The Conundrum of Genetic “Drivers” in Benign Conditions

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 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.

Preoperative Circulating Tumor DNA in Patients with Peritoneal Carcinomatosis is an Independent Predictor of Progression-Free Survival

“…34 Other limitations of ctDNA, as it becomes more sensitive, may theoretically include the ability to discern genomic mutations derived from benign tissue. 35 However, the methods used herein are approaching a practical limit with sensitivity as low as 1–2 DNA molecular fragments in 10 mL of blood without evidence of ctDNA from benign lesions. Additional limitations of this project include modest sample size, single-institution setting, and incomplete follow-up due to referral patterns.…”

Evolution of Premalignant Disease

“…Many so-called driver alterations are also found in normal and premalignant tissues, occasionally at even higher frequencies than found in corresponding malignancies (Kato et al 2016). As a recent example, Martincorena and colleagues found putative driver mutations in 18% to 32% of normal, sun-exposed skin cells at a density of 140 driver mutations per square centimeter (Martincorena et al 2015).…”

Liquid biopsy - emergence of a new era in personalized cancer care

“…Benign and premalignant conditions of various cancers express higher frequencies of alterations in BRAF, RAS, EGFR, HER2, FGFR3, PIK3CA, TP53, CDKN2A, and NF1/2 genes as compared to malignant tissues. Similarly, human HER2 is more commonly overexpressed in ductal carcinoma in situ (∼27%-56%) when compared with invasive breast cancer [157]. Though Uehiro and colleagues were able to predict early cancers with high sensitivity and specificity using their prediction model, they did not find any significant trend toward a higher detection index in patients with advanced stage breast cancer [82].…”