The Conundrum of Genetic "Drivers" in Benign Conditions

Advances in deep genomic sequencing have identified a spectrum of cancer-specific passenger and driver aberrations. Clones with driver anomalies are believed to be positively selected during carcinogenesis. Accumulating evidence, however, shows that genomic alterations, such as those inBRAF,RAS,EGFR...

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Veröffentlicht in:JNCI : Journal of the National Cancer Institute Jg. 108; H. 8
Hauptverfasser: Kato, Shumei, Lippman, Scott M, Flaherty, Keith T, Kurzrock, Razelle
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 01.08.2016
Schlagworte:
Carcinogenesis - genetics
Class I Phosphatidylinositol 3-Kinases
Cyclin-Dependent Kinase Inhibitor p18 - genetics
Gene Rearrangement
GTP-Binding Protein alpha Subunits, Gq-G11 - genetics
Humans
Mutation
Neoplasms - genetics
Neoplasms - prevention & control
Neurofibromin 1 - genetics
Neurofibromin 2 - genetics
Phosphatidylinositol 3-Kinases - genetics
Precancerous Conditions - genetics
Proto-Oncogene Proteins B-raf - genetics
ras Proteins - genetics
Receptor Protein-Tyrosine Kinases - genetics
Receptor, ErbB-2 - genetics
Receptor, Fibroblast Growth Factor, Type 3 - genetics
Tumor Suppressor Protein p53 - genetics
ISSN:1460-2105, 1460-2105
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Zusammenfassung:Advances in deep genomic sequencing have identified a spectrum of cancer-specific passenger and driver aberrations. Clones with driver anomalies are believed to be positively selected during carcinogenesis. Accumulating evidence, however, shows that genomic alterations, such as those inBRAF,RAS,EGFR,HER2,FGFR3,PIK3CA,TP53,CDKN2A, andNF1/2, all of which are considered hallmark drivers of specific cancers, can also be identified in benign and premalignant conditions, occasionally at frequencies higher than in their malignant counterparts. Targeting these genomic drivers can produce dramatic responses in advanced cancer, but the effects on their benign counterparts are less clear. This benign-malignant phenomenon is well illustrated in studies ofBRAFV600E mutations, which are paradoxically more frequent in benign nevi (∼80%) than in dysplastic nevi (∼60%) or melanoma (∼40%-45%). Similarly, human epidermal growth factor receptor 2 is more commonly overexpressed in ductal carcinoma in situ (∼27%-56%) when compared with invasive breast cancer (∼11%-20%).FGFR3mutations in bladder cancer also decrease with tumor grade (low-grade tumors, ∼61%; high-grade, ∼11%). "Driver" mutations also occur in nonmalignant settings:TP53mutations in synovial tissue from rheumatoid arthritis andFGFR3mutations in seborrheic keratosis. The latter observations suggest that the oncogenicity of these alterations may be tissue context-dependent. The conversion of benign conditions to premalignant disease may involve other genetic events and/or epigenetic reprogramming. Putative driver mutations can also be germline and associated with increased cancer risk (eg, germlineRASorTP53alterations), but germlineFGFR3orNF2abnormalities do not predispose to malignancy. We discuss the enigma of genetic "drivers" in benign and premalignant conditions and the implications for prevention strategies and theories of tumorigenesis.
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SourceType-Scholarly Journals-1
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ISSN:1460-2105
1460-2105
DOI:10.1093/jnci/djw036