期刊
CANCER RESEARCH
卷 77, 期 9, 页码 2179-2185出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-16-1553
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资金
- NIH [P01 CA91955, R01 CA149566, R01 CA170595, R01 CA185138, R01 CA140657, K99 CA215256]
- CDMRP Breast Cancer Research Program Award [BC132057]
- Don and Ruth Seiler Fund
- NCI Cancer Target Discovery and Development (CTDD) Consortium [U01CA17629901]
- NCI Integrative Cancer Biology Program [U01CA17629901]
- Doris Duke Charitable Foundation Clinical Scientist Development Award
- American Cancer Society [RSG 13 297 01 TBG]
- Howard Hughes Medical Institute
- Stanford University Dean's Postdoctoral Fellowship Award
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. (C) 2017 AACR.
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