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PEDIATRIC ONCOLOGY SERIES ARTICLES FROM THE AACR CHILDHOOD CANCER PREDISPOSITION WORKSHOP

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CCR Pediatric Oncology SeriesClinical Cancer Research (CCR) is proud to present a special collection of articles from the AACR ChildhoodCancer Predisposition Workshop. The initial series of manuscripts was generated by an international cohort ofleading pediatric cancer experts in order to provide recommendations for screening surveillance of childhoodcancer predisposition syndromes in an effort to facilitate early detection and treatment of pediatric cancers. Wehope you enjoy this series of open access articles and continue to check back for additional relevant content andupdated recommendations. To access the complimentary full-text version of this collection, please visitclincancerres.aacrjournals.org/pediatricseries.

Editorial Schedule

June 1, 2017 Release

Pediatric Cancer Predisposition and Surveillance: An Overview, and a Tribute to Alfred G. Knudson JrGarrett M. Brodeur, Kim E. Nichols, Sharon E. Plon, Joshua D. Schiffman, and David MalkinClin Cancer Res June 1, 2017 23:11; doi: 10.1158/1078-0432.CCR-17-0702

Pediatric Cancer Predisposition Imaging: Focus on Whole-Body MRIMary-Louise C. Greer, Stephan D. Voss, and Lisa J. StatesClin Cancer Res June 1, 2017 23:11; doi: 10.1158/1078-0432.CCR-17-0515

Recommendations for Surveillance for Children with Leukemia-Predisposing ConditionsChristopher C. Porter, Todd E. Druley, Ayelet Erez, Roland P. Kuiper, Kenan Onel, Joshua D. Schiffman,Kami Wolfe Schneider, Sarah R. Scollon, Hamish S. Scott, Louise C. Strong, Michael F. Walsh, and Kim E. NicholsClin Cancer Res June 1, 2017 23:11; doi: 10.1158/1078-0432.CCR-17-0428

Recommendations for Childhood Cancer Screening and Surveillance in DNA Repair DisordersMichael F. Walsh, Vivian Y. Chang, Wendy K. Kohlmann, Hamish S. Scott, Christopher Cunniff, Franck Bourdeaut,Jan J. Molenaar, Christopher C. Porter, John T. Sandlund, Sharon E. Plon, Lisa L. Wang, and Sharon A. SavageClin Cancer Res June 1, 2017 23:11; doi: 10.1158/1078-0432.CCR-17-0465

Clinical Management and Tumor Surveillance Recommendations of Inherited MismatchRepair Deficiency in ChildhoodUri Tabori, Jordan R. Hansford, Maria Isabel Achatz, Christian P. Kratz, Sharon E. Plon, Thierry Frebourg, and Laurence BrugièresClin Cancer Res June 1, 2017 23:11; doi: 10.1158/1078-0432.CCR-17-0574

Cancer Screening Recommendations for Individuals with Li-Fraumeni SyndromeChristian P. Kratz, Maria Isabel Achatz, Laurence Brugières, Thierry Frebourg, Judy E. Garber, Mary-Louise C. Greer,Jordan R. Hansford, Katherine A. Janeway, Wendy K. Kohlmann, Rose McGee, Charles G. Mullighan, Kenan Onel,Kristian W. Pajtler, Stefan M. Pfister, Sharon A. Savage, Joshua D. Schiffman, Katherine A. Schneider, Louise C. Strong,D. Gareth R. Evans, Jonathan D. Wasserman, Anita Villani, and David MalkinClin Cancer Res June 1, 2017 23:11; doi: 10.1158/1078-0432.CCR-17-0408

June 15, 2017 Release

Cancer and Central Nervous System Tumor Surveillance in Pediatric Neurofibromatosis 1D. Gareth R. Evans, Hector Salvador, Vivian Y. Chang, Ayelet Erez, Stephan D. Voss, Kami Wolfe Schneider,Hamish S. Scott, Sharon E. Plon, and Uri TaboriClin Cancer Res June 15, 2017 23:12; doi: 10.1158/1078-0432.CCR-17-0589

