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1 Introduction

More attention has been paid to the inherited nature of malignant tumors in children and adolescents, lately. Children with rare tumors may be at an increased risk of cancer because of a known cancer predisposition syndrome as Li-Fraumeni syndrome in case of adrenocortical tumors or multiple endocrine neoplasia (MEN2) in case of medullary thyroid tumors. Such cancer syndromes are commonly suspected in case of multiple malignancies within a family or a patient himself and/or in case of an adult-type tumor in children or adolescents. Interestingly though, it could be shown that strong predisposing mutations like BRCA1 and BRCA2, leading to individual risks of breast cancer of around 60% by age 70, together account for less than 5% of overall breast cancer incidence (Ponder 2001). Also, pediatric oncologists are not trained to pick up minor signs of cancer susceptibility, and therefore, syndromes might be overlooked. As discussed further down, it could be shown that the prevalence of minor and major morphological abnormalities is higher in patients with childhood cancers compared with controls – once more stressing the importance of constitutional genetic defects in pediatric oncogenesis and maybe pointing to so far unknown predisposition syndromes (Merks et al. 2008). This article gives an overview of mechanisms leading to cancer susceptibility, of known cancer syndromes (Table 6.1), and of the diagnostic approach and management, which can be followed in case of a suspected genetic predisposition for cancer. Within the single chapters of this book discussing the etiology of specific rare entities, several cancer syndromes are mentioned. Please refer to these chapters for detailed information on specific cancer syndromes and related malignancies.

Table 6.1 Childhood tumor predisposition syndromes
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2 Hallmarks of Cancer Cells

Each cancer has traveled a specific route to arrive at its full phenotype. However, this multistep process can be reduced to a specific spectrum of acquired dysregulated cellular properties. Hanahan and Weinberg (2000) identified six ‘hallmark characteristics’ of the cancer cell phenotype:

  1. 1.

    Self-sufficiency in growth signals: Normal cells depend on mitogenic growth signals before they can enter a proliferative phase. Growth signals are transmitted to the cell via transmembrane receptors, binding three classes of signaling molecules: diffusible growth factors, extracellular matrix (ECM) components, and cell-to-cell adhesion/interaction molecules. Self-sufficiency in growth signals can be achieved by three mechanisms: (a) autocrine stimulation, i.e., cells producing their own growth factors; (b) transmembrane receptors abnormalities, such as overexpression of receptors (making the cell hyperresponsive to normal levels of growth factors), structural alterations of receptors leading to ligand independent signaling, or changes in the type of expressed ECM receptors (integrins), favoring pro-growth signals; and (c) alterations of the intracellular signaling circuit, e.g., the SOS-Ras-Raf-MAP kinase pathway playing a central role in signaling downstream of receptor tyrosine kinases (RTKs; binding diffusible growth factors) and integrins (Fig. 6.1, Hanahan and Weinberg 2000).

    Fig. 6.1
    figure 1_6

    The emergent integrated circuit of the cell (Courtesy of Hanahan and Weinberg 2000, with permission from Elsevier)

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  2. 2.

    Insensitivity to antigrowth signals: Antigrowth signals are essential to block a cell from entering from the G1 into the S phase by inducing a quiescent (G0) state or postmitotic differentiation. Similar to growth factor signaling, antigrowth factors (soluble factors and immobilized factors embedded in the ECM) have their effect via binding to specific ­transmembrane receptors, inducing an intracellular signaling cascade. The intranuclear retinoblastoma protein (Rb-protein) has a central role here; in a hypophosphorylated state, Rb-protein binds to and inactivates the E2F transcription factors that control the expression of groups of genes essential for progression from G1 into S phase, blocking the cell from progression to the S phase (Weinberg 1995) (Fig. 6.1). Normal cells are responsive to soluble antigrowth signals such as TGF-β that binds to its receptor (TGF-βR), signaling successively downstream via Smad4, p15 (INK4B), the CyclinD-CDK4 complex, eventually keeping the Rb-protein in a hypophos­phorylated state (Fig. 6.1), thus blocking cell progression to a proliferative state. Disruption of the several steps of this pathway may result in insufficient response to antigrowth signals, making the cell insensitive to physiological growth inhibitory factors.

  3. 3.

