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To investigate germline predisposition in lymphoma, we performed whole-exome sequencing and discovered a novel variant (c.817-1G>T) in programmed cell death 1 ligand 2 (PD-L2) in a family with early-onset lymphomas and other cancers. The variant was present in the proband with follicular lymphoma and his son with Hodgkin's lymphoma. It was in the terminal splice acceptor site of PD-L2 and embedded in a putative enhancer of Janus kinase 2 (JAK2) and programmed cell death 1 ligand (PD-L1). We also found that gene expression of PD-L2, PD-L1, and JAK2 was significantly increased. Using 3' rapid amplification of cDNA ends (3' RACE), we detected an abnormal PD-L2 transcript in the son. Thus, the c.817-1G>T variant may result in the elevated PD-L2 expression due to the abnormal PD-L2 transcript and the elevated PD-L1 and JAK2 expression due to increased enhancer activity of PD-L1 and JAK2. The PD-L2 novel variant likely underlies the genetic etiology of the lymphomas in the family. As PD-L2 plays critical roles in tumor immunity, identification of PD-L2 as a germline predisposition gene may inform personalized immunotherapy in lymphoma patients.
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Antígeno B7-H1 , Linfoma , Proteína 2 Ligante de Morte Celular Programada 1 , Antígeno B7-H1/genética , Exoma , Predisposição Genética para Doença , Humanos , Ligantes , Linfoma/genética , Proteína 2 Ligante de Morte Celular Programada 1/genética , Sequenciamento do ExomaRESUMO
PURPOSE: Individuals with cancer predisposition syndromes (CPS) are often followed in cancer screening programs, which aim to detect early stage tumors. While cancer surveillance has the potential to improve patient outcomes, its psychosocial impact is uncharacterized in the pediatric population. We examined the cancer surveillance experience from the perspectives of adolescents and parents of children at risk of developing cancer. PATIENTS AND METHODS: Using grounded theory and thematic analysis qualitative methodology, we conducted semi-structured interviews with parents and adolescents, separately. Interviews were transcribed verbatim and coded separately to derive overlapping and unique themes. RESULTS: We completed 20 semi-structured interviews (11 parents and nine adolescents). Positive experiences were related to feelings of reassurance and taking a proactive approach. Both adolescents and parents experienced worry, related to practical aspects of screening, and related to the reminder of cancer risk that manifests with surveillance appointments. This worry was cyclical, associated with appointments, and generally waned over time. Participants felt that the benefits of surveillance outweighed perceived challenges. Open communication with health care providers, and equipping parents/adolescents with vocabulary to discuss their diagnosis and care with others, were felt to be important for mitigating worries associated with cancer risk and surveillance. CONCLUSION: Parents and adolescents experience worry associated with surveillance for CPS, which may warrant regular psychosocial support, particularly during the first year following CPS diagnosis. Enhancing communication with the health care team and among and beyond immediate family members represents an additional important strategy to mitigate adverse experiences and perceptions.
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Cuidadores , Suscetibilidade a Doenças , Neoplasias , Adolescente , Criança , Comunicação , Humanos , Neoplasias/diagnóstico , Pais , Pesquisa QualitativaRESUMO
OBJECTIVE: Disease spectrum in pediatric sarcoma differs substantially from adults. We report a cohort of very young children with non-rhabdomyosarcoma soft tissue sarcoma (NRSTS) detailing their molecular features, treatment, and outcome. METHODS: We report features of consecutive children (age <2 years) with NRSTS (2000-2017). Archival pathological material was re-reviewed, with additional molecular techniques applied where indicated. RESULTS: Twenty-nine patients (16 females, 55%) were identified (median age 6 months; range 0-23). Most common diagnoses included infantile fibrosarcoma (IFS, n = 14, 48%), malignant rhabdoid tumor (MRT, n = 4, 14%), and undifferentiated sarcoma (n = 4, 14%). Twenty-seven of 29 (93%) had tumor molecular characterization to confirm diagnosis. Clinical presentation included a swelling/mass (n = 23, 79%). Disease extent was localized (n = 20, 69%), locoregional (n = 6, 21%), or metastatic (n = 3, 10%). Seventeen of 29 (59%) who underwent surgery achieved complete resection (R0). Other treatments included conventional chemotherapy (n = 26, 90%), molecularly targeted therapies (n = 3, 10%), and radiation (n = 5, 17%). At last follow-up (median 3 years; range 0.3-16.4), 23 (79%) were alive, disease-free and six (21%) had died of disease. All patients with IFS were alive and all those with MRT died. A cancer predisposition syndrome (CPS) was confirmed in three of 10 (30%) genetically tested patients. CONCLUSION: We recommend tumor molecular characterization in all young patients including evaluation for CPS to optimize treatment options and prognostication.
