The Conundrum of Genetic "Drivers" in Benign Conditions

Shumei Kato; Scott M. Lippman; Keith T. Flaherty; Razelle Kurzrock


J Natl Cancer Inst. 2016;108(8) 

In This Article

Abstract and Introduction


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 in BRAF, RAS, EGFR, HER2, FGFR3, PIK3CA, TP53, CDKN2A, and NF1/2, 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 of BRAF V600E 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%). FGFR3 mutations in bladder cancer also decrease with tumor grade (low-grade tumors, ~61%; high-grade, ~11%). "Driver" mutations also occur in nonmalignant settings: TP53 mutations in synovial tissue from rheumatoid arthritis and FGFR3 mutations 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, germline RAS or TP53 alterations), but germline FGFR3 or NF2 abnormalities 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.


Cancers are known to arise, at least in part, as a result of acquired changes in DNA, and such changes accumulate over time.[1] With the advent of next-generation sequencing (NGS), the full complement of genetic alterations in a given cancer can be identified.[2] Some of these abnormalities are "passengers" that do not drive progression to metastatic disease.[3] Other alterations, termed genetic "drivers",[4,5] are implicated in pathways crucial to the ability of cancer cells to grow and survive. Clones harboring driver anomalies are presumed to be positively selected in the evolution of neoplasia to invasive and advanced cancer.[3] Overall, a basic premise in oncology is that, via the process of clonal selection, driver mutations are rare in benign conditions, variably present in premalignancy (depending on severity and cancer risk), and most frequent in advanced cancer.[3,6] Recent studies, albeit limited, have suggested that genetic drivers can occur in early cancer[7] and premalignancy.[8–18]

The identification of genetic drivers has resulted in the development of targeted therapies with promising outcomes in patients with advanced cancers that harbor actionable alterations.[19] In this review, we describe an emerging body of literature indicating that genomic drivers, considered a hallmark of specific cancers, can also be found in benign conditions and in premalignant lesions, sometimes at frequencies higher than in the corresponding tumors (Table 1), and discuss the implications of these findings for current theories of carcinogenesis and designing prevention strategies.