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Cancer Res. 2017 May 1;77(9):2179-2185. doi: 10.1158/0008-5472.CAN-16-1553. Epub 2017 Apr 21.

Genomic Instability in Cancer: Teetering on the Limit of Tolerance.

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Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, California.
Biodesign Center for Personalized Diagnostics and School of Life Sciences, Arizona State University, Tempe, Arizona.
Centre for Evolution and Cancer, Institute of Cancer Research, London, United Kingdom.
Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, California.
Stanford Genome Technology Center, Stanford University, Palo Alto, California.


Cancer genomic instability contributes to the phenomenon of intratumoral genetic heterogeneity, provides the genetic diversity required for natural selection, and enables the extensive phenotypic diversity that is frequently observed among patients. Genomic instability has previously been associated with poor prognosis. However, we have evidence that for solid tumors of epithelial origin, extreme levels of genomic instability, where more than 75% of the genome is subject to somatic copy number alterations, are associated with a potentially better prognosis compared with intermediate levels under this threshold. This has been observed in clonal subpopulations of larger size, especially when genomic instability is shared among a limited number of clones. We hypothesize that cancers with extreme levels of genomic instability may be teetering on the brink of a threshold where so much of their genome is adversely altered that cells rarely replicate successfully. Another possibility is that tumors with high levels of genomic instability are more immunogenic than other cancers with a less extensive burden of genetic aberrations. Regardless of the exact mechanism, but hinging on our ability to quantify how a tumor's burden of genetic aberrations is distributed among coexisting clones, genomic instability has important therapeutic implications. Herein, we explore the possibility that a high genomic instability could be the basis for a tumor's sensitivity to DNA-damaging therapies. We primarily focus on studies of epithelial-derived solid tumors. Cancer Res; 77(9); 2179-85. ©2017 AACR.

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