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Sarcoma , Neoplasias de Tecidos Moles , Intervalo Livre de Doença , Feminino , Fibrossarcoma/diagnóstico , Fibrossarcoma/terapia , Humanos , Lactente , Recém-Nascido , Masculino , Tumor Rabdoide/diagnóstico , Tumor Rabdoide/terapia , Sarcoma/diagnóstico , Sarcoma/terapia , Neoplasias de Tecidos Moles/diagnóstico , Neoplasias de Tecidos Moles/terapiaRESUMO
Von Hippel-Lindau disease (VHL) is a heritable condition caused by pathogenic variants in VHL and is characterized by benign and malignant lesions in the central nervous system (CNS) and abdominal viscera. Due to its variable expressivity, existing efforts to collate VHL patient data do not adequately capture all VHL manifestations. We developed a comprehensive and standardized VHL database in the web-based application, REDCap, that thoroughly captures all VHL manifestation data. As an initial trial, information from 86 VHL patients from the University Health Network/Hospital for Sick Children was populated into the database. Analysis of this cohort showed missense variants occurring with the greatest frequency, with all variants localizing to the α- or ß-domains of VHL. The most prevalent manifestations were central nervous system (CNS), renal, and retinal neoplasms, which were associated with frameshift variants and large deletions. We observed greater age-related penetrance for CNS hemangioblastomas with truncating variants compared to missense, while the reverse was true for pheochromocytomas. We demonstrate the utility of a comprehensive VHL database, which supports the standardized collection of clinical and genetic data specific to this patient population. Importantly, we expect that its web-based design will facilitate broader international collaboration and lead to a better understanding of VHL.
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Hemangioblastoma/genética , Feocromocitoma/genética , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Doença de von Hippel-Lindau/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Canadá/epidemiologia , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/patologia , Criança , Pré-Escolar , Feminino , Hemangioblastoma/epidemiologia , Hemangioblastoma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto/genética , Linhagem , Penetrância , Feocromocitoma/epidemiologia , Feocromocitoma/patologia , Adulto Jovem , Doença de von Hippel-Lindau/epidemiologia , Doença de von Hippel-Lindau/patologiaRESUMO
BACKGROUND: von Hippel-Lindau (vHL) syndrome is a rare autosomal-dominant disorder that confers a lifelong risk for developing both benign and malignant tumours in multiple organs. Recent evidence suggests that vHL may exhibit genetic anticipation (GA). The aim of this study was to determine if GA occurs in vHL, and if telomere shortening may be a factor in GA. METHODS: A retrospective chart review of vHL families seen at The Hospital for Sick Children between 1984 and 2016 was performed. Age of onset (AOO, defined as the age of first physician-diagnosed vHL-related manifestation) was confirmed for 96 patients from 20 unrelated families (80 clinically affected and 16 unaffected carriers). Flow-FISH(flow cytometry sorting of cells whose telomeres are labeled by Fluorescence In Situ Hybridization) was used to measure mean telomere length of six white blood cell subtypes from 14 known VHL pathogenic variant carriers. RESULTS: The median AOO for generations I, II and III were 32.5, 22.5 and 12.0 years, respectively. The differences in the AOO between generations were highly significant using a Cox proportional hazards model (P=6.00×10-12). Telomere lengths were significantly different for granulocytes and natural killer lymphocytes of patients with vHL compared with age-matched controls. For six vHL parent-child pairs, median white blood cell telomere lengths between parent and child were not significantly different. CONCLUSIONS: Our results suggest that vHL telomere abnormalities may be primarily somatic in origin rather than a cause of GA. As tumour development exhibits GA in our cohort, vHL surveillance guidelines may need to account for a patient's generational position within a vHL pedigree.