Cancer and Central Nervous System Tumor Surveillance in Pediatric Neurofibromatosis 2 and Related DisordersD. Gareth R. Evans, Hector Salvador, Vivian Y. Chang, Ayelet Erez, Stephan D. Voss, Harriet Druker, Hamish S. Scott, and Uri TaboriClin Cancer Res June 15, 2017 23:12; doi: 10.1158/1078-0432.CCR-17-0590

CCR Pediatric Oncology Series

Cancer Surveillance in Gorlin Syndrome and Rhabdoid Tumor Predisposition SyndromeWilliam D. Foulkes, Junne Kamihara, D. Gareth R. Evans, Laurence Brugières, Franck Bourdeaut, Jan J. Molenaar,Michael F. Walsh, Garrett M. Brodeur, and Lisa DillerClin Cancer Res June 15, 2017 23:12; doi: 10.1158/1078-0432.CCR-17-0595

Von Hippel-Lindau and Hereditary Pheochromocytoma/Paraganglioma Syndromes:Clinical Features, Genetics, and Surveillance Recommendations in ChildhoodSurya P. Rednam, Ayelet Erez, Harriet Druker, Katherine A. Janeway, Junne Kamihara, Wendy K. Kohlmann, Katherine L. Nathanson,Lisa J. States, Gail E. Tomlinson, Anita Villani, Stephan D. Voss, Joshua D. Schiffman, and Jonathan D. WassermanClin Cancer Res June 15, 2017 23:12; doi: 10.1158/1078-0432.CCR-17-0547

PTEN, DICER1, FH and their Associated Tumor Susceptibility Syndromes: Clinical Features, Genetics, and SurveillanceRecommendations in ChildhoodKris Ann P. Schultz, Surya P. Rednam, Junne Kamihara, Leslie Doros, Maria Isabel Achatz, Jonathan D. Wasserman, Lisa R. Diller,Laurence Brugières, Harriet Druker, Katherine A. Schneider, Rose B. McGee, and William D. FoulkesClin Cancer Res June 15, 2017 23:12; doi: 10.1158/1078-0432.CCR-17-0629

Recommendations for Cancer Surveillance in Individuals with RASopathies and other Rare GeneticConditions with Increased Cancer RiskAnita Villani, Mary-Louise C. Greer, Jennifer M. Kalish, Akira Nakagawara, Katherine L. Nathanson, Kristian W. Pajtler,Stefan M. Pfister, Michael F. Walsh, Jonathan D. Wasserman, Kristin Zelley, and Christian P. KratzClin Cancer Res June 15, 2017 23:12; doi: 10.1158/1078-0432.CCR-17-0631

July 1, 2017 Release

Genetic Counselor Recommendations for Cancer Predisposition Evaluation and Surveillance in the PediatricOncology PatientHarriet Druker, Kristin Zelley, Rose B. McGee, Sarah Scollon, Wendy Kohlmann, Katherine A. Schneider, and Kami Wolfe SchneiderClin Cancer Res July 1, 2017 23:13; doi: 10.1158/1078-0432.CCR-17-0834

Retinoblastoma and Neuroblastoma Predisposition and SurveillanceJunne Kamihara, Franck Bourdeaut, William D. Foulkes, Jan J. Molenaar, Yaël P. Mossé, Akira Nakagawara, Andreu Parareda-Salles,Sarah R. Scollon, Kami Wolfe Schneider, Lisa J. States, Michael F. Walsh, Lisa R. Diller, and Garrett M. BrodeurClin Cancer Res July 1, 2017 23:13; doi: 10.1158/1078-0432.CCR-17-0652

Cancer Screening Recommendations and Clinical Management of Inherited GastrointestinalCancer Syndromes in ChildhoodMaria Isabel Achatz, Christopher C. Porter, Laurence Brugières, Harriet Druker, Thierry Frebourg, William D. Foulkes,Christian P. Kratz, Roland P. Kuiper, Jordan R. Hansford, Hector Salvador Hernandez, Katherine L. Nathanson, Wendy K. Kohlmann,Leslie Doros, Kenan Onel, Kami Wolfe Schneider, Sarah R. Scollon, Uri Tabori, Gail E. Tomlinson, D. Gareth R. Evans, and Sharon E. PlonClin Cancer Res July 1, 2017 23:13; doi: 10.1158/1078-0432.CCR-17-0790

