Childhood Cancers

Lee J. Helman

David Malkin

The biologic nature of tumors of childhood is clinically, histopathologically, and biologically distinct from that of adult-onset malignancies. Childhood cancers tend to have short latency periods, are often rapidly growing and aggressively invasive, are rarely associated with exposure to carcinogens implicated in adult-onset cancers, and are generally more responsive to standard modalities of treatment, in particular chemotherapy. Most childhood tumors occur sporadically in families with at most a weak history of cancer. In at least 10% to 15% of cases, however, a strong familial association is recognized or the child has a congenital or genetic disorder that imparts a higher likelihood of specific cancer types.¹ Examples of genetic disorders that render a child at increased risk of tumor development include xeroderma pigmentosa, Bloom syndrome, or ataxia-telangiectasia, which predispose to skin cancers, leukemias, or lymphoid malignancies, respectively. In all three cases, constitutional gene alterations that disrupt normal mechanisms of genomic DNA repair are blamed for the propensity to cell transformation. Other hereditary disorders, including Beckwith-Wiedemann syndrome (BWS), von Hippel-Lindau disease, Rothmund-Thomson syndrome, and the multiple endocrine neoplasias types 1 and 2, are thought to be associated with their respective tumor spectra through constitutional activation of molecular pathways of deregulated cellular growth and proliferation. The cancers that occur in these syndromes are generally secondary phenotypic manifestations of disorders that have distinctive recognizable physical stigmata. On the other hand, some cancer predisposition syndromes are recognized only by their malignant manifestations, with nonmalignant characteristics being virtually absent. These include hereditary retinoblastoma, Li-Fraumeni syndrome (LFS), familial Wilms tumor, and familial adenomatous polyposis coli. Each of these presents with distinct cancer phenotypes, and the identified molecular defect is unique for each (Table 29.1). Careful attention to detailed cancer family histories continues to lead to the discovery of new cancer predisposition syndromes and the coincident identification of novel cancer genes.²

The study of pediatric cancer and rare hereditary cancer syndromes and associations has led to the identification of numerous cancer genes, including dominant oncogenes, DNA repair genes, and tumor suppressor genes. These genes are important not only in hereditary predisposition but also in the normal growth, differentiation, and proliferation pathways of all cells. Alterations of these genes have been consistently found in numerous sporadic tumors of childhood and led to studies of their functional role in carcinogenesis. The numerous properties of transformed malignant cells in culture or in vivo can be explained by the complex abnormal interaction of numerous positive and negative growth-regulatory genes. Pediatric cancers offer unique models in which to study these pathways in that they are less likely to be disrupted by nongenetic factors. The embryonic ontogeny of many childhood cancers suggests that better understanding of the nature of the genetic events leading to these cancers will also augment the understanding of normal embryologic growth and development.

This chapter begins with an outline of tumor suppressor genes—the most frequently implicated class of cancer genes in childhood malignancy. This leads into a discussion of molecular features of retinoblastoma, the paradigm of cancer genetics, followed by analysis of the molecular pathways associated with other common pediatric cancers. Evaluations of the importance of molecular alterations in familial cancers, as well as new approaches in molecular therapeutics, are also addressed.

TUMOR SUPPRESSOR GENES

Faulty regulation of cellular growth and differentiation leads to neoplastic transformation and tumor initiation. Many inappropriately activated growth-potentiating genes, or oncogenes, have been identified through the study of RNA tumor viruses and the transforming effects of DNA isolated from malignant cells. However, activated dominant oncogenes themselves do not readily explain a variety of phenomena related to transformation and tumor formation. Among these is the suppression of tumorigenicity by fusion of malignant cells with their normal counterparts. If these malignant cells carried an activated dominant oncogene, it would be expected that such a gene would initiate transformation of the normal cells, likely leading to either embryonic or fetal death. The observation is more readily explained by postulating the existence of a factor in the normal cell that acts to suppress growth of the fused malignant cells. Malignant cells commonly exhibit specific chromosomal deletions (Table 29.2). The best example of this occurs in retinoblastoma, a rare pediatric eye tumor in which a small region of the long arm of chromosome 13 is frequently missing. The presumed loss of genes in specific chromosomal regions argues strongly against the concept of a dominantly acting gene being implicated in the development of the tumor. Hereditary forms of cancer are not readily explained by altered growth-potentiating genes. Comparisons between the frequencies of familial tumors and their sporadic counterparts led Knudson³ to suggest that the familial forms of some tumors could be explained by constitutional mutations in growth-limiting genes. The resulting inactivation of these genes would facilitate cellular transformation.⁴ Such growth-limiting genes were termed tumor suppressor genes.

