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 |