Faculty Collaboration Database

The Conundrum of Genetic "Drivers" in Benign Conditions. J Natl Cancer Inst 2016 Aug;108(8)

Date

04/10/2016

Pubmed ID

27059373

Pubmed Central ID

PMC5017937

DOI

10.1093/jnci/djw036

Scopus ID

2-s2.0-84989964975 (requires institutional sign-in at Scopus site)   106 Citations

Abstract

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.

Author List

Kato S, Lippman SM, Flaherty KT, Kurzrock R

Author

Razelle Kurzrock MD Center Associate Director, Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Carcinogenesis
Class I Phosphatidylinositol 3-Kinases
Cyclin-Dependent Kinase Inhibitor p16
Cyclin-Dependent Kinase Inhibitor p18
GTP-Binding Protein alpha Subunits, Gq-G11
Gene Rearrangement
Humans
Mutation
Neoplasms
Neurofibromin 1
Neurofibromin 2
Phosphatidylinositol 3-Kinases
Precancerous Conditions
Proto-Oncogene Proteins B-raf
Receptor Protein-Tyrosine Kinases
Receptor, ErbB-2
Receptor, Fibroblast Growth Factor, Type 3
Tumor Suppressor Protein p53
ras Proteins