biopsies showed amplification of HER-2/neu or PRAD-1. Five samples exhibited low-level immunoreactivity to the HER-2/neu protein product. Fourteen samples exhibited focal or diffuse immunoreactivity to the p53 protein. Point mutations in the p53 gene were found in five samples: three of these samples exhibited mutations that altered the amino acid sequence. Only two of five samples with p53 mutation exhibited p53 overexpression. Histologic diagnoses on three samples with nonconservative p53 mutation were, respectively, nonproliferative fibrocystic change, papillomatous hyperplasia, and fibroadenoma.
The clinical significance of p53 mutation, p53 overexpression, and low-level HER-2/neu expression in benign breast tissue remains to be determined. Further research will be necessary to evaluate whether these markers could serve as useful adjuncts to histology in evaluation of the malignant potential of benign breast tissue.
乳腺活检显示非典型上皮增生或纤维腺瘤的良性乳腺疾病患者发生浸润性乳腺癌的风险可能增加。我们推测分子标志物或许也有助于评估非肿瘤性乳腺组织的恶性潜能。
研究对象来自1967年至1981年间在梅奥诊所及罗切斯特附属医院因非恶性乳腺疾病接受活检的6805名女性队列。作为一项巢式病例对照研究的一部分，该研究比较了发生浸润性乳腺癌的受试者与未发生者，我们分析了60份良性乳腺活检样本，检测以下标志物：通过免疫组织化学检测HER-2/neu和p53过表达，使用差异聚合酶链反应（PCR）检测HER-2/neu和PRAD-1扩增，以及使用单链构象分析（SSCA）和不对称PCR直接DNA测序检测p53突变。
60份活检样本均未显示HER-2/neu或PRAD-1扩增。5份样本对HER-2/neu蛋白产物呈低水平免疫反应性。14份样本对p53蛋白呈局灶性或弥漫性免疫反应性。在5份样本中发现了p53基因的点突变：其中3份样本的突变改变了氨基酸序列。5份p53突变样本中只有2份显示p53过表达。3份p53非保守性突变样本的组织学诊断分别为非增殖性纤维囊性变、乳头状增生和纤维腺瘤。
p53突变、p53过表达以及良性乳腺组织中HER-2/neu低水平表达的临床意义仍有待确定。有必要进一步研究以评估这些标志物是否可作为组织学的有用辅助手段，用于评估良性乳腺组织的恶性潜能。