Surveillance Recommendations for Children with Overgrowth Syndromes and Predisposition to WilmsTumors and HepatoblastomaJennifer M. Kalish, Leslie Doros, Lee J. Helman, Raoul Hennekam, Roland P. Kuiper, Saskia M. Maas, Eamonn R. Maher, Kim E. Nichols,Sharon E. Plon, Christopher C. Porter, Surya Rednam, Kris Ann P. Schultz, Lisa J. States, Gail E. Tomlinson, Kristin Zelley, and Todd E. DruleyClin Cancer Res July 1, 2017 23:13; doi: 10.1158/1078-0432.CCR-17-0710

Multiple Endocrine Neoplasia and Hyperparathyroid-Jaw Tumor Syndromes: Clinical Features, Genetics,and Surveillance Recommendations in ChildhoodJonathan D. Wasserman, Gail E. Tomlinson, Harriet Druker, Junne Kamihara, Wendy Kohlmann, Christian P. Kratz, Katherine L. Nathanson, Kristian W.Pajtler, Andreu Parareda, Surya P. Rednam, Lisa J. States, Anita Villani, Michael F. Walsh, Kristin Zelley, and Joshua D. SchiffmanClin Cancer Res July 1, 2017 23:13; doi: 10.1158/1078-0432.CCR-17-0548

Fall 2017 Release

The Future of Surveillance in the Setting of Cancer Predisposition: Through the Looking GlassDavid Malkin, et al.Clin Cancer Res Fall 2017

For more information, please visit www.aacrjournals.org

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CCR Pediatric Oncology Series

Pediatric Cancer Predisposition andSurveillance: An Overview, and a Tributeto Alfred G. Knudson JrGarrett M. Brodeur1, Kim E. Nichols2, Sharon E. Plon3,Joshua D. Schiffman4, and David Malkin5

Abstract

The prevalence of childhood cancer attributable to geneticpredisposition was generally considered very low. However,recent reports suggest that at least 10%of pediatric cancer patientsharbor a germline mutation in a cancer predisposition gene.Although some of these children will have a family historysuggestive of a cancer predisposition syndrome, many others willnot. Evidence from recent pediatric studies suggests that surveil-lance and early detection of cancer in individuals carrying agermline cancer predisposing mutation may result in improvedoutcomes. However, there is a lack of consistency in the design ofcancer surveillance regimens across centers both nationally andinternationally. To standardize approaches, the Pediatric CancerWorking Group of the American Association for Cancer Research(AACR) convened aworkshop, during which consensus screeningrecommendations for children with the most common cancer

predisposition syndromes were developed. In general, we con-sidered a 5% or greater chance of developing a childhood cancertobe a reasonable threshold to recommend screening. Conditionsfor which the cancer risk was between 1% to 5% were addressedindividually. In a series of manuscripts accompanying this article,we provide recommendations for surveillance, focusing on whento initiate and/or discontinue specific screening measures, whichmodalities to use, and the frequency of screening. Points ofcontroversy are also reviewed. We present the outcome of ourdeliberations on consensus screening recommendations for spe-cific disorders in 18 position articles as Open Access publications,which are freely available on an AACR-managed website. ClinCancer Res; 23(11); e1–e5. �2017 AACR.

See all articles in the online-only CCR Pediatric OncologySeries.

Tribute to Alfred G. Knudson JrDr. AlfredG. Knudson is considered bymany to be the father of

modern cancer genetics and heritable predisposition. Al died onJuly 10, 2016, as this workshop was still in its planning stages. Itwas the unanimous consensus of the workshop participants todedicate our efforts to Al Knudson and his pioneering work in thisfield. In his initial statistical analysis of hereditary and nonhered-itary cancer, he hypothesized that "retinoblastoma is a cancercaused by two mutational events. In the dominantly inheritedform, one mutation is inherited via the germinal cells and thesecond occurs in somatic cells. In the nonhereditary form, bothmutations occur in somatic cells" (1). This "two-hit theory" of thegenetic origin of retinoblastoma was extended to other pediatriccancers, such as neuroblastoma andWilms tumor (2, 3), aswell asmany cancers occurring in adults. Although this model may notexplain the genetic etiology of all heritable cancers, it has been a

guiding principle for cancer susceptibility and pathogenesisaround the world for 45 years.

