 the most common form of neurofibromatosis, is characterised by the development of benign neurofibromas on or around peripheral nerves (44), whereas in neurofibromatosis type II, the vestibulocochlear nerve develops schwannomas. In the third condition, Schwannomatosis, schwannomas develop on cranial, spinal and peripheral nerves (44).
Neurofibromatosis type I is associated with mutations in the NF1 gene that function in an autosomal dominant fashion (45). NF1 is responsible for the regulation of cell division through the inactivation of RAS-GTP, a fundamental step in the regulation of the RAS and PI3K pathways. In the absence of NF1, signaling is increased through these pathways, resulting in cell proliferation and inhibited apoptosis (45). Approximately half of all neurofibromatosis type I cases are diagnosed without a known family history, and are thought to represent sporadic NF1 mutations (46).
A number of other developmental syndromes are associated with RAS pathway deregulation and are collectively referred to RASopathies (47). Somatic mutations in RAS subtypes occur frequently in human cancers, and germline mutations in these genes are the cause of complex syndromes with increased susceptibility to cancer, such as Noonan syndrome, Costello syndrome, Leopard syndrome and cardio-facio-cutaneous syndrome (48). The genetic characteristics of these conditions and their relationships with cancer development are listed in Table 1. While having some different features, RASopathies have common characteristics including dysmorphic appearance, skin abnormalities, congenital heart disease and an increased risk of malignancies (47). For example, embryonic rhabdomyosarcoma and neuroblastoma develop in up to 20% of Costello syndrome patients (49).
RAS mosaicism occurs when mutations are acquired during the post-zygotic stage, leading to the presence of the mutation in only a subset of cells (50). Often, this condition is identifiable because of the presence of birthmarks such as epidermal nevi or hemangiomas (51), and may confer a predisposition to cancer, according to Knudson’s “two hit” theory (50). Although malignant tumors have only rarely been reported in association with epidermal nevi, the risk of cancer might depend on the extent of mosaicism, the tissues involved, and the specific gene mutation. Also, children who are mosaic for RAS mutations but do not present with skin birthmarks may never be identified as such (50,52). Oncogene mutation mosaicism may therefore contribute to cancer causation to a greater extent than is presently appreciated.
Down syndrome, or constitutional trisomy 21, is the most common human aneuploidy syndrome, and affected children have an elevated risk of acute leukemia which is up to 500-fold higher than that of the general population (53). Approximately 1% of children with Down syndrome develop spontaneously regressing transient myeloproliferative syndrome, acute myeloid leukaemia of Down syndrome, and/or B-lineage acute lymphoblastic leukaemia (53,54), which are commonly linked to dosage effects of chromosome 21 genes (54). Interestingly, acquired trisomy or tetrasomy 21 with the involvement of RUNX1 at chromosome 21q22 has also been described in many children with sporadic leukemias (55).
Trisomy 21 likely contributes to the development of GATA1 mutations, which are a feature of transient myeloproliferative syndrome, and also contribute to acute myeloid leukemia (AML) of Down syndrome (54). GATA1 mutations may also be responsible for the sensitivity of this disease to therapy, which is characterised by high cure rates (54). The molecular etiology of B-precursor acute lymphoblastic leukaemia in Down syndrome is very different, as GATA1 mutations are not detected, and clinical outcomes are worse than in patients without Down syndrome (54). B-precursor acute lymphoblastic leukaemia in Down syndrome is characterised by IKZF1 deletions and JAK2 tyrosine kinase mutations, the latter highlighting the possibility of targeted therapy for these patients (56).
The guidelines for referring cancer patients to genetic testing have changed over the years. For example, since their description, the definitions of Li-Fraumeni and Li-fraumeni-like syndromes have been refined, notably by Chompret et al. (57), where TP53 mutations were expected to be identified in 20% of cases. In a subsequent study, 29% of patients meeting Chompret’s criteria (57) were identified as TP53 mutation carriers (58). DNA sequencing methods also have evolved from gene-specific tests using Sanger sequencing to whole exome or genome next-generation sequencing (59). With the use of next-generation sequencing, the number of recognised cancer predisposing mutations has dramatically increased, and has allowed genetic information to be associated with other medical conditions or drug responses (60).