    Evading apoptosis: Sensors and effectors constitute a complex circuit monitoring the intra- and extracellular environment for (ab)normalities and determining whether the cell should live or enter a phase of programmed cell death. Extracellular survival signals (e.g., IGF-1, IGF-2, and IL-3) and death signals (e.g., Fas ligand and TNFα) bind to their corresponding receptors (Fig. 6.1). Together with intracellular sensor signals, many converge on the mitochondria via different (often interacting) pathways such as the PI3–AKT pathway, members of the Bcl-2 family of proteins, and p53. When pro-apoptotic signals predominate, mitochondria release cytochrome C, catalyzing apoptosis. The ultimate effectors of apoptosis are a family of proteases, termed caspases, finally executing the death program (Fig. 6.1). Alterations in the several steps of this complex network, either potentiating the inhibitors of apoptosis (e.g., the upregulation of the Bcl-2 oncogene in lymphoma (Korsmeyer 1992)) or restraining the physiological death signals or apoptosis effectors (e.g., the epigenetic silencing of caspase 8 in neuroblastoma (Teitz et al. 2000)), withdraw the cell from its physiological “health security system.”

  4. 4.

    Limitless replicative potential: Each cell seems to have a “counting device” for cell generations, called telomeres; the ends of chromosomes are composed of thousands of repeats of a short 6-base pair sequence element. Each cell replication leads to loss of 50–100 base pairs of the telomeric DNA of both ends of each chromosome. Multiple replications will lead to progressive shortening of the telomere ends, finally disabling the protective function of the telomeres after 60–70 replications (in cultured cells). This then leads to end-to-end chromosomal fusions, finally resulting in the death of the affected cell (Hayflick 1997). Telomere maintenance is a capacity virtually all cancers have obtained, either by upregulating expression of the telomerase enzyme (which adds hexanucleotide repeats onto telomeric ends) or by activating ALT, which maintains telomeres through recombination-based interchromosomal exchanges of sequence information.

  5. 5.

    Sustained angiogenesis: Like normal cells, tumor cells depend on nutrients and oxygen, obliging them to reside within 100 μm of a capillary. In a physiological state, proliferating cells are unable to induce angiogenesis. Tumor progression requires the neoplastic cells to gain angiogenic ability. Many tumors show increased expression of soluble growth factors like VEGF and FGF, both binding to their corresponding transmembrane tyrosine kinase receptors on endothelial cells. On the other hand, endogenous angiogenesis inhibitors, such as thrombospondin-1 or β-interferon, may be downregulated. Integrins and adhesion molecules, respectively mediating cell-matrix and cell-cell adhesion, play crucial roles in the regulation of angiogenesis. Proteases in the ECM can control the bioavailability of angiogenic activators and inhibitors. Disturbances at the different levels of the “angiogenic switch” may result in a sustained pro-angiogenic state.

  6. 6.

    Tissue invasion and metastasis: Cadherins, cell adhesion molecules (CAMs) (Cavallaro and Christofori 2004), integrins, and proteases (Fig. 6.1) play key roles in the ability of cancer cells to become invasive or metastatic. Normal epithelial cells show intercellular E-cadherin bridges with their neighbors, resulting in antigrowth signals via β-catenin. In most epithelial cancers this pathway is disrupted. Changes in the isoform of the cell adhesion molecule N-CAM, from a highly adhesive to a poorly adhesive or even repulsive isoform, and reductions in overall expression of the N-CAM molecule will lead to reduced cell-cell adhesion, favoring the metastatic capacity of tumor cells. Alterations of integrin expression enable the adaptation of tumor cells to a changing microenvironment in their invasive and metastatic journeys. Finally, upregulation of protease genes and downregulation of protease inhibitor genes will enable the docking of active proteases on the cancer cell surface, facilitating invasion of cancer cells into nearby structures.

3 Acquisition of Tumorigenic Alterations

Apparent from the six hallmarks, for a cell to become a cancer cell, multiple (epi)genetic changes have to occur to establish conflict with maintenance of genomic integrity. Acquired or constitutive malfunction of genomic caretaker systems is often required to allow cells to take the multiple steps on the cancer ladder.

Host factors influencing the acquisition of tumorigenic alterations: The several steps in the evolution of a cancer are influenced by multiple factors from in and outside the cell (Fig. 6.2; Ponder 2001 and references therein (Ponder 2001)).

Fig. 6.2
figure 2_6

A framework for genetic effects on cancer development (Courtesy of Bruce Ponder 2001, with permission from Nature Publishing Group).