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Antecipação Genética , Predisposição Genética para Doença , Encurtamento do Telômero/genética , Doença de von Hippel-Lindau/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Citometria de Fluxo , Granulócitos/metabolismo , Granulócitos/patologia , Heterozigoto , Humanos , Hibridização in Situ Fluorescente , Lactente , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/patologia , Masculino , Linhagem , Telômero/genética , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Adulto Jovem , Doença de von Hippel-Lindau/patologiaRESUMO
BACKGROUND: To expand the current knowledge of DICER1 syndrome and to propose criteria for genetic testing based on experience at a pediatric tertiary care center. PROCEDURE: This study involved a retrospective chart review of the 78 patients (47 probands and 31 family members) seen in the Cancer Genetics Program at The Hospital for Sick Children (SickKids) who were offered genetic testing for DICER1. RESULTS: Of 47 probands offered genetic testing for DICER1, 46 pursued testing: 11 (23.9%) carried a pathogenic variant and one proband (2.1%) carried a missense variant of uncertain significance with evidence for pathogenicity. Thirty-one family members of variant-positive probands were offered testing: eight of the 25 who agreed to testing carried their familial variant (32.0%). Overall, 20 patients were identified to have a variant in DICER1 (eight males, 12 females). Of these, 13 (65.0%) presented with clinical manifestations associated with the syndrome. The most common lesions were pleuropulmonary blastoma (PPB) (five of 20 patients, 25.0%) and pineoblastoma (three of 20 patients, 15.0%). The average age at which individuals were diagnosed with a primary neoplasm was 5.2 years (range 0.8-20 years, median 3.0). Surveillance at our institution, with a median follow-up time of 23 months, has identified PPB in two asymptomatic individuals. These lesions were identified at early stages, thus potentially reducing treatment-related morbidity and mortality. CONCLUSION: This study further delineates the DICER1 syndrome phenotype and demonstrates the feasibility of a DICER1 syndrome surveillance protocol for the early detection of tumors.
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Neoplasias Encefálicas/genética , Síndromes Neoplásicas Hereditárias/genética , Glândula Pineal , Pinealoma/genética , Blastoma Pulmonar/genética , Adolescente , Adulto , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Síndromes Neoplásicas Hereditárias/mortalidade , Síndromes Neoplásicas Hereditárias/patologia , Pinealoma/mortalidade , Pinealoma/patologia , Blastoma Pulmonar/mortalidade , Blastoma Pulmonar/patologiaRESUMO
BACKGROUND: DICER1 syndrome, arising from a mutation in the DICER1 gene mapped to chromosome 14q32, is associated with an increased risk of a range of benign and malignant neoplasms. OBJECTIVE: To determine the spectrum of abnormalities and imaging characteristics in patients with DICER1 syndrome at a tertiary pediatric hospital. MATERIALS AND METHODS: This retrospective analysis evaluated imaging in patients ≤18 years with DICER1 germline variants between January 2004 and July 2016. An imaging database search including keywords pleuropulmonary blastoma, cystic nephroma, pineoblastoma, embryonal rhabdomyosarcoma, ovarian sex cord-stromal tumor, ovarian Sertoli-Leydig cell tumor and DICER1 syndrome, was cross-referenced against the institutional Cancer Genetics Program database, excluding patients with negative/unknown DICER1 gene testing. RESULTS: Sixteen patients were included (12 females; mean age at presentation: 4.2 years, range: 14 days to 17 years), with surveillance imaging encompassing the following modalities: chest X-ray and CT; abdominal, pelvic and neck US; and brain and whole-body MRI. Malignant lesions (68.8% of patients) included pleuropulmonary blastoma (5), pineoblastoma (3), ovarian Sertoli-Leydig cell tumor (1), embryonal rhabdomyosarcoma (1) and renal sarcoma (1); benign lesions (37.5% of patients) included thyroid cysts (2), thyroid nodules (2), cystic nephroma (2), renal cysts (1) and pineal cyst (1). A common lesional appearance observed across modalities and organs was defined as the "cracked windshield" sign. CONCLUSION: The spectrum of DICER1-related tumors and the young age at presentation suggest early surveillance of at-risk patients is critical, while minimizing exposure to ionizing radiation.
