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Table 2 Examples of hereditary germline syndromes and of somatic mosaicism associated with examples of alterations in cancer-driver genes, their relationship with cancer in affected patients, and targeted drugs that might be useful

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

Gene Alteration Syndrome Descriptions Increased incidence of cancer (if yes, most common cancers) Treatment potentially/theoretically targeting the alteration
APC Most common nonsense changes are C>T mutations [48] Familial adenomatous polyposis [49] Multiple non-cancerous (benign) growths (polyps) in the colon with strong predisposition to cancer Yes (colorectal [49, 50]) Sorafenib and WNT inhibitors [13, 44]
ARAF S214P [51] Central conducting lymphatic anomaly [52] Not listed None found mTOR inhibitors such as sirolimus [53] or MEK inhibitors such as trametinib [51]
BRAF Q257R, S467A, G596V, V600G Cardiofaciocutaneous syndrome [54] Cardiac abnormalities, distinctive craniofacial appearance, and cutaneous abnormalities Yes (juvenile myelomonocytic leukemia, brain tumors, acute lymphoblastic leukemia, rhabdomyosarcoma, and neuroblastoma [55]) BRAF inhibitors [9] and/or MEK inhibitors such as dabrafenib [5] and cobimetinib [7]
G469E, F595L, L597V Noonan syndrome [56, 57] Unusual facial features, short stature, heart defects, bleeding problems, and skeletal malformations Yes (juvenile myelomonocytic leukemia, brain tumor, acute lymphoblastic leukemia, rhabdomyosarcoma, and neuroblastoma [55])
ERBB4 R927Q, R1275W Amyotrophic lateral sclerosis subtype 19 [58] Degeneration of motor neurons and anterior horns of spinal cord None found Pan-ERBB inhibitors such as neratinib [59] will not be effective because the mutations have an inactivating effect
FGFR1 L165S, L191S Hartsfield syndrome [60] Holoprosencephaly, ectrodactyly, and cleft lip/palate None found These FGFR1 mutations may cause loss of function, so FGFR inhibitors such as erdafitinib [23] will not be effective
Multiple loss of function mutations Kallman syndrome [61] Hypogonadotropic hypogonadism and impaired sense of smell None found
P252R Pfeiffer syndrome [62] Premature fusion of certain skull bones None found Gain-of-function alterations and hence may be targeted by FGFR inhibitors such as erdafitinib [23]
FGFR2 S252W or P253R Apert syndrome [63] Premature fusion of certain skull bones (craniosynostosis*) and syndactyly Hepatoblastoma [64]* Mutations are gain of function and hence may be targeted by FGFR inhibitors such as erdafitinib [23]
Y375C or S372C Beare-Stevenson cutis gyrata syndrome [65] Premature fusion of certain skull bones (craniosynostosis*) Hepatoblastoma [64]*
  S351C Pfeiffer syndrome [62] Premature fusion of certain skull bones (craniosynostosis*) Hepatoblastoma [64]*
FGFR3 G380R; R248C, G372C, G382R Achondroplasia [66] Short-limbed dwarfism None found Mutations are gain of function and hence may be targeted by FGFR inhibitors such as erdafitinib [23]
N540K Hypochondroplasia [67] Short-limbed dwarfism that is milder than achondroplasia None found
D513N Lacrimo-auriculo-dento-digital syndrome [68] Abnormal tear production, malformed ears with hearing loss, decreased saliva production, small teeth, and hand deformities None found
P250R Muenke syndrome [69] Craniosynostosis*, hearing loss, subtle hand and foot abnormalities, and developmental delay Hepatoblastoma [64]*
R248C, K650E, S249C, Y373C Thanatophoric dysplasia [70] Extremely short limbs and folds of extra (redundant) skin on the arms and legs None found FGFR3 inhibitor in mice [71]
GNAS R201C, R201H, Q227L McCune-Albright syndrome [72] Abnormal scar-like (fibrous) tissue in their bones, a condition called polyostotic fibrous dysplasia Yes (breast, thyroid, testicular [73]) MEK inhibitors [74] such as trametinib [75]
HRAS G12S, G12C Costello syndrome Delayed development/intellectual disability, loose folds of skin, unusually flexible joints, and distinctive facial features including a large mouth, heart problems Yes (juvenile myelomonocytic leukemia, brain tumor, acute lymphoblastic leukemia, rhabdomyosarcoma, and neuroblastoma [55]) MEK inhibitors [76] such as trametinib [75]
