Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Proc Natl Acad Sci U S A. 2012 Aug 28;109(35):14098-103. doi: 10.1073/pnas.1120062109. Epub 2012 Aug 13.
Several lines of evidence suggest that defects in telomere maintenance play a significant role in the initiation of genomic instability during carcinogenesis. Although the general concept of defective telomere maintenance initiating genomic instability has been acknowledged, there remains a critical gap in the direct evidence of telomere dysfunction in human solid tumors. To address this topic, we devised a multiplex PCR-based assay, termed TAR (telomere-associated repeat) fusion PCR, to detect and analyze chromosome end-to-end associations (telomere fusions) within human breast tumor tissue. Using TAR fusion PCR, we found that human breast lesions, but not normal breast tissues from healthy volunteers, contained telomere fusions. Telomere fusions were detected at similar frequencies during early ductal carcinoma in situ and in the later invasive ductal carcinoma stage. Our results provide direct evidence that telomere fusions are present in human breast tumor tissue and suggest that telomere dysfunction may be an important component of the genomic instability observed in this cancer. Development of this robust method that allows identification of these genetic aberrations (telomere fusions) is anticipated to be a valuable tool for dissecting mechanisms of telomere dysfunction.
有几条证据表明，端粒维持缺陷在致癌过程中基因组不稳定性的起始中起着重要作用。尽管已经承认了端粒维持缺陷引发基因组不稳定性的一般概念，但在人类实体瘤中端粒功能障碍的直接证据方面仍然存在关键差距。为了解决这个问题，我们设计了一种基于多重 PCR 的检测方法，称为 TAR（端粒相关重复）融合 PCR，用于检测和分析人类乳腺肿瘤组织中的染色体端到端关联（端粒融合）。使用 TAR 融合 PCR，我们发现人类乳腺病变，而不是健康志愿者的正常乳腺组织，含有端粒融合。在早期导管原位癌和晚期浸润性导管癌阶段，端粒融合的检测频率相似。我们的结果提供了直接证据，证明端粒融合存在于人类乳腺肿瘤组织中，并表明端粒功能障碍可能是这种癌症中观察到的基因组不稳定性的一个重要组成部分。这种能够识别这些遗传异常（端粒融合）的强大方法的开发有望成为剖析端粒功能障碍机制的有用工具。