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RNA Helicases DEAD-box/genética , Neoplasias/diagnóstico por imagem , Neoplasias/genética , Ribonuclease III/genética , Adolescente , Criança , Pré-Escolar , Diagnóstico Diferencial , Feminino , Predisposição Genética para Doença , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , Fenótipo , Estudos Retrospectivos , SíndromeRESUMO
BACKGROUND: Carriers of a germline TP53 pathogenic variant have a substantial lifetime risk of developing cancer. In 2011, we did a prospective observational study of members of families who chose to either undergo a comprehensive surveillance protocol for individuals with Li-Fraumeni syndrome or not. We sought to update our assessment of and modify the surveillance protocol, so in this study we report both longer follow-up of these patients and additional patients who underwent surveillance, as well as update the originally presented surveillance protocol. METHODS: A clinical surveillance protocol using physical examination and frequent biochemical and imaging studies (consisting of whole-body MRI, brain MRI, breast MRI, mammography, abdominal and pelvic ultrasound, and colonoscopy) was introduced at three tertiary care centres in Canada and the USA on Jan 1, 2004, for carriers of TP53 pathogenic variants. After confirmation of TP53 mutation, participants either chose to undergo surveillance or chose not to undergo surveillance. Patients could cross over between groups at any time. The primary outcome measure was detection of asymptomatic tumours by surveillance investigations. The secondary outcome measure was 5 year overall survival established from a tumour diagnosed symptomatically (in the non-surveillance group) versus one diagnosed by surveillance. We completed survival analyses using an as-treated approach. FINDINGS: Between Jan 1, 2004, and July 1, 2015, we identified 89 carriers of TP53 pathogenic variants in 39 unrelated families, of whom 40 (45%) agreed to surveillance and 49 (55%) declined surveillance. 19 (21%) patients crossed over from the non-surveillance to the surveillance group, giving a total of 59 (66%) individuals undergoing surveillance for a median of 32 months (IQR 12-87). 40 asymptomatic tumours have been detected in 19 (32%) of 59 patients who underwent surveillance. Two additional cancers were diagnosed between surveillance assessments (false negatives) and two biopsied lesions were non-neoplastic entities on pathological review (false positives). Among the 49 individuals who initially declined surveillance, 61 symptomatic tumours were diagnosed in 43 (88%) patients. 21 (49%) of the 43 individuals not on surveillance who developed cancer were alive compared with 16 (84%) of the 19 individuals undergoing surveillance who developed cancer (p=0·012) after a median follow-up of 46 months (IQR 22-72) for those not on surveillance and 38 months (12-86) for those on surveillance. 5 year overall survival was 88·8% (95% CI 78·7-100) in the surveillance group and 59·6% (47·2-75·2) in the non-surveillance group (p=0·0132). INTERPRETATION: Our findings show that long-term compliance with a comprehensive surveillance protocol for early tumour detection in individuals with pathogenic TP53 variants is feasible and that early tumour detection through surveillance is associated with improved long-term survival. Incorporation of this approach into clinical management of these patients should be considered. FUNDING: Canadian Institutes for Heath Research, Canadian Cancer Society, Terry Fox Research Institute, SickKids Foundation, and Soccer for Hope Foundation.
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Biomarcadores Tumorais/metabolismo , Mutação em Linhagem Germinativa/genética , Síndrome de Li-Fraumeni/genética , Imagem Multimodal/métodos , Neoplasias/genética , Vigilância da População , Proteína Supressora de Tumor p53/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Seguimentos , Predisposição Genética para Doença , Heterozigoto , Humanos , Lactente , Recém-Nascido , Síndrome de Li-Fraumeni/diagnóstico por imagem , Síndrome de Li-Fraumeni/metabolismo , Síndrome de Li-Fraumeni/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias/diagnóstico por imagem , Neoplasias/metabolismo , Neoplasias/patologia , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida , Adulto JovemRESUMO
The discovery of disease-causing mutations typically requires confirmation of the variant or gene in multiple unrelated individuals, and a large number of rare genetic diseases remain unsolved due to difficulty identifying second families. To enable the secure sharing of case records by clinicians and rare disease scientists, we have developed the PhenomeCentral portal (https://phenomecentral.org). Each record includes a phenotypic description and relevant genetic information (exome or candidate genes). PhenomeCentral identifies similar patients in the database based on semantic similarity between clinical features, automatically prioritized genes from whole-exome data, and candidate genes entered by the users, enabling both hypothesis-free and hypothesis-driven matchmaking. Users can then contact other submitters to follow up on promising matches. PhenomeCentral incorporates data for over 1,000 patients with rare genetic diseases, contributed by the FORGE and Care4Rare Canada projects, the US NIH Undiagnosed Diseases Program, the EU Neuromics and ANDDIrare projects, as well as numerous independent clinicians and scientists. Though the majority of these records have associated exome data, most lack a molecular diagnosis. PhenomeCentral has already been used to identify causative mutations for several patients, and its ability to find matching patients and diagnose these diseases will grow with each additional patient that is entered.