IDH2 R140Q D-2-hydroxyglutaric aciduria [77] Delayed development, seizures, weak muscle tone (hypotonia), and abnormalities in the cerebrum Yes (high-grade glioma [78]) IDH2 inhibitors such as enasidenib [79]
JAK3 R651W, V599G, W709R Severe combined immunodeficiency [80] Lack the necessary immune cells to fight bacteria, viruses, and fungi None found Mutations cause loss of function and hence JAK inhibitors such as tofacitinib [81] will not be effective
KRAS P34R Cardiofaciocutaneous syndrome [54, 82] Distinctive craniofacial appearance, and cutaneous abnormalities (including but not limited to xerosis, hyperkeratosis, pigmented moles, hemangiomas) Yes (juvenile myelomonocytic leukemia, brain tumor, acute lymphoblastic leukemia, rhabdomyosarcoma, and neuroblastoma [55]) MEK inhibitors [83] such as trametinib [75]
MET F841V DFNB97 hearing loss [84] Non-syndromic sensorineural hearing loss with prelingual onset None found The mutation is damaging, so MET inhibitors such as cabozantinib [85] should not be effective
NOTCH1 C1496Y, D1989N Adams-Oliver syndrome [86] Congenital aplasia cutis and malformations of the limbs None found Loss-of-function mutations so Notch inhibitors such as LY3039478 [87] will be ineffective
NF1 R304X, Y2264X, R1825W, R1809C, N1229S, D176E Neurofibromatosis type 1 [88] Changes in skin coloring (pigmentation) and the growth of benign neoplasms along nerves in the skin, brain, and other parts of the body [89] Yes (malignant peripheral nerve sheath tumors, optic gliomas, brain tumors, breast cancer [90]) MEK inhibitors [91] such as trametinib [75] or selumetinib [92]
NF2 L46R, L141P, A211D, K413E, Q324L, and L535P Neurofibromatosis type 2 [93] Growth of benign neoplasms in the nervous system; vestibular schwannomas or acoustic neuromas None found mTOR inhibitors [94] such as sirolimus [53]
RET P155L, T278A, T278P, D300N, S316I, C620R Hirschsprung disease [95] Absence of nerves in distal colon Yes (medullary thyroid [96, 97]) Mutations generally cause loss of function, so RET inhibitors such as LOXO-292 [98] or cabozantinib [83] would be ineffective; RET C620R may cause both gain and loss of functions
STK11 40 different somatic STK11 mutations [99] Peutz-Jegher syndrome Gastrointestinal hamartomatous polyps and hyperpigmentation of the lips, buccal mucosa, digits Yes (gastrointestinal tract, pancreas, cervix, ovary, and breast [100]) mTOR inhibitors such as everolimus [101]
TP53 Multiple loss of function mutations Li-Fraumeni [102,103,104,105] Greatly increases the risk of several cancers Yes (sarcoma, breast, brain, adrenocortical [102]) Bevacizumab may target angiogenesis associated with TP53 mutations [39]
Somatic mosaicism
AKT1 E17K (gain of function) Proteus syndrome [106] Overgrowth of the bones, skin, and other tissues Yes (meningiomas, ovarian cystadenomas, breast cancer, parotid monomorphic adenoma, mesothelioma [107]) AKT inhibitors such as ipatasertib [108]
GNAQ R183Q Sturge-Weber syndrome [109] Port-wine stains affecting the skin, leptomeningeal vascular malformations None found Some MEK inhibitors may have activity
PIK3CA E545K Hemimegalencephaly [110] Rare neurological condition in which one-half of the brain, or one side of the brain, is abnormally larger than the other None found PIK3CA inhibitors such as alpelisib [24]
H1047R, C420R, Q542K CLOVES syndrome [111] Tissue overgrowth and complex vascular anomalies; CLOVES stands for congenital lipomatous (fatty) overgrowth, vascular malformations, epidermal nevi and scoliosis/skeletal/spinal anomalies Yes (Wilms tumor [112]) PIK3CA inhibitors such as alpelisib [26, 113]
H1047R and H1047L Fibroadipose hyperplasia [114] Patchy overgrowth of a limb or part/region of the body None found PIK3CA or mTOR inhibitors [115] such as alpelisib [26] or everolimus [101]
  1. *A recent publication [64] shows that craniosynososis may be associated with increased incidence of hepatoblastoma, although the authors did not define which syndromes were affected