Genetic predisposition to childhood cancer

Abstract

The etiology of childhood cancer remains largely unknown. Recent evidence suggests that genetic factors play a substantial role in pediatric tumorigenesis. Unlike adult cancers, pediatric cancers typically have a higher prevalence of germline pathogenic variants in cancer predisposition genes. Inherited cancer predisposition syndromes account for approximately 10% of all childhood cancers. Over the years, the diagnosis of cancer predisposition syndromes was based on clinical suspicion prompting referral to a specialized geneticist. However, advances in molecular technologies have led to a shift toward a “genotype-first” approach. Identification of genetic variants related to cancer predisposition enables tailored treatment, improves clinical outcome, optimizes surveillance, and facilitates genetic counseling of the affected child and the family.

Key Words: Cancer; Children; Etiology; Genetics; Cancer predisposition syndromes

Core Tip: Genetic predisposition to childhood cancer has gained increasing attention in recent years as a result of our growing knowledge and advancements in molecular biology. It is estimated that at least 10% of children with cancer have an underlying genetic susceptibility to cancer. Identifying germline pathogenic variants in cancer predisposition genes can be of great importance, both for research studies and clinical implications, including preventive measures, a tailored treatment approach to minimize toxicities, comorbidity evaluation, surveillance and follow-up strategies, comprehensive genetic testing and counseling, psychological support of affected children and their families, and ethical considerations.

INTRODUCTION

According to the latest Global Burden of Disease Study, 2019, 291300 new cases of childhood cancers (children aged 0-14 years) occurred worldwide in 2019[1]. Cancer in children, although rare, is one of the leading disease-related causes of death in developed countries[1]. The etiology of childhood cancer has been systematically investigated in recent decades but remains largely unclear. Unlike adult cancers, very few environmental risk factors have been associated with cancer risk in children, including ionizing radiation, prior chemotherapy, and parental occupational exposure[2,3]. Due to the early age at diagnosis and the short period of postnatal environmental exposure, it has become increasingly evident that a considerable proportion of pediatric malignancies results from a genetic predisposition. It is estimated that at least 10% of children diagnosed with cancer have inherited cancer predisposition syndrome (CPS)[4]. The most recent studies suggest that this proportion is higher, with germline pathogenic variants in cancer predisposition genes detected in up to 18% of children with cancer[5]. This editorial provides an overview of key aspects of cancer predisposition in pediatric oncology.

TOOL DEVELOPMENT

Identifying children with susceptibility for cancer may lead to modified oncologic treatment in cases of expected syndrome-related increased toxicity or drug resistance as well as intensified screening for early detection of a new cancer. Affected family members may also benefit from appropriate surveillance strategies[6]. Moreover, genetic testing, genetic counseling, and psychological support for the affected children and their families might be warranted.

Due to the potential clinical benefits, it is important for pediatric care providers to become aware of the features of the major inherited CPS. The criteria from Jongmans et al[6] and a modified version of these criteria provide a useful framework for identification of children at risk[7-9]. These include: (1) A positive family history of cancer spanning at least three generations [two or more malignancies that occurred in family members before the age of 18 years, including the affected child, a first degree relative (parent or sibling) with cancer < 45 years of age, two or more first or second degree relatives with cancer in the same parental lineage < 45 years, or cancer in a consanguineous family]; (2) Special cancer types and/or cancer features (e.g., childhood onset of an adult type of cancer) known to be strongly associated with CPS; (3) Genetic tumor analysis reveals a defect suggesting germline predisposition (e.g., a pathogenic variant is identified that is known to represent germline cancer predisposition); (4) A child with two or more malignancies (secondary, bilateral, multifocal, synchronous, or metachronous); (5) A child with cancer and obvious nonmalignant signs suggestive of a genetic condition (congenital anomalies, facial dysmorphism, developmental delay and mental impairment, skin anomalies, hematological abnormalities not explained by the current cancer, immune deficiency, and endocrine anomalies); and (6) A child with excessive treatment toxicity.

A child presenting with any of these features should be referred to an experienced clinical geneticist or genetic counselor for further evaluation[7,10]. An updated easy-to-use screening tool, based on the modified Jongmans criteria and useful for the selection of children who may benefit from genetic testing, is shown in Table 1.

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.

