TY - JOUR
T1 - Genomic instability in cancer
T2 - Teetering on the limit of tolerance
AU - Andor, Noemi
AU - Maley, Carlo
AU - Ji, Hanlee P.
N1 - Funding Information:
C. Maley was supported by NIH grants P01 CA91955, R01 CA149566, R01 CA170595, R01 CA185138, and R01 CA140657 as well as CDMRP Breast Cancer Research Program Award BC132057. N. Andor and H. Ji were supported by the awards from the Don and Ruth Seiler Fund, the NCI Cancer Target Discovery and Development (CTDD) Consortium (U01CA17629901), and the NCI Integrative Cancer Biology Program (U01CA17629901). Additional support to H. Ji came from the Doris Duke Charitable Foundation Clinical Scientist Development Award, Research Scholar Grant, RSG-13-297-01-TBG from the American Cancer Society and a Howard Hughes Medical Institute Early Career Grant. Additional support to N. Andor came from Stanford University Dean's Postdoctoral Fellowship Award, and NIH grant K99 CA215256.
Publisher Copyright:
© 2017 American Association for Cancer Research.
PY - 2017/5/1
Y1 - 2017/5/1
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-16-1553
DO - 10.1158/0008-5472.CAN-16-1553
M3 - Article
C2 - 28432052
AN - SCOPUS:85019027256
SN - 0008-5472
VL - 77
SP - 2179
EP - 2185
JO - Cancer Research
JF - Cancer Research
IS - 9
ER -