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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

GeneAlterationSyndromeDescriptionsIncreased incidence of cancer (if yes, most common cancers)Treatment potentially/theoretically targeting the alteration
APCMost 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 cancerYes (colorectal [49, 50])Sorafenib and WNT inhibitors [13, 44]
ARAFS214P [51]Central conducting lymphatic anomaly [52]Not listedNone foundmTOR inhibitors such as sirolimus [53] or MEK inhibitors such as trametinib [51]
BRAFQ257R, S467A, G596V, V600GCardiofaciocutaneous syndrome [54]Cardiac abnormalities, distinctive craniofacial appearance, and cutaneous abnormalitiesYes (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, L597VNoonan syndrome [56, 57]Unusual facial features, short stature, heart defects, bleeding problems, and skeletal malformationsYes (juvenile myelomonocytic leukemia, brain tumor, acute lymphoblastic leukemia, rhabdomyosarcoma, and neuroblastoma [55])
ERBB4R927Q, R1275WAmyotrophic lateral sclerosis subtype 19 [58]Degeneration of motor neurons and anterior horns of spinal cordNone foundPan-ERBB inhibitors such as neratinib [59] will not be effective because the mutations have an inactivating effect
FGFR1L165S, L191SHartsfield syndrome [60]Holoprosencephaly, ectrodactyly, and cleft lip/palateNone foundThese FGFR1 mutations may cause loss of function, so FGFR inhibitors such as erdafitinib [23] will not be effective
Multiple loss of function mutationsKallman syndrome [61]Hypogonadotropic hypogonadism and impaired sense of smellNone found
P252RPfeiffer syndrome [62]Premature fusion of certain skull bonesNone foundGain-of-function alterations and hence may be targeted by FGFR inhibitors such as erdafitinib [23]
FGFR2S252W or P253RApert syndrome [63]Premature fusion of certain skull bones (craniosynostosis*) and syndactylyHepatoblastoma [64]*Mutations are gain of function and hence may be targeted by FGFR inhibitors such as erdafitinib [23]
Y375C or S372CBeare-Stevenson cutis gyrata syndrome [65]Premature fusion of certain skull bones (craniosynostosis*)Hepatoblastoma [64]*
 S351CPfeiffer syndrome [62]Premature fusion of certain skull bones (craniosynostosis*)Hepatoblastoma [64]*
FGFR3G380R; R248C, G372C, G382RAchondroplasia [66]Short-limbed dwarfismNone foundMutations are gain of function and hence may be targeted by FGFR inhibitors such as erdafitinib [23]
N540KHypochondroplasia [67]Short-limbed dwarfism that is milder than achondroplasiaNone found
D513NLacrimo-auriculo-dento-digital syndrome [68]Abnormal tear production, malformed ears with hearing loss, decreased saliva production, small teeth, and hand deformitiesNone found
P250RMuenke syndrome [69]Craniosynostosis*, hearing loss, subtle hand and foot abnormalities, and developmental delayHepatoblastoma [64]*
R248C, K650E, S249C, Y373CThanatophoric dysplasia [70]Extremely short limbs and folds of extra (redundant) skin on the arms and legsNone foundFGFR3 inhibitor in mice [71]
GNASR201C, R201H, Q227LMcCune-Albright syndrome [72]Abnormal scar-like (fibrous) tissue in their bones, a condition called polyostotic fibrous dysplasiaYes (breast, thyroid, testicular [73])MEK inhibitors [74] such as trametinib [75]
HRASG12S, G12CCostello syndromeDelayed development/intellectual disability, loose folds of skin, unusually flexible joints, and distinctive facial features including a large mouth, heart problemsYes (juvenile myelomonocytic leukemia, brain tumor, acute lymphoblastic leukemia, rhabdomyosarcoma, and neuroblastoma [55])MEK inhibitors [76] such as trametinib [75]
IDH2R140QD-2-hydroxyglutaric aciduria [77]Delayed development, seizures, weak muscle tone (hypotonia), and abnormalities in the cerebrumYes (high-grade glioma [78])IDH2 inhibitors such as enasidenib [79]
JAK3R651W, V599G, W709RSevere combined immunodeficiency [80]Lack the necessary immune cells to fight bacteria, viruses, and fungiNone foundMutations cause loss of function and hence JAK inhibitors such as tofacitinib [81] will not be effective
KRASP34RCardiofaciocutaneous 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]
METF841VDFNB97 hearing loss [84]Non-syndromic sensorineural hearing loss with prelingual onsetNone foundThe mutation is damaging, so MET inhibitors such as cabozantinib [85] should not be effective
NOTCH1C1496Y, D1989NAdams-Oliver syndrome [86]Congenital aplasia cutis and malformations of the limbsNone foundLoss-of-function mutations so Notch inhibitors such as LY3039478 [87] will be ineffective
NF1R304X, Y2264X, R1825W, R1809C, N1229S, D176ENeurofibromatosis 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]
NF2L46R, L141P, A211D, K413E, Q324L, and L535PNeurofibromatosis type 2 [93]Growth of benign neoplasms in the nervous system; vestibular schwannomas or acoustic neuromasNone foundmTOR inhibitors [94] such as sirolimus [53]
RETP155L, T278A, T278P, D300N, S316I, C620RHirschsprung disease [95]Absence of nerves in distal colonYes (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
STK1140 different somatic STK11 mutations [99]Peutz-Jegher syndromeGastrointestinal hamartomatous polyps and hyperpigmentation of the lips, buccal mucosa, digitsYes (gastrointestinal tract, pancreas, cervix, ovary, and breast [100])mTOR inhibitors such as everolimus [101]
TP53Multiple loss of function mutationsLi-Fraumeni [102,103,104,105]Greatly increases the risk of several cancersYes (sarcoma, breast, brain, adrenocortical [102])Bevacizumab may target angiogenesis associated with TP53 mutations [39]
Somatic mosaicism
AKT1E17K (gain of function)Proteus syndrome [106]Overgrowth of the bones, skin, and other tissuesYes (meningiomas, ovarian cystadenomas, breast cancer, parotid monomorphic adenoma, mesothelioma [107])AKT inhibitors such as ipatasertib [108]
GNAQR183QSturge-Weber syndrome [109]Port-wine stains affecting the skin, leptomeningeal vascular malformationsNone foundSome MEK inhibitors may have activity
PIK3CAE545KHemimegalencephaly [110]Rare neurological condition in which one-half of the brain, or one side of the brain, is abnormally larger than the otherNone foundPIK3CA inhibitors such as alpelisib [24]
H1047R, C420R, Q542KCLOVES syndrome [111]Tissue overgrowth and complex vascular anomalies; CLOVES stands for congenital lipomatous (fatty) overgrowth, vascular malformations, epidermal nevi and scoliosis/skeletal/spinal anomaliesYes (Wilms tumor [112])PIK3CA inhibitors such as alpelisib [26, 113]
H1047R and H1047LFibroadipose hyperplasia [114]Patchy overgrowth of a limb or part/region of the bodyNone foundPIK3CA 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