Selection criteria for assembling a pediatric cancer predisposition syndrome gene panel

AbstractIncreasing use of genomic sequencing enables standardized screening of all childhood cancer predisposition syndromes (CPS) in children with cancer. Gene panels currently used often include adult-onset CPS genes and genes without substantial evidence linking them to cancer predisposition. We have developed criteria to select genes relevant for childhood-onset CPS and assembled a gene panel for use in children with cancer. We applied our criteria to 381 candidate genes, which were selected through two in-house panels (n = 338), a literature search (n = 39), and by assessing two Genomics England’s PanelApp panels (n = 4). We developed evaluation criteria that determined a gene’s eligibility for inclusion on a childhood-onset CPS gene panel. These criteria assessed (1) relevance in childhood cancer by a minimum of five childhood cancer patients reported carrying a pathogenic variant in the gene and (2) evidence supporting a causal relation between variants in this gene and cancer development. 138 genes fulfilled the criteria. In this study we have developed criteria to compile a childhood cancer predisposition gene panel which might ultimately be used in a clinical setting, regardless of the specific type of childhood cancer. This panel will be evaluated in a prospective study. The panel is available on (pediatric-cancer-predisposition-genepanel.nl) and will be regularly updated.

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Proportion of children with cancer that have an indication for genetic counseling and testing based on the cancer type irrespective of other features

Familial Cancer ◽

10.1007/s10689-021-00234-4 ◽

2021 ◽

Author(s):

Thi Minh Kha Nguyen ◽

Astrid Behnert ◽

Torsten Pietsch ◽

Christian Vokuhl ◽

Christian Peter Kratz

Keyword(s):

Childhood Cancer ◽

Rhabdoid Tumor ◽

Juvenile Myelomonocytic Leukemia ◽

Cancer Type ◽

Nerve Sheath Tumor ◽

Children With Cancer ◽

Pediatric Pathology ◽

Cancer Trial ◽

Cancer Predisposition Syndrome ◽

Cancer Types

Abstract In children with cancer, specific clinical features such as physical anomalies, occurrence of cancer in young relatives, specific cancer histologies, and unique mutation/methylation signatures may indicate the presence of an underlying cancer predisposition syndrome (CPS). The proportion of children with a cancer type suggesting a CPS among all children with cancer is unknown. To determine the proportion of children with cancer types suggesting an underlying CPS among children with cancer. We evaluated the number of children with cancer types strongly associated with CPS diagnosed in Germany between 2007 and 2016. Data were obtained from various sources including two national pediatric pathology reference laboratories for brain and solid tumors, respectively, various childhood cancer trial offices as well as the German Childhood Cancer Registry. Among 21,127 children diagnosed with cancer between 2007 and 2016, 2554 (12.1%) had a cancer type strongly associated with a CPS. The most common diagnoses were myelodysplastic syndrome and juvenile myelomonocytic leukemia, retinoblastoma, malignant peripheral nerve sheath tumor, infantile myofibromatosis, medulloblastomaSHH, rhabdoid tumor as well as atypical teratoid/rhabdoid tumor. Based on cancer type only, 12.1% of all children with cancer have an indication for a genetic evaluation. Pediatric oncology patients require access to genetic counselling and testing.

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Recognizing and Managing Children with a Pediatric Cancer Predisposition Syndrome: A Guide for the Pediatrician

Pediatric Annals ◽

10.3928/19382359-20180424-02 ◽

2018 ◽

Vol 47 (5) ◽

pp. e204-e216 ◽

Cited By ~ 2

Author(s):

Stephanie A. Coury ◽

Katherine A. Schneider ◽

Jaclyn Schienda ◽

Wen-Hann Tan

Keyword(s):

Pediatric Cancer ◽

Cancer Predisposition ◽

Cancer Predisposition Syndrome

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Utility of a Cancer Predisposition Screening Tool for Predicting Subsequent Malignant Neoplasms in Childhood Cancer Survivors

Journal of Clinical Oncology ◽

10.1200/jco.21.00018 ◽

2021 ◽

pp. JCO.21.00018

Author(s):

Noelle Cullinan ◽

Ian Schiller ◽

Giancarlo Di Giuseppe ◽

Mohammed Mamun ◽

Lara Reichman ◽

...