In addition to this and many other contributions to ourunderstanding of the genetic basis of cancer, Al was also an"intellectual pollinator." He took great delight in going to meet-ings and visiting scientists around the world, and then sharing hisinsights with the other scientists whom he encountered. He was ahumblemanwhodidnot seekpersonal credit or acknowledgmentfor his contributions, but rather, he delighted in the successes ofothers. Nevertheless, Al certainly won his share of accolades,including the Charles S. Mott Prize from the General MotorsFoundation in 1988, election to theNational Academy of Sciencesin 1992, the David A. Karnofsky Memorial Award and Lecturefrom the American Society of Clinical Oncology in 1997, theLaskerClinicalMedical ResearchAward in1998, theKyotoPrize in2004, and the Award for LifetimeAchievement inCancer Researchfrom the American Association for Cancer Research (AACR) in2005. However, his contributions to science and inspiration tomany cannot be measured by awards or words. He was a gentleand inspiring giant in the field, and he will be deeply missed.

Pediatric Cancer Predisposition:Introduction

Cancer in children is generally considered a rare and sporadicevent, and only a small percentage of cases were previouslythought to result from a genetic predisposition. However, anumber of features suggest that at least a subset of pediatriccancers result from a genetic predisposition. These include (i)family history of the same or related cancers; (ii) bilateral,

1Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. 2St. Jude Chil-dren's Research Hospital, Memphis, Tennessee. 3Baylor College of Medicine andTexas Children's Hospital, Houston, Texas. 4Intermountain Primary Children'sHospital and Huntsman Cancer Institute/University of Utah, Salt Lake City, Utah.5The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.

Corresponding Author: Garrett M. Brodeur, Children's Hospital of Philadelphia,University of Pennsylvania, 3501 Civic Center Boulevard, CTRB Room 3018,Philadelphia, PA 19104-4302. Phone: 215-590-2817; Fax: 215-590-3770; E-mail:Brodeur@email.chop.edu.

doi: 10.1158/1078-0432.CCR-17-0702

�2017 American Association for Cancer Research.

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multifocal, or multiple cancers; (iii) earlier age at diagnosis thansporadic tumors of the same type; (iv) physicalfindings suggestiveof a predisposition syndrome; and (v) occurrence of specifictumor types that frequently occur in the context of geneticpredisposition (4). A child presenting with any of these fivefeatures should be referred for evaluation to a cancer predispo-sition program (5). Examples of physical findings associated withspecific cancer predisposition syndromes include caf�e-au-laitmacules in neurofibromatosis type I, macroglossia in Beck-with–Wiedemann syndrome (BWS), or macrocephaly in PTENhamartoma tumor syndrome; however, these findings also occurin individuals without cancer predisposition. Examples of specificpediatric cancer diagnoses that are frequently seen in the setting ofunderlying cancer susceptibility include pleuropulmonary blas-toma in DICER1 syndrome, malignant rhabdoid tumors in rhab-doid tumor syndrome, and adrenocortical carcinoma in Li-Frau-meni syndrome (LFS).

Recent reports using genome-scale germline sequencing ofpediatric cancer cohorts not selected for genetic risk (6–8) suggestat least 10% of pediatric cancer patients harbor a germlinemutation in known cancer predisposition genes. This is probablyan underestimate, because there are also patients who fulfillclinical criteria for a cancer predisposition syndrome but lackidentifiable germline mutation in the known gene(s) currentlyassociated with those conditions. In addition, there are pediatricpatients with cancer whose families exhibit a higher frequency ofcancer than expected yet do not fit any patterns for a knownpredisposition syndrome. Furthermore, some individuals arepredisposed to develop cancer on the basis of epigenetic changes(e.g., BWS or hemihypertrophy) that would not be detected bytraditional DNA sequencing. Cancer genomes are increasinglyscrutinized to identify variants that are actionable for targetedtherapy, but changes or patterns of somatic mutation can some-times be identified that may represent an unanticipated germlinepredisposition.

