MEETING REPORT Update on Pediatric Cancer Predisposition Syndromes

The American Society of Pediatric Hematology/Oncology (ASPHO) 2012 Annual Meeting included an interactive workshop on the rapidly expanding topic of hereditary cancer syndromes in children. As discussed, the Sword of Damocles is an appropriate analogy to consider when approaching families with extraordinarily high risk for developing cancer [1]. This expression is based on the story of a sword hanging above Damocles’ head by a horse’s hair while he spends the day sitting in the king’s throne and Damocles does not know when or if the sword will drop [2,3]. Similarly, the “Sword of Cancer” constantly hangs over high risk families with hereditary cancer syndromes, and it is the job of the pediatric oncologist to try to help families live with this pervasive threat. In adults, the percentage of cancer attributed to underlying, inherited genetic mutations has been quoted at 5–10% [4]. However, the rate of cancer predisposition in children was never investigated until recently. Knapke et al. [5] embedded a genetic counselor into a pediatric cancer survivorship clinic and interviewed survivors and families (N1⁄4 370) over a 2-year time-period. Individuals were screened for family history, demographics, and tumor characteristics that would suggest an underlying cancer predisposition syndrome. They found a surprisingly high 29% (N1⁄4 109) of individuals who were identified as candidates for further cancer genetics evaluation. Of those at risk, 61%were due to family history of cancer, 18% were due to cancer strongly associated with hereditary cancer, 16% were due to medical history suggesting genetic diagnosis, and 6% were due to family history of another condition. As has been stated previously [6], this extremely high rate of over one in four pediatric cancer patients being eligible for cancer genetics evaluation may actually be an underestimate as Knapke’s study was performed in a survivorship clinic and several hereditary cancer syndromes can cause very aggressive cancers in children that may lead to rapid death (i.e., Atypical Teratoid Rhabdoid Tumors (ATRT) in Rhadboid Syndrome, Adrenocortical Carcinoma (ACC) in Li-Fraumi Syndrome). These children with cancer predisposition syndromes who died early from their tumors would not be included in a study performed in a survivorship clinic. This means that over a quarter, possibly as high as a third, of all new pediatric cancer diagnosesmay be due to an inherited genetic cause. For pediatric oncologists, Li-Fraumeni Syndrome (LFS) offers an excellent example of how identifying children with hereditary cancer syndrome can improve outcome and increase survival. LFS is a rare, autosomal dominant syndrome that affects both children and adults [7]. It is characterized by early onset of bone and soft tissue sarcomas, adrenocortical carcinoma, choroid plexus carcinomas, and other tumors, as well as multiple primary tumors in a single individual [8]. Themajority of families with classic LFS have an inherited or de novo TP53 germline mutation [9]. Previously, the testing in children and adults for TP53 mutation raised important ethical and psychosocial issues as it was unclear what to dowith the information. It is now clear that identification of at risk individuals leads to early cancer screening programs that can detect tumors while they are still small and able to be removed. Villani et al. [10] recently demonstrated that biochemical screening combined with regular whole body MRI imaging studies resulted in 3-year overall survival of 100% in the surveillance group versus 21% (95% CI, 4– 48%) in the non-surveillance group (P1⁄4 0.0155). However, this was not a randomized investigation and so prospective controlled trials must now be done to prove the effectiveness of this approach and validate compliance with this screening protocol. These initial results remain promising and we are at the point in the field of pediatric cancer genetics that identifying these children at risk for cancer predisposition may translate into lives saved. The purpose of this report is to aid in the identification of some of the rarer pediatric cancer predisposition syndromes, to summarize the concepts behind testing and screening for these syndromes, to discuss some of the ethical issues in the field of Hereditary cancer syndromes in children and adolescents are becoming more recognized in the field of pediatric hematology/ oncology. A recent workshop held at the American Society of Pediatric Hematology/Oncology (ASPHO) 2012 Annual Meeting included several interactive sessions related to specific familial cancer syndromes, genetic testing and screening, and ethical issues in caring for familieswith inherited cancer risk. This reviewhighlights the workshop presentations, including a brief background about pediatric cancer predisposition syndromes and the importance of learning about them for the practicing pediatric hematologists/ oncologists. This is followed by a brief summary of the newly described cancer predisposition syndromes including Rhabdoid Tumor Predisposition Syndrome, Hereditary Paragangliomas and Pheochromocytoma Syndrome, and Familial Pleuropulmonaryblastoma Tumor Predisposition (DICER1) Syndrome. The next section covers genetic testing and screening for pediatric cancer predisposition syndromes. Ethical issues are also discussed including preimplantation genetic diagnosis or testing (PGD/PGT), suspicious lesions found on tumor screening, and incidental mutations discovered by whole genome sequencing. Finally, the perspective of a family with Li-Fraumeni Syndrome is shared. Pediatr Blood Cancer 2013;60:1247–1252. # 2013 Wiley Periodicals, Inc.