Wang Zhigang C, Lin Ming, Wei Lee-Jen, Li Cheng, Miron Alexander, Lodeiro Gabriella, Harris Lyndsay, Ramaswamy Sridhar, Tanenbaum David M, Meyerson Matthew, Iglehart James D, Richardson Andrea
Departments of Surgery and Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
Cancer Res. 2004 Jan 1;64(1):64-71. doi: 10.1158/0008-5472.can-03-2570.
Gene expression array profiles identify subclasses of breast cancers with different clinical outcomes and different molecular features. The present study attempted to correlate genomic alterations (loss of heterozygosity; LOH) with subclasses of breast cancers having distinct gene expression signatures. Hierarchical clustering of expression array data from 89 invasive breast cancers identified four major expression subclasses. Thirty-four of these cases representative of the four subclasses were microdissected and allelotyped using genome-wide single nucleotide polymorphism detection arrays (Affymetrix, Inc.). LOH was determined by comparing tumor and normal single nucleotide polymorphism allelotypes. A newly developed statistical tool was used to determine the chromosomal regions of frequent LOH. We found that breast cancers were highly heterogeneous, with the proportion of LOH ranging widely from 0.3% to >60% of heterozygous markers. The most common sites of LOH were on 17p, 17q, 16q, 11q, and 14q, sites reported in previous LOH studies. Signature LOH events were discovered in certain expression subclasses. Unique regions of LOH on 5q and 4p marked a subclass of breast cancers with "basal-like" expression profiles, distinct from other subclasses. LOH on 1p and 16q occurred preferentially in a subclass of estrogen receptor-positive breast cancers. Finding unique LOH patterns in different groups of breast cancer, in part defined by expression signatures, adds confidence to newer schemes of molecular classification. Furthermore, exclusive association between biological subclasses and restricted LOH events provides rationale to search for targeted genes.
基因表达阵列谱可识别出具有不同临床结果和不同分子特征的乳腺癌亚类。本研究试图将基因组改变（杂合性缺失；LOH）与具有不同基因表达特征的乳腺癌亚类相关联。对89例浸润性乳腺癌的表达阵列数据进行层次聚类，确定了四个主要的表达亚类。从这四个亚类中选取34例具有代表性的病例进行显微切割，并使用全基因组单核苷酸多态性检测阵列（Affymetrix公司）进行等位基因分型。通过比较肿瘤和正常单核苷酸多态性等位基因型来确定LOH。使用一种新开发的统计工具来确定频繁发生LOH的染色体区域。我们发现乳腺癌具有高度异质性，LOH的比例在杂合标记的0.3%至>60%之间广泛分布。LOH最常见的位点位于17p、17q、16q、11q和14q，这些位点在先前的LOH研究中已有报道。在某些表达亚类中发现了标志性的LOH事件。5q和4p上独特的LOH区域标志着一类具有“基底样”表达谱的乳腺癌亚类，与其他亚类不同。1p和16q上的LOH优先发生在雌激素受体阳性乳腺癌亚类中。在不同组的乳腺癌中发现独特的LOH模式，部分由表达特征定义，这为更新的分子分类方案增添了信心。此外，生物学亚类与受限的LOH事件之间的排他性关联为寻找靶向基因提供了理论依据。