In addition, pediatric oncologists are increasingly sendingpatient samples for paired tumor/normal sequencing, with aprimary goal to identify potentially targetable genetic lesions inthe tumor. This analysis may also inadvertently lead to theidentification of pathogenic variants that reflect germline muta-tions in cancer susceptibility genes, a possibility forwhichpatientsand their families donot always receive pretest genetic counseling.It is likely that this type of systematic analysis of tumors (andpaired germline samples) will become routine in pediatric oncol-ogy clinical care in the next few years, maybe even one daybecoming the standard of care at diagnosis and even more likelyat relapse. For example, the NCI/Children's Oncology GroupPediatric MATCH trial will use such a study design for its sequenc-ing. Overall, we expect that the proportion of cancer patientsidentified as carriers of cancer susceptibility mutations willincrease as both targeted genetic evaluations and genomic anal-yses of cancer cells are implemented.

Individuals with cancer predisposition syndromes carry a sig-nificantly increased risk of developing one or more cancers.Therefore, focused surveillance on the types of cancer(s) to whichthe individual is most predisposed, and during the period ofgreatest risk, should substantially improve their outcome throughearly detection. Indeed, many centers are starting to follow pro-posed early tumor surveillance protocols that have been pub-lished for a few disorders such as LFS and BWS/hemihypertrophy(9–11). However, even for these disorders, surveillance has not

been performed consistently across different centers, and there arestill many inherited cancer predisposition disorders for whicheither no protocols or multiple published protocols exist. Thispractice variability makes it difficult to compare studies fromdifferent centers or groups and creates uncertainty for clinicianscaring for patients with these individually rare disorders.

An AACR-sponsored workshop was held in Boston, Massachu-setts, from October 6 to 8, 2016, to develop consensus recom-mendations for cancer surveillance of children and adolescentswith heritable cancer predisposition. Sixty-five professionals from11 countries were present, including 51 physician directors orcodirectors of cancer predisposition programs (pediatric oncol-ogists or medical geneticists), seven genetic counselors, threeradiologists, three directors of adult cancer predisposition pro-grams, and one pediatric endocrinologist. The main goal of thismeeting and the postworkshop activities was to review the exist-ing data and practices, and to establish international consensusrecommendations for cancer surveillance for the most commoncancer predisposition syndromes. These pediatric cancer syn-dromeswere organized intonine groups basedon specific themes.Attendees were organized into these groups based on priorexperience and expertise.

Major Cancer Predisposition SyndromesThis AACR workshop focused on the 50 most common syn-

dromes that predispose individuals to the development of cancerin the first 20 years of life. These syndromes were then divided intoninemajor groupsbasedon themajor cancer typeswithwhich theyare associated: (i) LFS, (ii) neurofibromatoses, (iii) overgrowthsyndromes and Wilms tumor, (iv) neural tumors, (v) gastrointes-tinal cancer predisposition, (vi) neuroendocrine syndromes, (vii)leukemia predisposition, (viii) DNA instability syndromes, and(ix) miscellaneous syndromes. The disorders and associated genesfor each of these categories are summarized in Table 1.

Cancer Surveillance ConsiderationsPrior to the workshop, each group reviewed the published liter-

ature to determine the current state of screening recommendationsfromexperts,professionalorganizations,orgroupsthatcare forsuchpatients. Attendees also provided information from their owncentersaswellaspersonalexperiencewithregardtocancer incidenceand surveillance protocols. The groups frequently consulted addi-tional experts on specific disorders for their input both before andafter the workshop. In general, the recommended surveillanceprotocols are designed for asymptomatic individuals who aregenetically predisposed to develop cancer, although some indivi-duals are identified only after the development of their first cancer.