TABLE 29.1 HEREDITARY SYNDROMES ASSOCIATED WITH CHILDHOOD CANCER PREDISPOSITION

Syndrome	OMIM Entry^a	Major Tumor Types	Mode of Inheritance	Genes
HEREDITARY GASTROINTESTINAL MALIGNANCIES
Adenomatous polyposis of the colon	175100	Colon, thyroid, stomach, intestine, hepatoblastoma	Dominant	APC
Juvenile polyposis	174900	Gastrointestinal	Dominant	SMAD4/DPC4
Peutz-Jeghers syndrome	175200	Intestinal, ovarian, pancreatic	Dominant	STK11
GENODERMATOSES WITH CANCER PREDISPOSITION
Nevoid basal cell carcinoma syndrome	109400	Skin, medulloblastoma	Dominant	PTCH
Neurofibromatosis type 1	162200	Neurofibroma, optic pathway glioma, peripheral nerve sheath tumor	Dominant	NF1
Neurofibromatosis type 2	101000	Vestibular schwannoma	Dominant	NF2
Tuberous sclerosis	191100	Hamartoma, renal angiomyolipoma, renal cell carcinoma	Dominant	TSC1/TSC2
Xeroderma pigmentosum	278730, 278700, 278720, 278760, 278740, 278780, 278750, 133510	Skin, melanoma, leukemia	Recessive	XPA,B,C,D,E,F,G, POLH
Rothmund Thomson syndrome	268400	Skin, bone	Recessive	RECQL4
LEUKEMIA/LYMPHOMA PREDISPOSITION SYNDROMES
Bloom syndrome	210900	Leukemia, lymphoma, skin	Recessive	BLM
Fanconi anemia	227650	Leukemia, squamous cell carcinoma, gynecological system	Recessive	FANCA,B,C,D₂, E,F,G
Shwachman Diamond syndrome	260400	Leukemia/myelodysplasia	Recessive	SBDS
Nijmegen breakage syndrome	251260	Lymphoma, medulloblastoma, glioma	Recessive	NBS1
Ataxia telangiectasia	208900	Leukemia, lymphoma	Recessive	ATM
GENITOURINARY CANCER PREDISPOSITION SYNDROMES
Simpson-Golabi-Behmel syndrome	312870	Embryonal tumors, Wilms tumor	X-linked	GPC3
Von Hippel-Lindau syndrome	193300	Retinal and central nervous hemangioblastoma, pheochromocytoma, renal cell carcinoma	Dominant	VHL
Beckwith-Wiedemann syndrome	130650	Wilms tumor, hepatoblastoma, adrenal carcinoma, rhabdomyosarcoma	Dominant	CDKN1C/NSD1
Wilms tumor syndrome	194070	Wilms tumor	Dominant	WT1
WAGR syndrome	194072	Wilms tumor, gonadoblastoma	Dominant	WT1
Costello syndrome	218040	Neuroblastoma, rhabdomyosarcoma, bladder carcinoma	Dominant	H-Ras
CENTRAL NERVOUS SYSTEM PREDISPOSITION SYNDROMES
Retinoblastoma	180200	Retinoblastoma, osteosarcoma	Dominant	RB1
Rhabdoid predisposition syndrome	601607	Rhabdoid tumor, medulloblastoma, choroid plexus tumor		SNF5/INI1
Medulloblastoma predisposition	607035	Medulloblastoma	Dominant	SUFU
SARCOMA/BONE CANCER PREDISPOSITION SYNDROMES
Li-Fraumeni syndrome	151623	Soft tissue sarcoma, osteosarcoma, breast, adrenocortical carcinoma, leukemia, brain tumor	Dominant	TP53
Multiple exostosis	133700, 133701	Chondrosarcoma	Dominant	EXT1/EXT2
Werner syndrome	277700	Osteosarcoma, meningioma	Recessive	WRN
ENDOCRINE CANCER PREDISPOSITION SYNDROMES
MEN1	131000	Pancreatic islet cell tumor, pituitary adenoma, parathyroid adenoma	Dominant	MEN1
MEN2	171400	Medullary thyroid carcinoma, pheochromocytoma, parathyroid hyperplasia	Dominant	RET
WAGR, Wilms tumor, aniridia, genitourinary abnormalities, mental retardation; MEN, multiple endocrine neoplasia.
^aOnline Mendelian Inheritance in Man, http://www-ncbi-nlm-nih-gov.proxy3.library.mcgill.ca/Omim/getmorbid.cgi. (Adapted from ref. 137.)

