Genetic Issues in Pediatric Cancers
by Beth A. Pletcher, MD, November 1999

Although retinoblastoma and Wilms tumor are the most well known pediatric cancers associated with a "genetic risk", a number of other tumor types and familial cancer syndromes can impact pediatric patients. As advances are made in the understanding of gene mutations leading to cancer predisposition, and localization of genes is occurs at lightening speed, more and more hereditary factors will be identified that will affect not only adults but children as well.

• Retinoblastoma is the most common eye tumor in children and frequently manifests itself as leukocoria or a white pupil. About 40 % of retinoblastomas are felt to be due to heredity, while the remaining 60% are sporadic. Hereditary retinoblastomas are more likely multifocal, bilateral or have an earlier age of onset. Family history is also important in the assessment although only 20% of the hereditary cases have a positive family history. This means that the other 80% of the genetically determined tumors are due to a new mutation occurring in the patient. Heritable retinoblastoma most often appears before the age of one (compared to over age two in the sporadic cases) and is associated with an increased risk for other primaries including osteosarcomas, soft tissue sarcomas, certain brain tumors or melanomas. The RB1 gene has a tumor suppressor function and carriers have a 50% chance of passing this gene on to their children. Children with hereditary retinoblastoma who receive external beam radiation have a five fold increased risk of developing secondary primaries and therefore this treatment option should be avoided whenever possible. Advances in chemotherapy in recent years have reduced the need for radiation therapy and still allowed for preservation of visual function in many patients.

• Wilms tumor is second only to neuroblastoma in frequency of non-CNS solid tumors in childhood. As with retinoblastoma, Wilms tumor may be sporadic or heritable, but multigenerational Wilms tumor is rare indeed with most of the genetic cases resulting from new mutational events. Genetically determined Wilms tumor is more often bilateral with the mean age of diagnosis 24 months compared to 36 months in the sporadic cases. More than 90% of Wilms tumors are sporadic with 5 - 7% bilateral and presumed genetic and only 1% with a positive family history. Unlike RB1 with a single identified genetic locus, there are at least 5 loci identified for Wilms tumor. Individual mutations in the WT1 gene located at 11p13 are found in < 10% of genetic Wilms tumor, with certain mutations in this same gene causing Denys-Drash syndrome which leads to more significant GU anomalies including male pseudohermaphroditism and progressive mesangial sclerosis leading to renal failure. Larger deletions of genetic material including the WT1 gene result in WAGR syndrome that is characterized by aniridia, GU anomalies and mental retardation in addition to a high risk for developing Wilms tumor. Beckwith-Wiedemann syndrome (BWS) is associated with overgrowth, hypoglycemia, enlarged tongue and increased risk for Wilms tumor and hepatoblastoma. The genes linked to this condition are nearby but not identical to the WT1 gene region and are more distal on chromosome 11 at p15. It appears that a double paternal contribution of genes in this area cause BWS. Another overgrowth syndrome also associated with increased risk for Wilms tumor is an X-linked condition called Simpson-Golabi-Behmel syndrome. Mutations in the GPC3 gene on the long arm of the X chromosome has been implicated in this condition. Two other individual loci have been associated with familial Wilms tumor, one on chromosome 17q and the other on 19q. In the future as more genes are mapped and studied it is likely that a variety of Wilms tumor genes will be better characterized.

• Li-Fraumeni syndrome (LFS) is a rare familial cancer syndrome but may result in a number of childhood tumors including bone tumors, soft tissue sarcomas, leukemia and brain tumors. The full spectrum of tumors include breast cancer and adrenocortical tumors as well. In children with one of these tumor types a careful family history should be constructed to make sure that LFS is not a consideration. Individuals with multiple primary tumors or multiple family members with these tumor types should raise suspicion about a possible autosomal dominant LFS TP53 gene mutation. In some clinical settings, molecular testing may be offered, but the testing of minors raises some ethical concerns.

• Familial Adenomatous Polyposis (FAP) is an autosomal dominant condition resulting in development of hundreds of colonic adenomas during childhood and adulthood leading to colorectal cancer in all patients who do not undergo total colectomy. Because colon cancer can develop quite early, current recommendations would be to offer molecular testing and/or colonoscopy by age 10-12 years so that timing for prophylactic colectomy can be discussed in at-risk children. Mutations in the APC gene sometimes result in extracolonic manifestations that may appear before there is evidence of polyposis coli. In some families, congenital hypertrophy of the retinal pigment epithelium (CHRPE) is a benign clinical finding associated with the gene mutation and may be identified on focused eye exam in infancy. An FAP variant called Gardner syndrome, in addition to the polyposis, has other features including: epidermal cysts, osteomas of the long bones, mandible or skull, supernumerary teeth and desmoid tumors that may be seen in childhood. Other malignant tumors that have been associated with FAP include hepatoblastoma, brain tumors and thyroid cancer.

• Von Hippel-Lindau disease (VHL) is also an autosomal dominant cancer syndrome that may manifest in childhood. Tumors associated with this condition include: cerebellar and spinal cord hemangioblastomas, renal cell carcinomas, pheochromocytomas, islet cell tumors and epididymal cystadenomas. Other features of VHL that may be evident even in young children include: retinal angiomas, pancreatic cysts or renal cysts. The gene has been identified and, for some families, direct gene testing may be possible if a specific gene mutation is found. For other children and adults who are at risk or choose not to have molecular testing, a number of screening recommendations have been promulgated. Routine MRI or CT of the head and spine may not be very practical, however, a head imaging study should be pursued vigorously if anyone at risk develops neurologic symptoms. Blood pressure should be monitored at least twice a year with urinary catecholamines and metanephrines checked if there is a single elevated measurement. Annual abdominal ultrasounds and ophthalmologic exams are indicated to insure that there are no hidden abnormalities that need to be addressed. Other centers have recommended routine MRIs or CTs as well as routine urine studies and this may indeed be the more cautious and sound approach to surveillance. Only time will tell which routine studies improve management while decreasing morbidity and mortality.

As more cancer predisposition genes are discovered, the primary care provider will increasingly be asked to provide guidance about the appropriateness of molecular testing. Since children cannot provide consent for such testing and written informed consent is the "gold standard", clinicians need to think very carefully before proceeding with such investigations. If the child is likely to benefit from this information from a medical perspective prior to the age of majority, then consideration should be given to proceeding with testing if the parents request it. On the other hand, if the minor is unlikely to benefit from such testing, either because it is a later onset problem or there are no reasonable medical interventions, then testing should be deferred until that individual can consent for himself or herself.