The first question addressed was whether or not it was appro-priate to undertake cancer surveillance for children or adolescentswith a given cancer predisposition syndrome. For this decision,the consensus of the group was that surveillance was recom-mended when there is a 5% or greater risk of developing cancerduring the first 20 years of life and when effective screeningmodalities existed. Surveillance was not recommended or con-sideredworthwhile if the risk for an individualmalignancy duringthe first 20 years of life was less than 1%. Conditions in which thecancer risk during childhood fell between 1% and 5% werediscussed on an individual basis. We supported surveillance ifthe screening modalities were relatively cost-effective and nonin-vasive, and/or if the outcome was so poor for clinically detected

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tumors that any possibility for early detection might enhancesurvival. If screening was indicated, then the remaining questionsfor surveillance included the following:1. What procedure(s) should be done?2. How often should screening be performed?3. At what age should screening start, and if/when should it

stop?4. Should the screening procedures change over time, such as a

change in frequency or type of screening with age to accountfor changes in cancer risk?

Wealso askedwhether any evidence exists that the recommendedsurveillance leads to improved clinical outcome, but formost cases,this will have to await the implementation of the recommendationsproposed in the position articles for the respective disorders.

Evidence that Surveillance ImprovesOutcome

It is generally accepted that early identification of tumors whensmaller and less likely to be metastatic will improve clinicaloutcome. This is the underlying principle that supports cancersurveillance approaches for adults (e.g., screening for colon,breast, prostate, or other cancers, especially in predisposed indi-viduals). However, relatively few studies of cancer surveillance inchildren and adolescents have been published. In a recent study, aclinical surveillance protocol was implemented using frequentbiochemical and imaging studies for asymptomatic individualswith LFS (9, 10). Forty subjects underwent surveillance, whereas49 did not, and the 5-year overall survival (OS) was 89% in thesurveillance group versus 60% in the nonsurveillance group.These data suggest that surveillance was associatedwith improvedOS from tumors detected in patients with germline TP53 muta-tions even after 11 years of follow-up (9, 10).

Another group undertook a cost–benefit analysis of childrenwith BWS undergoing screening for Wilms tumor and hepato-

blastoma (11). Using a conservative model, they determined thatscreening for these tumors with abdominal ultrasound was pre-dicted to be cost-effective. Although the focus of the studywas noton outcome, screening also resulted in an improved survival (11).A review of characteristics and outcome of children with BWS andWilms tumor treated on National Wilms Tumor Study Groupprotocols showed a trend toward smaller tumors over time thatwas not seen in non-BWS patients with Wilms tumor, suggestingthat existing screening protocols led to earlier detection (12).Together, these data on cancer surveillance of LFS and BWSsuggest that screening enables the detection of smaller tumors,allowing for less-intensive therapy, less organ toxicity, and betteroutcomes.

Consistent Approach to Pediatric CancerPatients and Their Families

The primary goal of this CCR Pediatric Oncology Series is todevelop consensus recommendations for the management ofchildren at significant hereditary risk for cancer. However, aparallel issue discussed in more detail elsewhere in this series(see ref. 5) includes the need for a consistent and thoughtfulapproach to genetic testing for these families. Training in pediatrichematology-oncology does not emphasize the importance andmethods with which to obtain and record a complete familycancer history. Similarly, gaps exist in training around the appro-priate methods for germline genetic testing and the issues thatshould be addressed when obtaining consent for tumor testing.Genomic testing of tumor tissue can reveal mutations in genesthat may also be present in the germline. Mutations present in thetumor at an allele frequency near 50% can be acquired, or theymay reflect a germline mutation (13). A number of studies havedemonstrated that parents of children with cancer are concernedabout a hereditary contribution to the cancer diagnosis in theirchild, with possible implications for other family members (14).