Whereas acquired alterations of dominant oncogenes most commonly occur in somatic cells, mutant tumor suppressor genes may be found either in germ cells or somatic cells. In the former, they may arise de novo or be transmitted from generation to generation within a family. The diversity of functions, cellular locations, and tissue-specific expression of the tumor suppressor genes suggest the existence of a complex, yet coordinated, cellular pathway that limits cell growth by linking nuclear processes with the intra- and extracytoplasmic environment. This discussion is limited to those genes for which pediatric tumors are frequently associated.

TABLE 29.2 COMMON CYTOGENETIC REARRANGEMENTS IN SOLID TUMORS OF CHILDHOOD

Solid Tumor	Cytogenetic Rearrangement	Genes^a
Ewing sarcoma	t(11;22) (q24;q12), +8	EWS(22) FLi-1(11)
Neuroblastoma	del1p32-36, DMs, HSRs, +17q21-qter	N-MYC
Retinoblastoma	del13q14	Rb
Wilms tumor	del11p13, t(3;17)	WT1
Synovial sarcoma	t(X;11) (p11;q11)	SSX(X) SYT(18)
Osteogenic sarcoma	del13q14	?
Rhabdomyosarcoma	t(2;13) (q37;q14), t(2;11),3p-,11p-	PAX3(2) FKHR(13)
Peripheral neuroepithelioma	t(11;22) (q24;q12), +8	EWS(22) FLi-1(11)
Astrocytoma	i(17q)	?
Meningioma	delq22, -22	MN1, NF2, ?
Atypical teratoid/rhabdoid tumor	delq22.11	SNF 5
Germ cell tumor	i(12p)
^aChromosomal location in parentheses.

RETINOBLASTOMA: THE PARADIGM

Retinoblastoma is the prototype cancer caused by mutations of a tumor suppressor gene. It is a malignant tumor of the retina that occurs in infants and young children, with an incidence of approximately 1:20,000.⁵ Approximately 40% of retinoblastoma cases are of the heritable form in which the child inherits one mutant allele at the retinoblastoma susceptibility locus (Rb1) through the germ line, and a somatic mutation in a single retinal cell causes loss of function of the remaining normal allele, leading to tumor formation. Tumors are often bilateral and multifocal. The disease is inherited as an autosomal dominant trait, with a penetrance approaching 100%.⁶ The remaining 60% of retinoblastoma cases are sporadic (nonheritable), in which both Rb1 alleles in a single retinal cell are inactivated by somatic mutations. As one can imagine, such an event is rare, and these patients usually have only one tumor that presents itself later than in infants with the heritable form. Fifteen percent of unilateral retinoblastoma is heritable⁶ but by chance develops in only one eye. Survivors of heritable retinoblastoma have a several 100-fold increased risk of developing mesenchymal tumors such as osteogenic sarcoma, fibrosarcomas, and melanomas later in life.⁷ It is thought that several genetic mechanisms may be involved in elimination of the second wild type Rb1 allele in an evolving tumor. These mechanisms include chromosomal duplication or nondisjunction, mitotic recombination, or gene conversion.⁸

The Rb1 gene was eventually mapped to chromosome 13q14.⁹ Using Southern blot analysis, it was then possible to demonstrate that the second target gene that led to disease was actually the second copy of the Rb1 locus. Reduction to homozygosity of the mutant allele (or loss of heterozygosity [LOH] of the wild type allele) would lead to the loss of functional Rb1 and account for tumor development.

