CCR PEDIATRIC ONCOLOGY SERIES CCR Pediatric Oncology Series Pediatric Cancer Predisposition and Surveillance: An Overview, and a Tribute to Alfred G. Knudson Jr Garrett M. Brodeur1, Kim E. Nichols2, Sharon E. Plon3, Joshua D. Schiffman4, and David Malkin5 Abstract The prevalence of childhood cancer attributable to genetic predisposition syndromes were developed. In general, we con- predisposition was generally considered very low. However, sidered a 5% or greater chance of developing a childhood cancer recent reports suggest that at least 10% of pediatric cancer patients to be a reasonable threshold to recommend screening. Conditions harbor a germline mutation in a cancer predisposition gene. for which the cancer risk was between 1% to 5% were addressed Although some of these children will have a family history individually. In a series of manuscripts accompanying this article, suggestive of a cancer predisposition syndrome, many others will we provide recommendations for surveillance, focusing on when not. Evidence from recent pediatric studies suggests that surveil- to initiate and/or discontinue specific screening measures, which lance and early detection of cancer in individuals carrying a modalities to use, and the frequency of screening. Points of germline cancer predisposing mutation may result in improved controversy are also reviewed. We present the outcome of our outcomes. However, there is a lack of consistency in the design of deliberations on consensus screening recommendations for spe- cancer surveillance regimens across centers both nationally and cific disorders in 18 position articles as Open Access publications, internationally. To standardize approaches, the Pediatric Cancer which are freely available on an AACR-managed website. Clin Working Group of the American Association for Cancer Research Cancer Res; 23(11); e1–e5. Ó2017 AACR. (AACR) convened a workshop, during which consensus screening See all articles in the online-only CCR Pediatric Oncology recommendations for children with the most common cancer Series. Tribute to Alfred G. Knudson Jr guiding principle for cancer susceptibility and pathogenesis around the world for 45 years. Dr. Alfred G. Knudson is considered by many to be the father of In addition to this and many other contributions to our modern cancer genetics and heritable predisposition. Al died on understanding of the genetic basis of cancer, Al was also an July 10, 2016, as this workshop was still in its planning stages. It "intellectual pollinator." He took great delight in going to meet- was the unanimous consensus of the workshop participants to ings and visiting scientists around the world, and then sharing his dedicate our efforts to Al Knudson and his pioneering work in this insights with the other scientists whom he encountered. He was a field. In his initial statistical analysis of hereditary and nonhered- humble man who did not seek personal credit or acknowledgment itary cancer, he hypothesized that "retinoblastoma is a cancer for his contributions, but rather, he delighted in the successes of caused by two mutational events. In the dominantly inherited others. Nevertheless, Al certainly won his share of accolades, form, one mutation is inherited via the germinal cells and the including the Charles S. Mott Prize from the General Motors second occurs in somatic cells. In the nonhereditary form, both Foundation in 1988, election to the National Academy of Sciences mutations occur in somatic cells" (1). This "two-hit theory" of the in 1992, the David A. Karnofsky Memorial Award and Lecture genetic origin of retinoblastoma was extended to other pediatric from the American Society of Clinical Oncology in 1997, the cancers, such as neuroblastoma and Wilms tumor (2, 3), as well as Lasker Clinical Medical Research Award in 1998, the Kyoto Prize in many cancers occurring in adults. Although this model may not 2004, and the Award for Lifetime Achievement in Cancer Research explain the genetic etiology of all heritable cancers, it has been a from the American Association for Cancer Research (AACR) in 2005. However, his contributions to science and inspiration to many cannot be measured by awards or words. He was a gentle 1 2 Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. St. Jude Chil- and inspiring giant in the field, and he will be deeply missed. dren's Research Hospital, Memphis, Tennessee. 