HEREDITARY PREDISPOSITION TO CHILDHOOD CANCER

CPS are a heterogeneous group of genetic conditions associated with a significantly increased risk of developing specific tumors at an earlier age. Classic CPS encompass: Neurofibromatosis type 1; Down syndrome; Fanconi anemia; Beckwith-Wiedemann syndrome; Li-Fraumeni syndrome; Louis Barr syndrome (ataxia telangiectasia); Von Hippel-Lindau syndrome; Denys-Drash syndrome; and multiple endocrine neoplasia, among others[8,11]. The main clinical manifestations include: Syndromic features (the most common are facial dysmorphism, skin anomalies, developmental delay, and growth disorders, but not all patients have an overt clinical phenotype, as well as endocrine disturbances, immune or hematological alterations, and solid organ dysfunction); earlier occurrence of specific cancer types; unusual types of cancer; multiple malignancies; familial clustering; and excessive toxicity of anticancer treatments[8,12]. The relationship between cancer and morphological abnormalities has been studied for decades in order to delineate the common critical pathways of embryogenesis and tumorigenesis[13]. In the genetic era, CPS, previously described on the basis of clinical features, have undergone dramatic changes[14].

Most CPS are inherited in an autosomal dominant manner, but in rare instances recessive inheritance and other inheritance patterns are possible. The majority of known cancer predisposition genes are tumor suppressor genes, which require biallelic inactivation to exert their activity. Rarely, proto-oncogenes are activated through germline gain-of-function alterations. The pathophysiology of each CPS varies according to the functions of the altered gene, such as DNA repair, cell proliferation, cell death, or signaling pathways, and according to the molecular mechanisms implicated[4,7]. A growing number of techniques are now available for genetic testing. Next generation sequencing has revolutionized our understanding of the genetic basis of childhood cancer and facilitated omics studies. Whole genome sequencing is the most powerful and comprehensive technique that identifies variants in coding and noncoding regions, detecting up to 85% of cancer-related variants[15,16]. Targeted analysis sequencing, as the name suggests, targets specific regions of the genes known to have strong associations with specific CPS[15,17].

Genomic studies have underscored major differences between pediatric and adult cancers. Pediatric cancers have 14 times fewer somatic alterations than adult tumors, but a higher prevalence of germline pathogenic variants in cancer predisposing genes, except in patients with germline alterations in DNA mismatch repair[15,18,19]. The low overall burden of somatic alterations in pediatric cancer is considered to be related to the embryonal origin of many cancers, dysregulation of developmental pathways, and the short period of exposure to environmental carcinogens[18]. A remarkable heterogeneity of the types of genetic alterations has been discovered in pediatric cancers, including copy number alterations and structural alterations. The list of cancer predisposition genes associated with CPS is continuing to grow. Some of them are associated with a specific subtype of cancer, whereas germline pathogenic variants in other genes can cause various malignancies. The range of cancers depends on age-specific and tissue-specific predisposition to cancer driver alterations and the biological function of the gene. Moreover, cancer predisposition genes are often associated with cancers that harbor somatic variants of the same gene[20,21]. Selected hereditary syndromes associated with childhood cancers and related genetic alterations are listed in Table 2.

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.

CLINICAL IMPLICATIONS OF GENETIC PREDISPOSITION TO CHILDHOOD CANCER

Identifying children with germline alterations can provide important information for treatment, prevention, surveillance, and genetic counseling. These patients may have increased toxicity to conventional chemotherapy[20,22]. Treatment strategies should, whenever possible, minimize the use of irradiation or alkylating agents that increase the risk of secondary malignancies[18]. There are very few established preventive strategies for children with CPS, such as prophylactic thyroidectomy in children with multiple endocrine neoplasia type 2 and prophylactic colectomy in children with APC-associated polyposis[14]. Focused surveillance protocols can detect early secondary malignancies. They differ between syndromes and integrate imaging (serial ultrasounds, whole-body magnetic resonance imaging) and non-imaging screening elements[5,14,23]. Children and families with a suspected or known CPS should be monitored in specialized centers that provide comprehensive genetic counseling and testing services.

Family medicine and pediatric primary care physicians will likely meet children with major inherited CPS during their practice. Their ongoing role is to recognize signs suggestive of hereditary cancer timely and to refer patients and their families to specialized centers for further evaluation and treatment. Undoubtedly, most cancer predisposition genes are yet to be discovered and characterized. The list of pediatric CPS will steadily grow, and the guidelines for referring children for genetic testing will change over time. Our greater awareness and increasing knowledge of the genetic basis of childhood cancer will have exciting clinical implications in the near future.

CONCLUSION

Genetic predisposition is an important and previously underestimated cause of cancer in children. Studying patients with CPS and underlying mechanisms, by employing comprehensive genomic analyses, is crucial in order to improve preventive strategies, surveillance, adapted treatment, close follow-up, and psychological support of affected children and their families.