期刊
CANCER DISCOVERY
卷 2, 期 6, 页码 503-511出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-11-0325
关键词
-
类别
资金
- National Cancer Institute [P50 CA89383, U54CA143798]
- Cellex foundation
- Human Frontier Science Program long-term fellowship
- Susan G. Komen Foundation
- Breast Cancer Research Foundation
- Calouste Gulbenkian Foundation
- Champalimaud Foundation
- Ministerio da Saude
- Fundacao para a Ciencia e Tecnologia, Portugal
BRCA1-associated breast tumors display loss of BRCA1 and frequent somatic mutations of PTEN and TP53. Here we describe the analysis of BRCA1, PTEN, and p53 at the single cell level in 55 BRCA1-associated breast tumors and computational methods to predict the relative temporal order of somatic events, on the basis of the frequency of cells with single or combined alterations. Although there is no obligatory order of events, we found that loss of PTEN is the most common first event and is associated with basal-like subtype, whereas in the majority of luminal tumors, mutation of TP53 occurs first and mutant PIK3CA is rarely detected. We also observed intratumor heterogeneity for the loss of wild-type BRCA1 and increased cell proliferation and centrosome amplification in the normal breast epithelium of BRCA1 mutation carriers. Our results have important implications for the design of chemopreventive and therapeutic interventions in this high-risk patient population. SIGNIFICANCE: Defining the temporal order of tumor-driving somatic events is critical for early detection, risk stratification, and the design of chemopreventive therapies. Our combined experimental and computational approach reveal that the loss of wild-type BRCA1 may not be the first event in the majority of BRCA1-associated breast tumors and may not be present in all cancer cells within tumors. Cancer Discov; 2(6); 503-11. (C) 2012 AACR.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据