42 Familial Tumor Syndromes

Xin Wang, Vijay Ramaswamy, and Michael D. Taylor

Although most tumors of the nervous system occur sporadically, both the central nervous system (CNS) and the peripheral nervous system are affected by a diverse and challenging collection of familial tumor syndromes.¹ Knowledge of these hereditary tumor syndromes is important from a diagnostic, therapeutic, and prognostic standpoint.

In the past many of these syndromes were known as phakomatoses because they involved both the skin and the nervous system. More recently, several genetic syndromes have been described that predispose to brain tumors but do not have cutaneous manifestations. Conversely, some of the classic phakomatoses, like Sturge-Weber, do not predispose to neoplasia. As such, the term phakomatosis is probably best abandoned in favor of cancer predisposition syndrome (CPS). Some CPSs are largely limited to the nervous system (e.g., neurofibromatosis type 2 [NF2]), whereas others predispose to cancers throughout the body (e.g., Li-Fraumeni syndrome). Targeted cancer surveillance and prevention is crucial among patients with an inherited genetic mutation conferring increased susceptibility to certain neoplasia.²

Diagnosing Cancer Predisposition Syndrome

Family History

The clinician should suspect the presence of a CPS whenever there are multiple cancers within a family, or especially multiple cancers within a single individual. Suspicion of a CPS must be tempered by the frequency of the cancer types being diagnosed. For example, two cousins in their 70s with colon cancer, a very common malignancy, are not nearly as alarming as two siblings under the age of 10 with pineoblastoma, a very rare tumor. A CPS should also be suspected when an individual also has one or more congenital anomalies or cutaneous abnormalities. The same genetic mutations that predispose to cancer often cause problems during normal development, such that mutation carriers have both developmental anomalies and cancer. When questioning a family to ascertain the presence of a CPS, the clinician should inquire about relatives with cancer, congenital abnormalities, epilepsy, frequent miscarriages, and psychiatric disorders. In the past, and today in developing countries, a brain tumor diagnosis could be missed or passed off as epilepsy or psychosis. Tumors diagnosed at a very early age like a colon cancer in a teenager should also suggest a CPS. Individuals who present with multiple simultaneous tumors such as synchronous renal and CNS rhabdoid tumors, likely have a CPS. It is not uncommon for family members to change the reported history over time as they recollect additional details prompted by the initial questioning. Questions about family history should probably be asked of every individual, and his or her family, with a primary brain tumor.

Importance of Diagnosis

It is clinically important to make the diagnosis of a CPS. In many cases, the spectrum of neoplastic disease and the natural history is known and can therefore influence future clinical management. For example, the treatment of vestibular schwannoma in a patient with NF2 is very different from the treatment of a sporadic vestibular schwannoma. Some tumors occur only in the setting of a CPS such as subependymal giant cell astrocytoma in tuberous sclerosis, and tumors have a different prognosis when made in the setting of a CPS. For example, malignant astrocytomas in patients with Turcot’s syndrome often have a comparatively mild course as compared with sporadic astrocytomas. The presence of a CPS may ultimately alter therapy for the neoplasm at hand. Sporadic optic gliomas are much more likely to be treated with radiation therapy than are optic gliomas in patients with neurofibromatosis type 1 (NF1) because NF1 patients are prone to developing malignancies after radiation. The clinical or genetic diagnosis of a CPS can profoundly affect individual and family decisions. In some cases interventions may be available to prevent neoplasia. For example, some women who carry mutations in the BRCA breast cancer susceptibility genes are choosing to undergo subcutaneous mastectomy to diminish their eventual chance of developing breast cancer. Similar approaches to prevent brain tumors in patients at risk are not yet available but are being developed in many centers. The ability of genetic tests to rule in or rule out a given genetic disorder can help unaffected individuals avoid a life of surveillance imaging and worry.

Some individuals may choose to alter their plans for procreation based on the presence or absence of a CPS. Excitingly, couples at risk to produce a child with a CPS can now elect to have preimplantation genetic testing, followed by transferring of only mutation-free embryos back to the mother using standard in vitro fertilization (IVF) techniques. This has been used to produce healthy children in cases of NF1, NF2, familial adenomatous polyposis coli, Li-Fraumeni syndrome, and von Hippel–Lindau disease.3,4 Thus, it is important to make the diagnosis of a CPS because it will enable the accurate diagnosis and appropriate treatment of the neoplasm, predict and conduct appropriate surveillance for future neoplasms, in some cases provide prophylaxis against future neoplasia, as well as enable patients to plan their life course and procreation. In many cases, having prior knowledge of a CPS will allow for informed genetic counseling and family planning.

Genetic Considerations

Cancer is caused by DNA mutations that result in the gain of function of proto-oncogenes, or loss of function of tumor suppressor genes. Mutations can exist at the time of conception (germline mutation in every cell of the body), or can arise later in a single cell (somatic mutation). In almost every case, cancer predisposition syndromes are secondary to germline loss of function mutations in tumor suppressor genes. Mutations can be inherited from a parent or occur de novo in the embryo. In almost every case, inheritance of a CPS is autosomal dominant, seen in 50% of children, with variable penetrance. In many cases, the affected gene and chromosomal locus is known, and genetic testing is available. Clinicians and families seeking genetic testing in their community are encouraged to refer the family to a local medical geneticist.

