The Conundrum of Genetic “Drivers” in Benign Conditions

open access

 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.....
 

TP53 Mutations in Cancer

TP53 mutations can result in both gain of function and loss of function; the latter is mostly associated with a dominant-negative effect over wild-type p53 (139). Mutations are especially frequent in serous ovarian (95% of patients) and serous endometrial carcinomas (89%) (134). Furthermore, patients with germline TP53 mutations have Li-Fraumeni syndrome that is associated with a high incidence of cancer (140).

....There are several clinically important questions that will need to be addressed. If certain genomic drivers are seen at similar (or greater) frequencies in benign conditions compared with malignant diseases, are we therapeutically targeting the right genetic driver? Are there underlying intact tumor suppressors in benign conditions that prevent driver mutations from promoting tumorigenesis? Can we reliably use genomic alterations as a screening tool for early detection of cancer or as a marker for prevention or treatment response such as with liquid biopsies? Finally, the role of certain driver mutations in tumor initiation and premalignancy, rather than progression and malignancy, merits exploration.