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 | ||
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 | 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]) | |
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]) | |
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 | 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]) | ||
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 | |
RET | P155L, T278A, T278P, D300N, S316I, C620R | Hirschsprung disease [95] | Absence of nerves in distal colon | 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 | 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]) | ||
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] | |