Horizontal arrows represent the successive pathway events giving the cell the full cancer phenotype. Many are somatic events, but in inherited cancer predisposition syndromes, one of the events is inherited. The diverging arrows on the right represent the variety of events that can lead to overtly similar cancers. Vertical arrows represent pathway event influencing factors

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3.1 Factors Affecting the Probability that Tumorigenic Alterations Will Occur

External influences include environmental exposures, such as cigarette smoke, diet, or UV-light exposure, the response to which may be modified by genetic variation in intra- and extracellular metabolism (Peto 2001). For example, less than 20% of smokers develop lung cancer, indicating that many host factors determine individual ­susceptibility, such as extent of carcinogen uptake, metabolic activation and detoxification, DNA repair ability, apoptosis and varying effects on genes in signal transduction pathways, and regulation of the cell cycle (Hecht 2002).

3.2 Factors that Influence the Effects of Tumorigenic Alterations

Variation of intracellular factors will modify the effect of a particular genetic pathway event on the cellular phenotype, or its response to signals from outside. Paracrine interactions with neighboring cells, systemic effects from circulating hormones or growth factors, and immunologic responses of the host comprise some of the external factors that modulate the effects of pathway events (Tlsty and Hein 2001; Dranoff 2004). Genetic variation of these factors probably accounts for much of the low-level predisposition to cancer, as it occurs in the “normal” population (Ponder 2001; Nadeau 2001).

4 Cancer Predisposition

Family history and clinical phenotype are the cardinal aspects of inherited tumor predisposition syndromes. In his review on cancer genetics, Ponder discerned strong and weak tumor predisposition (Ponder 2001). Paradoxically, the largest category of inherited tumor predisposition, in terms of its contribution to cancer incidence, is the one with the weakest genetic effects: tumor predisposition without evident family clustering, apparently caused by low-penetrance tumor predisposition genes. For example, in breast cancer, the strongly predisposing mutations in BRCA1 and BRCA2 lead to individual risks of around 60% by age 70. However, their combined contribution to overall breast cancer incidence is less than 5%. By contrast, a weak tumor predisposition gene, with a relative breast cancer risk of 2 and a population frequency of 20%, could account for up to 20% of breast cancer incidence (Ponder 2001).

Strong cancer predisposition: Strong tumor predisposition syndromes result from inheritance of either one of the events on the cancer pathway or a defective DNA repair system. Most syndromes show tissue specificity, although reasons for specific patterns of expression are mostly unclear. Another important characteristic is the variability of cancer incidence, and the type of cancers occurring within a given syndrome, but also within a single family. The within-syndrome variation can be accounted for by several factors: different germ line genes causing the same syndrome or different mutations in the same gene causing the same syndrome, genetic modifiers, environmental influences, or chance.

The within-family variation most probably is accoun­ted for by the effects of genetic modifiers (Ponder 2001).

Weak cancer predisposition: Weak predisposition may result from weak alleles of the pathway or caretaker genes and from genetic variations of host factors influencing cancer development, as depicted in Fig. 6.2. These genes might be collectively called low-penetrance tumor predisposing genes. As described above, the word “weak” is misleading: Low-penetrance genes are thought to account for a relatively large part of cancer incidence, and studying them may provide much information about many ­different cancers, with important potential public health implications.

5 Syndromes and Childhood Cancer

Cancer syndromes account for approximately 5–10% of all cancers in adulthood. Our understanding of familial cancer syndromes is increasing rapidly, with the emphasis shifting towards early detection of at-risk families. Anyway, so far, not much is known about the exact risk of children to be affected of malignant tumors in case of a cancer syndrome, and specific prevention programs are to be established.

To establish the incidence and spectrum of malformation syndromes associated with childhood cancer, Merks et al. (2005a) performed a clinical morphological examination on a series of 1,073 children with cancer. A syndrome was diagnosed in 42 patients (3.9%) and the presence of a syndrome suspected in another 35 patients (3.3%), for a total of 7.2%. Twenty of the 42 syndrome diagnoses were not recognized in the patients prior to this study, indicating that these diagnoses are commonly missed. Therefore, all children with a malignancy should be examined by a clinical geneticist or a pediatrician skilled in clinical morphology. Besides the known syndromes, new tumor predisposition syndromes can be recognized as a result of such a meticulous clinical genetic evaluation of a large cohort of childhood cancer patients (Merks et al. 2008).

