De Lange T
The Rockefeller University, New York, New York 10021, USA.
Cold Spring Harb Symp Quant Biol. 2005;70:197-204. doi: 10.1101/sqb.2005.70.032.
Genome instability is a hallmark of most human cancers. Although a mutator phenotype is not required for tumorigenesis, it can foster mutations that promote tumor progression. Indeed, several inherited cancer-prone syndromes are due to mutations in DNA repair pathways. However, sporadic tumors are usually proficient in DNA repair, making it unlikely that unrepaired lesions are a major source of genome instability in sporadic cancers. A decade ago, I argued in another CSHL Press publication that a "collapse in telomere function can explain a significant portion of the genetic instability in tumors" (de Lange 1995). Since that time, the structure of mammalian telomeres has been analyzed, the consequences of telomere dysfunction have been determined, a mouse model for cancer-relevant aspects of telomere biology has been developed, and the nature and magnitude of cancer genome rearrangements have been revealed. In light of these developments, this is an opportune time to revisit the conjecture that telomere dysfunction contributes to genome instability in human cancer.
基因组不稳定是大多数人类癌症的一个标志。虽然肿瘤发生并不需要突变体表型，但它可促进导致肿瘤进展的突变。事实上，几种遗传性癌症易感综合征是由DNA修复途径中的突变引起的。然而，散发性肿瘤通常具有正常的DNA修复能力，因此未修复的损伤不太可能是散发性癌症基因组不稳定的主要来源。十年前，我在冷泉港实验室出版社的另一篇出版物中提出，“端粒功能的崩溃可以解释肿瘤中很大一部分的遗传不稳定性”（德兰格，1995年）。从那时起，哺乳动物端粒的结构已得到分析，端粒功能障碍的后果已被确定，与癌症相关的端粒生物学方面的小鼠模型已被开发出来，癌症基因组重排的性质和程度也已被揭示。鉴于这些进展，现在是重新审视端粒功能障碍导致人类癌症基因组不稳定这一推测的恰当时机。