Specific Cancer Predisposition Syndromes

More than 20 CPSs of the nervous system have been well defined, and a great deal more have been described in less detail. The following subsections outline several of the more common and well-characterized syndromes that have prominent CNS manifestations.

Li-Fraumeni Syndrome

Li-Fraumeni syndrome (LFS) was initially recognized by clinicians in the late 1960s who noticed that among their pediatric patients with sarcoma, there was a high incidence of other types of cancer in family members. Individuals with LFS are at increased risk for several malignancies, most notably soft tissue and bone sarcomas, breast cancer, adrenal cortical carcinoma, brain tumors, and leukemia.⁵ The actual diagnosis of LFS is clinical, the definition is a proband under the age of 45 with a sarcoma who has a first-degree relative aged 45 or under with any cancer, and an additional first- or second- degree relative under 45 years in the same lineage with any cancer or a sarcoma. Families with a cancer spectrum similar to LFS who do not meet the criteria for a diagnosis of LFS are often said to have Li-Fraumeni–like (LFL) syndrome.⁶ Criteria for LFL are a proband with any childhood tumor or sarcoma, brain tumor, or adrenocortical tumor under the age of 45 years, plus a first- or second-degree relative with a typical LFS tumor at any age, and another first- or second-degree relative with any cancer under the age of 60.

About 12% of neoplasms seen in LFS families are in the CNS. Brain tumors seen in LFS include astrocytoma, medulloblastoma, primitive neuroectodermal tumor (PNET), choroid plexus carcinoma, and ependymoma. Patients with LFS are at risk to develop multiple tumors over their life span and thus must be observed in perpetuity. The variability in age of onset and spectrum of cancer types among LFS families suggest coexisting genetic events that can modify the underlying contribution of the mutant p53. Recent integrated genomics efforts have identified mutations and polymorphisms in the p53 regulatory pathway, such as the MDM2-SNP309 polymorphism, which significantly decrease the age at onset among carriers.⁷ Prospective biochemical and imaging surveillance has been shown to be feasible in detecting new cancers, and early results suggest a significant increase in survival in families undergoing a surveillance protocol.⁸

Two groups identified germline mutations of the p53 tumor suppressor gene in families with LFS.⁹ About 30% of families with LFS and a higher percentage of LFL families have no detectable p53 mutation. Most germline mutations of p53, localized on chromosome 17p13.1, are located between exons 5 and 8 that encode for the DNA-binding region of the p53 protein. LFS families with a high incidence of brain tumors have been reported, but no clear phenotype–genotype relationships are evident. However, germline missense mutations of p53 result in a more severe phenotype than protein-truncating mutations because individuals with missense mutations in the DNA-binding domain have a higher incidence of cancer and an earlier age at diagnosis. This is consistent with data suggesting that missense mutations can act in a dominant negative manner by binding to and inhibiting wild-type p53 protein.

Animal studies of both p53+/– and p53–/– mice are viable, and both types are predisposed to develop a variety of tumors, especially hematological malignancies and sarcomas.10 They only rarely develop brain tumors. Similarly, nf1 knockout mice do not commonly develop astrocytomas. However, p53+/–nf1+/– mice develop a range of astrocytic tumors with histology very reminiscent of human glial tumors.¹¹ The availability of mice with one mutant and one wild-type p53 allele (p53^R172H/+) has enabled the study of the dominant negative behavior of mutant p53.

Efforts by the International Agency for Research on Cancer (IARC) have resulted in the TP53 Mutation Database, which includes both germline and somatic mutations reported in the literature since 1989. This important resource, which includes data on mutation prevalence and cumulative cancer risk, is invaluable for clinicians when discussing the diagnosis with LFS patients.

Neurofibromatosis Type 1

Neurofibromatosis type 1 is a common autosomal dominant CPS that afflicts one in 3,000 people. It is probably the most common CPS known. Clinical features include skin lesions such as café-au-lait spots, intertriginous freckling, subcutaneous neurofibromas, and various neoplasms such as neurofibromas, plexiform neurofibromas, pilocytic astrocytoma, leukemia, and malignant peripheral nerve sheath tumor (Fig. 42.1).^12,13 Currently, the diagnosis of NF1 is made based on the presence of two of the following clinical features: café-au-lait spots, intertriginous freckling, Lisch nodules, neurofibromas, optic pathway gliomas (OPGs), distinctive bony lesions, and a first- degree family relative with NF1 (see text box).

Pilocytic astrocytoma of the optic pathway is particularly common in patients with NF1, who are also at high risk for developmental delay and cognitive disorders. With both cutaneous and neoplastic manifestations, NF1 is probably the classic phakomatosis. Due to the wide spectrum of disease phenotypes and severity, proper monitoring and thorough screening are critical. The role of genetic testing for asymptomatic patients is currently unclear in NF-1 specifically; genotype– phenotype correlations cannot currently be established.

The NF1 CPS is secondary to germline mutation of the NF1 gene on chromosome 17. This is an extremely large gene that is prone to mutation. As such, up to 50% of cases are new mutations, with the other 50% being inherited from the parents. All patients with an NF1 mutation will have some manifestation of the disease, but its severity is highly variable, even within families.^12,13 The NF1 gene encodes the neurofibromin protein. Importantly, the neurofibromin protein is responsible for inactivating the ras

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