Table 1. Major subgroups of pediatric cancer susceptibility disorders reviewed

Predisposition group Specific disorders reviewed

LFS LFS (TP53)Neurofibromatoses Neurofibromatosis type I (NF1), neurofibromatosis type II (NF2), Schwannomatosis (SMARCB1, LZTR1), meningioma

predisposition (SMARCE1)Overgrowth syndromes, Wilms tumor BWS/hemihypertrophy (11p15.5),Wilms tumor-aniridia-GU anomaly-retardation (WAGR) syndrome, Denys–Drash and

Frasier syndromes (WT1), Perlman syndrome (DIS3L2), Bohring–Opiz syndrome (ASXL1), Mulibrey Nanism (TRIM37),Simpson–Golabi–Behmel syndrome (GPC3, GPC4), non-syndromic hereditary Wilms tumor

Neural tumor syndromes Hereditary retinoblastoma (RB1), hereditary neuroblastoma (ALK, PHOX2B), Gorlin syndrome (PTCH1, SUFU),malignant rhabdoid tumor syndrome (SMARCB1, SMARCA4)

GI cancer syndromes Familial adenomatous polyposis (APC, MUTYH), juvenile polyposis syndrome (SMAD4, BMPR1A), Peutz–Jegherssyndrome (STK11), Lynch syndrome (MSH2, MSH6, MLH1, PMS2, EPCAM), CMMRD (see Lynch syndrome genes)

Neuroendocrine syndromes Multiple endocrine neoplasia (MEN)-1 (MEN1), MEN2A (RET), MEN2B (RET), MEN4 (CDKN1B), von Hippel–Lindau(VHL), hereditary paraganglioma/pheochromocytoma syndrome (SDHA, SDHB, SDHC, SDHD, SDHAF2,TMEM127, MAX), familial thyroid cancer (RET, NTRK1), hyperparathyroidism-jaw tumor syndrome (CDC73)

Leukemia predisposition syndromes LFS, CMMRD, susceptibility to ALL 3 (PAX5), GATA2-associated predisposition to myelodynsplasia/AML, CEBPA-associated predisposition to AML, thrombocytopenia, type 5 (ETV6), familial platelet disorder with associatedmyeloid malignancy (RUNX1), ataxia-pancytopenia syndrome (SAMD9L), myelodysplasia, infection, restriction ofgrowth, adrenal hypoplasia, genital phenotypes, and enteropathy (SAMD9)

DNA instability syndromes Ataxia telangiectasia (ATM), Bloom syndrome (BLM), Fanconi anemia (FANCA-V, RAD51C), xeroderma pigmentosum(XPA, XPC, ERCC2, POLH, DDB2), Nijmegen breakage syndrome (NBN), Diamond–Blackfan syndrome (RPS7, -10, -17,-19, -24, -26; RPL5, -11, -19, -35A), dyskeratosis congenita (DKC1, TINF2, TERC, TERT, NHP2, NOP10, WRAP53),Rothmund–Thompson syndrome (RECQL4)

Miscellaneous syndromes PTEN hamartoma tumor syndrome (PTEN), pleuropulmonary blastoma syndrome (DICER1), Noonan syndrome(PTPN11, SOS1, RAF1, RIT1, KRAS, others), Costello syndrome (HRAS), Sotos syndrome (NSD1), Weaver syndrome(EZH2), Rubenstein–Taybi syndrome (CREBBP, EP300), Schinzel–Giedion syndrome (SETBP1), NKX2-1 syndrome(NKX2-1), hereditary leiomyomatosis and renal cancer syndrome (FH), metabolic disorders (L2HGA, FAH)

Abbreviations: AML, acute myeloid leukemia; GI, gastrointestinal; CMMRD, congenital mismatch repair syndrome.

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Thus, education around germline genetic testing, disclosure ofresults, and identification and testing of at-risk family membersare essential activities that are integral to the training of currentand future pediatric oncologists.

As the number of long-term survivors of childhood cancerincreases, it will be essential for survivorship clinics to incor-porate genetic counseling and testing of adult survivors, includ-ing those who were identified as children to carry a cancerpredisposing mutation or who may be at risk for an inheritedsyndrome but have never been tested. This allows adult survi-vors the opportunity to learn about the implications of thegenetic findings for ongoing cancer (and other health) risks, therisk of having affected children, and the opportunity for pre-natal or postnatal testing. Similarly, long-term survivors whopreviously had a malignancy that is now recognized to beassociated with a substantial germline genetic risk (e.g., adre-nocortical carcinoma or hypodiploid acute lymphoblastic leu-kemia) would benefit from a genetic consultation, as thisinformation might not have been available when they werediagnosed.

