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Table 1 Examples of sporadic benign conditions, many with negligible potential for malignant transformation, associated with somatic alterations in driver cancer genes

From: The paradox of cancer genes in non-malignant conditions: implications for precision medicine

GeneType of alterationBenign or premalignant conditionFrequency of alteration in benign condition (%)Examples of drug(s) that can potentially target the alterationExamples of malignancies associated with this gene alterationMechanism
BRAFV600E, D594V, V599EMelanocytic nevi70–88% [3,4,5,6,7,8,9,10,11,12]BRAF and/or MEK inhibitors such as dabrafenib and trametanib [13, 14]MelanomaRAS-RAF-MEK-ERK pathway upregulation [15]
NRASQ61KGiant congenital melanocytic nevi6–14% [10, 11]MEK inhibitors [12] such as trametinib [16]MelanomaRAS-RAF-MEK-ERK pathway upregulation [15]
Q61K and Q61RMelanocytic nevi70–95% [17, 18]MEK inhibitors such as trametinib [16]MelanomaRAS-RAF-MEK-ERK pathway upregulation [15]
FGFR3R248C, S249C, G372C, S373C, A393E, K652E, K652MSeborrheic keratosis 18–85% [19,20,21,22]FGFR inhibitors such as erdafitinib [23]Urothelial carcinomaActivation of the FGF/FGFR machinery [24]
R248C, G372C, G382REpidermal nevi33% [25]FGFR inhibitors such as erdafitinib [23]Urothelial carcinomaActivation of the FGF/FGFR machinery [24]
PIK3CAE542K, E545K, H1047RSeborrheic keratosis 16% [20]PIK3CA inhibitors such as alpelisib [26]Breast cancerPI3K-AKT-mTOR pathway activation
M1043VEndometriosis~  4% [27]PIK3CA inhibitors such as alpelisib [26]Breast cancerPI3K-AKT-mTOR pathway activation
H1047L, H1047RNormal esophagus mucosaNot listed [28]PIK3CA inhibitors such as alpelisib [26]Breast cancerPI3K-AKT-mTOR pathway activation
ALKTPM3-ALK, TPM4-ALKInflammatory myofibroblastic tumor 50% [29]ALK inhibitors [30] such as alectinib [31]Non-small cell lung cancerALK pathway activation [32]
NOTCH1Loci not specifiedAging esophagus12–80% [33]No specific inhibitors approvedColon cancerWnt-beta-catenin pathway activation [34]
KRASG12V or G12DArteriovenous malformations in brain 63% [35, 36]MEK inhibitors such as trametinib [16]Colorectal and pancreatic cancerRAS-RAF-MEK-ERK pathway upregulation [15]
G12C, G12V, G12A, G12D, G12REndometriosis~ 21% [27]MEK inhibitors such as trametinib [16]Colorectal and pancreatic cancerRAS-RAF-MEK-ERK pathway upregulation [15]
Q61RNormal testisNot listed [28]MEK inhibitors such as trametinib [16]Colorectal and pancreatic cancerRAS-RAF-MEK-ERK pathway upregulation [15]
TP53R177S, Q192L, R196*, K139R, H193Y, E224fs, N239SRheumatoid arthritis synovium17–46% [37, 38]Bevacizumab may target angiogenesis upregulation that results from TP53 mutations [39]Serous ovarian cancer (TP53 mutations are common across cancers)TP53 is a tumor suppressor gene [40]
Loci not specifiedAging esophagus2–37% [33]Bevacizumab may target angiogenesis upregulation that results from TP53 mutations [39]Serous ovarian cancer (TP53 mutations are common across cancers)TP53 is a tumor suppressor gene [40]
CTNNB1T41A and S45PDesmoid tumor88% [41]COX-2 inhibitors [42] such as celecoxib [43], as well as sorafenib (which can suppress CTNNB1-mediated activation of the WNT pathway) [13, 14, 44]Adrenocortical cancersWnt-beta-catenin pathway activation [45]
FGFR2Y376C, P286SKeratinocytic epidermal nevus5–10% [46]FGFR inhibitors such as erdafitinib [23]Urothelial carcinomaFGF/FGFR machinery [24]
AKT, MAPK, and AMPK pathway genesAlzheimer’s disease~ 27% [47]mTOR inhibitors or MEK inhibitorsMultiple tumor typesIncreases tau phosphorylation