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Predisposição Genética para Doença/genética , Disseminação de Informação/métodos , Doenças Raras/genética , Bases de Dados Genéticas , Variação Genética , Genótipo , Humanos , Fenótipo , Software , Interface Usuário-Computador , NavegadorRESUMO
In July 2023, the American Association for Cancer Research held the second Childhood Cancer Predisposition Workshop at which international experts in pediatric cancer predisposition met to update the previously published 2017 consensus statements on pediatric cancer predisposition syndromes. Since 2017, advances in tumor and germline genetic testing and increased understanding of cancer predisposition in pediatric cancer patients have led to significant changes in clinical care. Here, we provide an updated genetic counseling framework for pediatric oncology professionals. The framework includes: (1) referral indications and timing; (2) somatic and germline genetic testing options; (3) testing for adult-onset cancer predisposition syndromes in children with and without cancer; (4) evolving genetic counseling models to meet the increased demand for genetic testing; (5) barriers to cancer genetic testing and surveillance in children; and (6) psychosocial and equity considerations regarding cancer genetic testing and surveillance in children. Adaptable genetic counseling services are needed to provide support to pediatric oncology provider teams and diverse patients with pediatric cancer, cancer predisposition, and their families.
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Rhabdoid tumor predisposition syndrome type-1 (RTPS1) is characterized by germline pathogenic variants in SMARCB1 and development of INI1-deficient rhabdoid tumors in early childhood. Due to its poor prognosis, the risk of subsequent tumor development and the impact of surveillance at later ages are poorly understood. We retrospectively reviewed individuals referred to the Cancer Genetics Program at The Hospital for Sick Children for SMARCB1 genetic testing and/or surveillance for RTPS1. In addition, to explore characteristics of late-onset tumors in RTPS1, a literature review was conducted. Of eighty-three individuals (55 probands and 28 family members), 12 probands and 4 family members were genetically confirmed with RTPS1. Four pediatric probands with RTPS1 underwent surveillance. An additional three individuals, including one patient with 22q11.2 distal deletion without history of tumor, one patient with negative genetic testing results but clinically diagnosed with RTPS1, and one sibling identified through cascade testing, underwent surveillance. Three patients with RTPS1 developed tumors between the ages of 9 and 17, including malignant rhabdoid tumors (N = 3), schwannomas (N = 4), and epithelioid malignant peripheral nerve sheath tumor (N = 1). Three of these lesions were asymptomatically detected by surveillance. A literature review revealed 17 individuals with RTPS1 who developed INI1-deficient tumors after age five. Individuals with RTPS1 remain at elevated risk for developing INI1-deficient tumors after the peak age of rhabdoid tumor in early childhood. Extension of surveillance beyond 5 years of age could lead to improved survival and reduced morbidity for these patients, and prospective evaluation of revised approaches will be important.
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We conducted integrative somatic-germline analyses by deeply sequencing 864 cancer-associated genes, complete genomes and transcriptomes for 300 mostly previously treated children and adolescents/young adults with cancer of poor prognosis or with rare tumors enrolled in the SickKids Cancer Sequencing (KiCS) program. Clinically actionable variants were identified in 56% of patients. Improved diagnostic accuracy led to modified management in a subset. Therapeutically targetable variants (54% of patients) were of unanticipated timing and type, with over 20% derived from the germline. Corroborating mutational signatures (SBS3/BRCAness) in patients with germline homologous recombination defects demonstrates the potential utility of PARP inhibitors. Mutational burden was significantly elevated in 9% of patients. Sequential sampling identified changes in therapeutically targetable drivers in over one-third of patients, suggesting benefit from rebiopsy for genomic analysis at the time of relapse. Comprehensive cancer genomic profiling is useful at multiple points in the care trajectory for children and adolescents/young adults with cancer, supporting its integration into early clinical management.
