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2016 ; 108
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The Conundrum of Genetic "Drivers" in Benign Conditions
#MMPMID27059373
Kato S
; Lippman SM
; Flaherty KT
; Kurzrock R
J Natl Cancer Inst
2016[Aug]; 108
(8
): ä PMID27059373
show ga
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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