Importance of Consensus ProtocolsIdentification of children with an underlying cancer predispo-

sition syndrome provides critical information for testing other-wise healthy-appearing family members, in particular siblings ofchildhood age, to identify whether or not they also carry the samegenetic risk. If identified, these family members may have asymp-tomatic tumors found through the initiation of tumor surveil-lance protocols. With this increase in systematic assessment ofgermline status, it becomes increasingly important for bothprimary and specialty clinicians to have ready access to consensusprotocols to undertake appropriate surveillance. It also willbecome important to understand the nuances of early tumorfindings and how to appropriately interpret any indications of apossible early cancer.

As described throughout the articles in this series, the workinggroups strove to reach consensus by careful review of existingguidelines from professional organizations, prior publications,cancer risk estimates, and assessment of the potential side effectsassociated with screening, balanced against the potential mor-bidity and mortality of clinically detected tumors of moreadvanced stage. For some newly described or rare disorders, noprior guidelines existed, so the committees endeavored to developconsensus recommendations as to whether surveillance was indi-cated, and what tests and schedule would be a good starting pointfor surveillance recommendations, based on the principlesdescribed above. If substantial differences of opinion existed,these differing viewpoints are described in the individual articlesas well. However, there was unanimous agreement among allworkshop participants that providing surveillance recommenda-tionswhere none existedwould provide a foundation onwhich tomake rational decisions for the management of children withcancer predisposition going forward. Gathering data from pro-spective experience with these consistent approaches worldwide

will facilitate future revisions of the proposed recommendationsand evolution of surveillance protocols.

The major focus of the cancer surveillance protocols pro-posed in this series of articles was on individuals with agermline predisposition who have not yet developed their firstcancer. We did not address the implications of the underlyingdisorder for therapy of tumors that develop, or for secondcancers and subsequent surveillance. This will likely be verysyndrome specific, for example, a greater risk of therapy-relatedcancers in LFS, retinoblastoma predisposition, DNA instabilitysyndromes, etc., and less so in individuals with certain othersyndromes (15–17). The recommendations will likely needsubstantial personalization, as the surveillance recommenda-tions will depend on the child's risk of a second tumor, whiletaking into account their risk of recurrence, the therapy thatthey received, and the biological nature of the predispositionsyndrome.

Pediatric Cancer Predisposition:Conclusions

Consistent approaches to surveillance will allow clinical expe-rience and research fromdifferent centers, groups, and countries tobe compared. These recommendations will also provide a stan-dardized approach to patients and families with disorders that areencountered infrequently by centers with limited experience. Theoutcome of this AACR-sponsoredworkshop is to provide positionarticles on surveillance recommendations for the major cancerpredisposition syndromes likely tobe encountered in childrenandadolescents. These position articles will be published online asOpen Access publications, so they will be broadly available to themedical community. They will also provide a broadly acceptedinternational consensus of surveillance that may be useful forobtaining third-party coverage of the recommended tests. Never-theless, these recommendations are likely to change over time, asmore experience and information become available. New syn-dromes, as well as more specific information about genotype–phenotype associations and gene–gene or gene–environmentinteractions, will allow screening recommendations to be furthercustomized. Finally, newer technologies in molecular detectionand diagnostic imaging will likely provide less costly, increasinglyeffective, and noninvasive approaches for early cancer detection,which in turn could dramatically reduce required treatment,decrease systemic toxicity, and improve patient outcome.

Disclosure of Potential Conflicts of InterestS.E. Plon is a consultant/advisory board member for Baylor Genetics. No

potential conflicts of interest were disclosed by the other authors.

Grant SupportThis work was supported by the American Association for Cancer Research

and in part by NIH grant U01-HG006485 (to S.E. Plon).

Received March 14, 2017; revised April 20, 2017; accepted April 21, 2017;published online June 1, 2017.

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