Genetic predisposition to childhood cancer

Table 1 Recognition of genetic predisposition in pediatric cancer patients[6-9]

Characteristics	Conditions
Family history	≥ 2 malignancies occurred in family members before the age of 18 years, including the affected child
	First-degree relative (parent or sibling) with cancer < 45 years of age
	≥ 2 first- or second-degree relatives with cancer in the same parental lineage < 45 years
	Cancer in consanguineous family
Tumor type and/or cancer features known to be strongly associated with cancer predisposition syndrome
	Adrenocortical carcinoma/adenoma
	ALL (low hypodiploid)
	ALL (ring chromosome 21)
	ALL (Robertsonian translocation 15;21)
	ALL relapse (TP53 mutated)
	AML (Monosomy 7)
	Basal cell carcinoma
	Botryoid rhabdomyosarcoma of the urogenital tract (fusion-negative)
	Chondromesenchymal hamartoma
	Choroid plexus carcinoma/tumor
	Colorectal carcinoma
	Cystic nephroma
	Endolymphatic sack tumor
	Fetal rhabdomyoma
	Gastrointestinal stromal tumor
	Glioma of the optic pathway (with signs of NF1)
	Gonadoblastoma
	Hemangioblastoma
	Hepatoblastoma (CTNNB1 wildtype)
	Hepatocellular carcinoma
	Infantile myofibromatosis
	Juvenile myelomonocytic leukemia
	Keratocystic odontogenic tumor
	Large cell calcifying Sertoli-cell-tumor
	Malignant peripheral nerve sheath tumor
	Medullary thyroid carcinoma
	Medulloblastoma (SHH activated)
	Medulloblastoma (WNT activated, CTNNB1 wildtype)
	Medullary renal cell carcinoma
	Medulloepithelioma
	Melanoma
	Meningioma
	Myelodysplastic syndrome
	Myeloproliferative neoplasms (except CML)
	Myxoma
	Neuroendocrine tumor
	Paraganglioma/pheochromocytoma
	Parathyroid carcinoma/adenoma
	Pineoblastoma
	Pituitary adenoma/tumor
	Pituitary blastoma
	Pleuropulmonary blastoma
	Renal cell carcinoma
	Retinoblastoma
	Rhabdoid tumor
	Rhabdomyosarcoma with diffuse anaplasia
	Schwannoma
	Schwannomatosis
	Sertoli-Leydig cell tumor
	Sex cord-stromal tumor with annular tubules
	Small-cell carcinoma of the ovary, hypercalcemic type
	Squamous cell carcinoma
	Subependymal giant cell astrocytoma
	Thyroid carcinoma (non-medullary)
	Transient myeloproliferative disease
Other rare cancers or cancers that typically occur in adults, unusually early manifestation age
Genetic tumor analysis reveals a defect suggesting germline cancer predisposition
A child with ≥ 2 malignancies (secondary, bilateral in paired organs, multifocal, synchronous, or metachronous)
A child with cancer and obvious nonmalignant signs suggestive of a genetic condition	Congenital anomalies
	Facial dysmorphism
	Mental impairment, developmental delay
	Abnormal growth
	Skin anomalies (abnormal pigmentation, i.e. ≥ 2 café-au-lait spots, vascular lesions, hypersensitivity to sunlight, benign tumors)
	Immune deficiency
	Endocrine anomalies
A child with excessive treatment toxicity

ALL: Acute lymphoblastic leukemia; AML: Acute myeloid leukemia; CML: Chronic myeloid leukemia; SHH: Sonic hedgehog protein; WNT: Wingless/integrated signaling pathway.

Table 2 Selected cancer predisposition syndromes, associated malignancies and genetic alterations[4,5,7,21]

Cancer predisposition syndrome	Associated malignancy1	Genetic alteration
Ataxia telangiectasia	Lymphoma, leukemia	ATM
Beckwith-Wiedemann syndrome	Wilms’ tumor, hepatoblastoma, neuroblastoma, rhabdomyosarcoma, adrenocortical carcinoma	IGF-2, CDKN1C
Denys-Drash syndrome	Wilms’ tumor	WT1
Diamond-Blackfan anemia	AML, MDS, colon cancer, female genital cancers, osteosarcoma	RPL5, RPL11, RPL35A, RPS10, RPS17, RPS19, RPS24, RPS26
Down syndrome	ALL, AML, MDS, germ cell tumor, retinoblastoma	GATA1, GATA2, IKZF1, JAK2
Familial adenomatous polyposis	Ampullary adenocarcinoma, colorectal cancer, small bowel cancer, stomach cancer, thyroid cancer, pancreatic cancer, hepatoblastoma	APC
Fanconi anemia	AML, MDS, esophageal cancer, head and neck cancer, skin cancer	FANCA, FANCC, FANCG, RAD51C
Gorlin syndrome	Basal cell carcinoma, ependymoma, medulloblastoma, ovarian fibrosarcoma, rhabdomyosarcoma	PTCH1, SUFU, PTCH2
Li Fraumeni syndrome	Adrenocortical carcinoma, ALL, AML, brain tumor, breast cancer, colorectal cancer, neuroblastoma, osteosarcoma, rhabdomyosarcoma, Wilms’ tumor	TP53
Multiple endocrine neoplasia type 1	Ependymoma	MEN1
Multiple endocrine neoplasia type 2	Medullary thyroid cancer	RET
Neurofibromatosis type 1	Malignant peripheral nerve sheath tumor, breast cancer, optic glioma, gastrointestinal stromal tumor, JMML, neuroblastoma, embryonal rhabdomyosarcoma	NF1
Neurofibromatosis type 2	Astrocytoma, ependymoma, glioma	NF2
Von Hippel-Lindau syndrome	Clear cell carcinoma, carcinoid, pancreatic islet cell carcinoma, renal cell carcinoma	VHL
WAGR syndrome	Wilms’ tumor	WT1

¹Associated nonmalignant tumors are not included in the list. ALL: Acute lymphoblastic leukemia; AML: Acute myeloid leukemia; JMML: Juvenile myelomonocytic leukemia; MDS: Myelodysplastic syndrome; WAGR: Wilms tumor, aniridia, genitourinary anomalies, and range of developmental delays.