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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

Gene Type of alteration Benign or premalignant condition Frequency of alteration in benign condition (%) Examples of drug(s) that can potentially target the alteration Examples of malignancies associated with this gene alteration Mechanism
BRAF V600E, D594V, V599E Melanocytic nevi 70–88% [3,4,5,6,7,8,9,10,11,12] BRAF and/or MEK inhibitors such as dabrafenib and trametanib [13, 14] Melanoma RAS-RAF-MEK-ERK pathway upregulation [15]
NRAS Q61K Giant congenital melanocytic nevi 6–14% [10, 11] MEK inhibitors [12] such as trametinib [16] Melanoma RAS-RAF-MEK-ERK pathway upregulation [15]
Q61K and Q61R Melanocytic nevi 70–95% [17, 18] MEK inhibitors such as trametinib [16] Melanoma RAS-RAF-MEK-ERK pathway upregulation [15]
FGFR3 R248C, S249C, G372C, S373C, A393E, K652E, K652M Seborrheic keratosis  18–85% [19,20,21,22] FGFR inhibitors such as erdafitinib [23] Urothelial carcinoma Activation of the FGF/FGFR machinery [24]
R248C, G372C, G382R Epidermal nevi 33% [25] FGFR inhibitors such as erdafitinib [23] Urothelial carcinoma Activation of the FGF/FGFR machinery [24]
PIK3CA E542K, E545K, H1047R Seborrheic keratosis  16% [20] PIK3CA inhibitors such as alpelisib [26] Breast cancer PI3K-AKT-mTOR pathway activation
M1043V Endometriosis ~  4% [27] PIK3CA inhibitors such as alpelisib [26] Breast cancer PI3K-AKT-mTOR pathway activation
H1047L, H1047R Normal esophagus mucosa Not listed [28] PIK3CA inhibitors such as alpelisib [26] Breast cancer PI3K-AKT-mTOR pathway activation
ALK TPM3-ALK, TPM4-ALK Inflammatory myofibroblastic tumor  50% [29] ALK inhibitors [30] such as alectinib [31] Non-small cell lung cancer ALK pathway activation [32]
NOTCH1 Loci not specified Aging esophagus 12–80% [33] No specific inhibitors approved Colon cancer Wnt-beta-catenin pathway activation [34]
KRAS G12V or G12D Arteriovenous malformations in brain  63% [35, 36] MEK inhibitors such as trametinib [16] Colorectal and pancreatic cancer RAS-RAF-MEK-ERK pathway upregulation [15]
G12C, G12V, G12A, G12D, G12R Endometriosis ~ 21% [27] MEK inhibitors such as trametinib [16] Colorectal and pancreatic cancer RAS-RAF-MEK-ERK pathway upregulation [15]
Q61R Normal testis Not listed [28] MEK inhibitors such as trametinib [16] Colorectal and pancreatic cancer RAS-RAF-MEK-ERK pathway upregulation [15]
TP53 R177S, Q192L, R196*, K139R, H193Y, E224fs, N239S Rheumatoid arthritis synovium 17–46% [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 specified Aging esophagus 2–37% [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]
CTNNB1 T41A and S45P Desmoid tumor 88% [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 cancers Wnt-beta-catenin pathway activation [45]
FGFR2 Y376C, P286S Keratinocytic epidermal nevus 5–10% [46] FGFR inhibitors such as erdafitinib [23] Urothelial carcinoma FGF/FGFR machinery [24]
AKT, MAPK, and AMPK pathway genes Alzheimer’s disease ~ 27% [47] mTOR inhibitors or MEK inhibitors Multiple tumor types Increases tau phosphorylation