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

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 [102–105]	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]

*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