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Neoplasias , Adulto Jovem , Adolescente , Humanos , Criança , Neoplasias/tratamento farmacológico , Neoplasias/genética , Mutação , Genômica , Transcriptoma/genética , Recombinação HomólogaRESUMO
PURPOSE: The SickKids Cancer Sequencing (KiCS) Program, launched in 2016, evaluates the clinical utility of paired tumor/germline Next-Generation Sequencing (NGS) in pediatric oncology patients with hard-to-cure and rare cancers. In anticipation of further widespread adoption of NGS, we aimed to characterize the experiences and perspectives of adolescents and parents of patients who have already undergone NGS evaluation, focusing on the psychosocial impact and personal utility. METHODS: Parents of patients with pediatric cancer and adolescent patients who have participated in KiCS were invited to participate in semistructured interviews. Transcripts were analyzed using an inductive content analytic approach. RESULTS: Of 45 individuals invited, 22 parents and 10 adolescents were interviewed (71% response rate). Prominent psychosocial themes were low distress, relief, and sense of control; some expressed fear of the unknown. In exploring constructs of personal utility, parents highlighted hope for treatment options despite low expectations for results with clinical impact, whereas adolescents articulated altruistic motivations and less hope for personal clinical benefit. Bringing closure and answering the question of why the cancer occurred was a salient theme among both groups. Both parents and adolescents find benefit and clear decisional satisfaction with participation. No participants expressed regret. CONCLUSION: This study suggests that parents and adolescents benefit from NGS evaluation beyond the return of clinically relevant results. Our findings lay the framework for future work evaluating the value of NGS in pediatric precision oncology care through assessment of patient-reported outcomes and experiences. These results also guide provision of pre- and post-test education and support, which will facilitate patient-centered delivery of NGS practices.
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Neoplasias , Adolescente , Criança , Emoções , Humanos , Oncologia , Neoplasias/terapia , Pais/psicologia , Medicina de PrecisãoRESUMO
PURPOSE: Constitutional mismatch repair deficiency syndrome (CMMRD) is a lethal cancer predisposition syndrome characterized by early-onset synchronous and metachronous multiorgan tumors. We designed a surveillance protocol for early tumor detection in these individuals. PATIENTS AND METHODS: Data were collected from patients with confirmed CMMRD who were registered in the International Replication Repair Deficiency Consortium. Tumor spectrum, efficacy of the surveillance protocol, and malignant transformation of low-grade lesions were examined for the entire cohort. Survival outcomes were analyzed for patients followed prospectively from the time of surveillance implementation. RESULTS: A total of 193 malignant tumors in 110 patients were identified. Median age of first cancer diagnosis was 9.2 years (range: 1.7-39.5 years). For patients undergoing surveillance, all GI and other solid tumors, and 75% of brain cancers were detected asymptomatically. By contrast, only 16% of hematologic malignancies were detected asymptomatically (P < .001). Eighty-nine patients were followed prospectively and used for survival analysis. Five-year overall survival (OS) was 90% (95% CI, 78.6 to 100) and 50% (95% CI, 39.2 to 63.7) when cancer was detected asymptomatically and symptomatically, respectively (P = .001). Patient outcome measured by adherence to the surveillance protocol revealed 4-year OS of 79% (95% CI, 54.8 to 90.9) for patients undergoing full surveillance, 55% (95% CI, 28.5 to 74.5) for partial surveillance, and 15% (95% CI, 5.2 to 28.8) for those not under surveillance (P < .0001). Of the 64 low-grade tumors detected, the cumulative likelihood of transformation from low-to high-grade was 81% for GI cancers within 8 years and 100% for gliomas in 6 years. CONCLUSION: Surveillance and early cancer detection are associated with improved OS for individuals with CMMRD.