Using classic cloning techniques, a 4.7-kb complementary DNA fragment was isolated from retinal cells.¹⁰ This gene, Rb1, consisted of 27 exons and encoded a 105-kD nuclear phosphoprotein. As well as being altered in retinoblastoma, this gene and its protein product have been found to be altered in osteosarcomas, small cell lung carcinomas, and bladder, breast, and prostate carcinomas.¹⁰,¹¹ Rb1 plays a central role in the control of cell-cycle regulation, particularly in determining transition from G₁ through S (DNA synthesis) phase in virtually all cell types.

Although it is clear that Rb1 and its protein product play some role in growth regulation, the precise nature of this role remains obscure. In the developing retina, inactivation of the Rb1 gene is necessary and sufficient for tumor formation.¹² It is now clear, however, that these tumors develop as a result of a more complex interplay of aberrant expression of other cell-cycle control genes. In particular, a tumor surveillance pathway mediated by Arf, MDM2, MDMX, and p53 (see later discussion) is activated after loss of Rb1 during development of the retina. Rb1-deficient retinoblasts undergo p53-mediated apoptosis and exit the cell cycle. Subsequently, amplification of the MDMX gene and increased expression of MDMX protein are strongly selected for during tumor progression as a mechanism to suppress the p53 response in Rb1-deficient retinal cells.¹³ Not only do these observations provide a provocative biological
mechanism for tumor formation in retinoblastoma, but it also offers potential molecular targets for novel therapeutic approaches to this tumor.¹⁴,¹⁵ Although the Rb1 gene is expressed in virtually all mammalian tissues, only in the retina is its inactivation sufficient for tumor initiation. On the other hand, some Rb1 mutations appear to lead to an attenuated form of the disease, an observation that highlights the variable penetrance in families.¹⁶,¹⁷ Outside the retina, Rb1 inactivation is often a rate-limiting step in tumorigenesis generated by multiple genetic events. The molecular characteristics and potential functional activities of Rb1 are outlined in detail elsewhere in this volume.

The patterns of inheritance and presentation of retinoblastoma have been well described and the responsible gene identified. The basic mechanisms by which the gene is inactivated are understood, and provocative evidence indicates that the intricate functional interactions of pRB with its binding partners and other cell cycle targets will provide targets for development of novel small molecule therapies.

WILMS TUMOR: THREE DISTINCT LOCI

Wilms tumor, or nephroblastoma, is an embryonal malignancy that arises from remnants of an immature kidney. It affects approximately 1:10,000 children, usually before the age of 6 years (median age at diagnosis, 3.5 years). Five percent to 10% of children present with either synchronous or metachronous bilateral tumors. A peculiar feature of Wilms tumor is its association with nephrogenic rests, foci of primitive but nonmalignant cells whose persistence suggests a defect in kidney development. These precursor lesions are found within the normal kidney tissue of 30% to 40% of children with Wilms tumor. Nephrogenic rests may persist, regress spontaneously, or grow into a large mass that simulates a true Wilms tumor and presents a difficult diagnostic challenge.¹⁸ Another interesting feature of this neoplasm is its association with specific congenital abnormalities, including genitourinary anomalies, sporadic aniridia, mental retardation, and hemihypertrophy. The WT1 tumor suppressor gene is reduced to homozygosity, at least in part, in a small but highly informative set of sporadic Wilms tumors. In addition, sporadic and hereditary Wilms tumors have been described in which WT1 is specifically altered.

A genetic predisposition to Wilms tumor is observed in two distinct disease syndromes with urogenital system malformations: the WAGR (Wilms tumor, aniridia, genitourinary abnormalities, mental retardation) syndrome and the Denys-Drash syndrome (DDS)¹⁹ as well as in BWS, a hereditary overgrowth syndrome characterized by visceromegaly, macroglossia, and hyperinsulinemic hypoglycemia.²⁰ These congenital disorders have now been linked to abnormalities at specific genetic loci implicated in Wilms tumorigenesis.

The WAGR syndrome has been correlated with constitutional deletions of chromosome 11q13.²¹ Whereas it is now known that the WAGR deletion encompasses a number of contiguous genes, including the aniridia gene Pax6,²² the cytogenetic observation in patients with WAGR was also important in the cloning of the WT1 gene at chromosome 11p13.²³,²⁴,²⁵

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