An overview of syndromes with concurring tumors in childhood is presented in Table 6.1. Most tumor syndromes in childhood are listed, together with main references and a summary of their (presumed) ­pathogenic pathway. The role of metabolic defects in cancer development and pediatric syndromes appears to be of growing importance; a few well-known examples are listed too. For details on gastrointestinal cancer predisposition syndromes refer to Chap. 30.

In recent years, it has become apparent that biallelic mutation carriers of autosomal dominant adult cancer syndromes are at a very high risk of developing specific childhood cancers often at a very young age (Rahman and Scott 2007). Biallelic mutations of BRCA2 lead to the autosomal recessive childhood cancer syndrome Fanconi anemia D1. Biallelic mutations in the mismatch repair deficiency genes MSH2, MLH1, MSH6, and PMS2 lead to a mismatch-repair-deficiency syndrome with childhood malignancies occurring at a very young age, while monoallelic mutation carriers develop hereditary nonpolyposis colorectal cancer.

6 Diagnostic Approach and Management in Case of Suspected Genetic Predisposition

Hereditary malignant tumors tend to occur in an earlier stage of life than the same tumor occurring sporadically. It is difficult to decide when an inherited cancer predisposition should be considered. One should suspect the presence of a tumor predisposition syndrome in case:

  • An increased number of family members are diagnosed with cancer, e.g., two or more close relatives have had the same type of malignancy or two and more siblings develop a malignancy.

  • A malignant tumor is diagnosed at an unusual early stage of life.

  • Clustering of malignant tumors related to a known cancer syndrome is seen within a family (e.g., NCCN guidelines, link: http://www.nccn.org/index.asp).

  • Clustering of rare malignant tumors (e.g., sarcomas) within a family is seen (see Table 6.1 for associated syndromes).

  • More than one primary cancer is diagnosed within the patient.

  • Of the presence of precursor lesions or specific benign tumors, e.g., adenomatous polyps in case of familial adenomatous polyposis, atypical, dysplastic nevi of the skin in case of hereditary melanoma, or lipomas in case of multiple endocrine neoplasia type 1.

A family tree from each side of the family should be constructed. It should include specific information on cancer types, syndromes, and other health conditions possibly related to certain malignancies. Generally speaking, the closer the relationship to the patient, the more detailed information is needed. As most familial cancer syndromes are inherited autosomal dominant, malignant tumors are found in successive generations.

In addition to the family history, the clinical examination is an essential part of a screening exam for cancer predisposition. As discussed above, half of tumor predisposition syndromes are missed by pediatric oncologists (Merks et al. 2005). Therefore, we strongly feel that all children with a malignancy should be examined by a clinical geneticist or a pediatrician skilled in clinical morphology in order to evaluate for morphological abnormalities. Internet databases and handbooks can help classifying and interpreting morphological abnormalities (Jones 2006; Winter and Baraitser 2009; Sijmons http://www.facd.info). However, those databases work best for clinical geneticists trained in this field.

After all, it is important to be aware of a possible underlying genetic predisposition in any case of rare pediatric tumor. In fact, many pediatric cancers are very rare diseases in itself, and therefore every child deserves a clinical genetic examination once in the course of its disease.

6.1 Management in Case of Cancer Predisposition

Familial cancer syndromes and most associated malignant tumors are extremely rare in children. Therefore, it is important to get help from physicians who are expert in the field of these rare entities, and a multidisciplinary approach has to be coordinated. Patients with genetic predisposition to cancer may have other diseases and conditions (such as endocrine disorders and immune defects) which make a comprehensive approach crucial.

Ideally, a personalized plan in order to reduce the risk of a malignancy should be developed for the patient and/or family members. This plan may include:

  • Annual physical exams with additional examinations depending on the specific rare tumors that have occurred in the family

  • Evaluation of any symptoms, even though they may resemble common diseases, that have persisted for several weeks, such as abdominal pain, bone pain, growths, headaches, etc.

  • Education and awareness of the signs and symptoms of cancer

  • Recommendations for changes in lifestyle, such as diet, exercise, and other factors

  • Genetic testing

  • Participation in clinical trials to prevent and detect cancer

  • Psychological support

Although genetic testing is available for many familial cancer syndromes, there are genes that have yet to be discovered. Although many hospitals in the US have a “familial cancer clinic,” which is a team of health professionals with expertise in familial cancer syndromes, this is still not the case in most countries. In general, geneticists, oncologists, and social workers have to work together in order to assist individuals and families by providing risk assessment, support, screening and prevention recommendations, and genetic testing options.