3Baylor College of Medicine and 4 Texas Children's Hospital, Houston, Texas. Intermountain Primary Children's Pediatric Cancer Predisposition: Hospital and Huntsman Cancer Institute/University of Utah, Salt Lake City, Utah. 5The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada. Introduction Corresponding Author: Garrett M. Brodeur, Children's Hospital of Philadelphia, Cancer in children is generally considered a rare and sporadic University of Pennsylvania, 3501 Civic Center Boulevard, CTRB Room 3018, event, and only a small percentage of cases were previously Philadelphia, PA 19104-4302. Phone: 215-590-2817; Fax: 215-590-3770; E-mail: thought to result from a genetic predisposition. However, a [email protected]. number of features suggest that at least a subset of pediatric doi: 10.1158/1078-0432.CCR-17-0702 cancers result from a genetic predisposition. These include (i) Ó2017 American Association for Cancer Research. family history of the same or related cancers; (ii) bilateral, www.aacrjournals.org e1 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2017 American Association for Cancer Research. CCR PEDIATRIC ONCOLOGY SERIES multifocal, or multiple cancers; (iii) earlier age at diagnosis than been performed consistently across different centers, and there are sporadic tumors of the same type; (iv) physical findings suggestive still many inherited cancer predisposition disorders for which of a predisposition syndrome; and (v) occurrence of specific either no protocols or multiple published protocols exist. This tumor types that frequently occur in the context of genetic practice variability makes it difficult to compare studies from predisposition (4). A child presenting with any of these five different centers or groups and creates uncertainty for clinicians features should be referred for evaluation to a cancer predispo- caring for patients with these individually rare disorders. sition program (5). Examples of physical findings associated with An AACR-sponsored workshop was held in Boston, Massachu- specific cancer predisposition syndromes include cafe-au-lait setts, from October 6 to 8, 2016, to develop consensus recom- macules in neurofibromatosis type I, macroglossia in Beck- mendations for cancer surveillance of children and adolescents with–Wiedemann syndrome (BWS), or macrocephaly in PTEN with heritable cancer predisposition. Sixty-five professionals from hamartoma tumor syndrome; however, these findings also occur 11 countries were present, including 51 physician directors or in individuals without cancer predisposition. Examples of specific codirectors of cancer predisposition programs (pediatric oncol- pediatric cancer diagnoses that are frequently seen in the setting of ogists or medical geneticists), seven genetic counselors, three underlying cancer susceptibility include pleuropulmonary blas- radiologists, three directors of adult cancer predisposition pro- toma in DICER1 syndrome, malignant rhabdoid tumors in rhab- grams, and one pediatric endocrinologist. The main goal of this doid tumor syndrome, and adrenocortical carcinoma in Li-Frau- meeting and the postworkshop activities was to review the exist- meni syndrome (LFS). ing data and practices, and to establish international consensus Recent reports using genome-scale germline sequencing of recommendations for cancer surveillance for the most common pediatric cancer cohorts not selected for genetic risk (6–8) suggest cancer predisposition syndromes. These pediatric cancer syn- at least 10% of pediatric cancer patients harbor a germline dromes were organized into nine groups based on specific themes. mutation in known cancer predisposition genes. This is probably Attendees were organized into these groups based on prior an underestimate, because there are also patients who fulfill experience and expertise. clinical criteria for a cancer predisposition syndrome but lack identifiable germline mutation in the known gene(s) currently Major Cancer Predisposition Syndromes associated with those conditions. In addition, there are pediatric This AACR workshop focused on the 50 most common syn- patients with cancer whose families exhibit a higher frequency of dromes that predispose individuals to the development of cancer cancer than expected yet do not fit any patterns for a known in the first 20 years of life. These syndromes were then divided into predisposition syndrome. Furthermore, some individuals are nine major groups based on the major cancer types with which they predisposed to develop cancer on the basis of epigenetic changes are associated: (i) LFS, (ii) neurofibromatoses, (iii) overgrowth (e.g., BWS or hemihypertrophy) that would not be detected by syndromes and Wilms tumor, (iv) neural tumors, (v) gastrointes- traditional DNA sequencing. Cancer genomes are increasingly tinal cancer predisposition, (vi) neuroendocrine syndromes, (vii) scrutinized to identify variants that are actionable for targeted leukemia predisposition, (viii) DNA instability syndromes, and therapy, but changes or patterns of somatic mutation can some- (ix) miscellaneous syndromes. The disorders