Genetic testing of cancer patients and their relatives has helped to identify at-risk family members, thereby introducing surveillance and early intervention, and improving survival rates for familial cancers. As an example, a prospective study of asymptomatic germline TP53 mutation carriers showed 100% overall patient survival at 3 years in the enhanced surveillance group, compared with only 21% overall survival in the routine follow-up group (61). Given the complexity and gravity of Li-Fraumeni syndrome, guidelines and recommendations for patient management are extensive, and in addition to an annual physical examination, include age-specific breast cancer monitoring (or preventive mastectomy), colonoscopy every 2-5 years beginning no later than 25 years of age, and organ-targeted surveillance, based on cancers diagnosed in the family (62).
Point mutations in codon 918 of the RET oncogene have been identified in 98% of patients with multiple endocrine neoplasia type 2 (MEN2) (63). Thyroidectomy is recommended within the first 6 months of life, since codon 918 mutations are associated with early onset medullary thyroid cancers (63). For children with neurofibromatosis type I, annual surveillance for ocular signs of optic nerve glioma is recommended until 10 years of age, while annual blood pressure measurement is recommended for phaeochromocytoma detection (64). Individuals with neurofibromatosis type II are frequently screened to detect early acoustic neuroma, since surgery for hearing preservation has best chance of success when lesions are small at diagnosis (65). Similarly, the detection of RB1 mutations and early treatment of retinoblastoma has been shown to increase ocular retention and preserve vision (66), while screening for pineal tumors has increased the 5-year survival of trilateral retinoblastoma from 0% to 27% (67). Since the risk of developing Wilms’ tumor can be as high as 50% in children harbouring germline WT1 alterations, frequent renal ultrasounds are recommended from the age of syndrome diagnosis up to 5-7 years of age (68). Another example of successful intervention is the improved quality of life in children with familial adenomatous polyposis through enrolment on chemoprevention trials with celecoxib, which led to reduced colorectal polyp formation and delayed colectomies (69). Moreover, offering these patients prophylactic surgery significantly reduces mortality from colorectal cancer (70).
The growing use of genome-wide screening (71) and next-generation sequencing methods brings with it the possibility of identifying unexpected cancer-predisposing gene mutations, for example in members of unaffected families who have acquired de novo variations, as well as variations of unknown significance (72). These increasingly frequent scenarios highlight the importance of ethical approaches to the disclosure of incidental findings (73), and the psychological support needed by patients and families affected by cancer syndromes (74).
Although tumor predisposition underlies a comparatively small proportion of childhood cancer cases, the early age of diagnosis suggests that inherited cancer predisposition may underly a greater proportion of cases than is currently appreciated (69). The continued application of next-generation sequencing to childhood cancer patients and their family members will be expected to identify mutations in known cancer predisposition genes that have been previously associated with early onset adult cancer, as well as germline mutations in genes that are known to be somatically mutated in the same or other cancer types. Previously unrecognised tumor predisposition genes may also be uncovered through the study of patients with very rare cancers and/or unusual clinical presentation or features. Our current understanding of the genetic basis of tumor predisposition has already allowed the development of genetic tests that can assist in planning a life-long series of interventions that can include counselling, prevention, surveillance and early treatment, in the event of a cancer diagnosis. Expanding our knowledge of the genetic basis of cancer predisposition in children will have the exciting consequence of extending these benefits to larger numbers of patients and their families.
Funding: This publication was supported by funding to the Kids Cancer Alliance from the Cancer Institute NSW (Grant ID: 11/TRC/1-03), and from the University of Sydney.
Vogelstein B, Kinzler KW. eds. The Genetic Basis of Human Cancer. New York: McGraw Hill, 2002.
Schneider K, Zelley K, Nichols KE, et al. Li-Fraumeni Syndrome. In: Pagon RA, Adam MP, Ardinger HH, et al. eds. GeneReviews®. University of Washington: Seattle, WA, 2013.
scooters do often drive in between lanes, usually to get to the front of the intersection at a red light. if you look in front of that beige SUV, there is a white box marked at the edge of the intersection. it's intended for scooters to wait there when the light is red. in busy intersections, there may be another white box just inside the intersection for cross-traffic scooters to stop and wait to make a left-turn. here's an example from a youtube thumbnail [https://i.ytimg.com/vi/g4i47vTsVR8/maxresdefault.jpg](https