Keyword(s):

Cancer Survivors ◽

Childhood Cancer ◽

Conditional Logistic Regression ◽

Childhood Cancer Survivors ◽

Cancer Predisposition ◽

Malignant Neoplasms ◽

Primary Cancer ◽

Primary Malignancy ◽

Control Approach ◽

Cancer Predisposition Syndrome

PURPOSE Childhood cancer survivors (CCS) are at risk of developing subsequent malignant neoplasms (SMNs) resulting from exposure to prior therapies. CCS with underlying cancer predisposition syndromes are at additional genetic risk of SMN development. The McGill Interactive Pediatric OncoGenetic Guidelines (MIPOGG) tool identifies children with cancer at increased likelihood of having a cancer predisposition syndrome, guiding clinicians through a series of Yes or No questions that generate a recommendation for or against genetic evaluation. We evaluated MIPOGG's ability to predict SMN development in CCS. METHODS Using the provincial cancer registry (Ontario, Canada), and adopting a nested case-control approach, we identified CCS diagnosed and/or treated for a primary malignancy before age 18 years (1986-2015). CCS who developed an SMN (cases) were matched, by primary cancer and year of diagnosis, with CCS who did not develop an SMN (controls) over the same period (1:5 ratio). Potential predictors for SMN development (chemotherapy, radiation, and MIPOGG output) were applied retrospectively using clinical data pertaining to the first malignancy. Conditional logistic regression models estimated hazard ratios and 95% CIs associated with each covariate, alone and in combination, for SMN development. RESULTS Of 13,367 children with a primary cancer, 317 (2.4%) developed an SMN and were matched to 1,569 controls. A MIPOGG output recommending evaluation was significantly associated with SMN development (hazard ratio 1.53; 95% CI, 1.06 to 2.19) in a multivariable model that included primary cancer therapy exposures. MIPOGG was predictive of SMN development, showing value in nonhematologic malignancies and in CCS not exposed to radiation. CONCLUSION MIPOGG has additional value for SMN prediction beyond treatment exposures and may be beneficial in decision making for enhanced individualized SMN surveillance strategies for CCS.

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Predictors for participation in DNA self-sampling of childhood cancer survivors in Switzerland

10.1101/2021.05.25.21257796 ◽

2021 ◽

Author(s):

Nicolas Waespe ◽

Sven Strebel ◽

Denis Marino ◽

Veneranda Mattiello ◽

Fanny Muet ◽

...

Keyword(s):

Cancer Survivors ◽

Childhood Cancer ◽

Age Groups ◽

Childhood Cancer Survivors ◽

Cross Sectional Study ◽

Cancer Predisposition ◽

Second Primary ◽

Cross Sectional ◽

Cancer Predisposition Syndrome ◽

Foreign Nationality

Research on germline genetic variants relies on a sufficient number of eligible participants which is difficult to achieve for rare diseases such as childhood cancer. With self-collection kits using saliva or buccal swabs, participants can contribute genetic samples conveniently from their home. We identified determinants of participation in DNA self-collection in this cross-sectional study. We invited 928 childhood cancer survivors in Switzerland with a median age of 26.5 years (interquartile range 18.8-36.5), of which 463 (50%) participated. Foreign nationality (odds ratio [OR] 0.5, 95%-confidence interval [CI] 0.4-0.7), survivors aged 30-39 years at study versus other age groups (OR 0.5, CI 0.4-0.8), and those with a known cancer predisposition syndrome (OR 0.5, CI 0.3-1.0) participated less. Survivors with a second primary neoplasm (OR 1.9, CI 1.0-3.8) or those living in a French or Italian speaking region (OR 1.3, 1.0-1.8) tended to participate more. We showed that half of survivors participate in germline DNA self-sampling relying completely on mailing of sample kits. Foreign nationality, age 30-39 years, and cancer predisposition syndromes were associated with less participation. More targeted recruitment strategies may be advocated for these subgroups. To increase participation in DNA self-sampling, understanding and perceptions of survivors need to be better understood.

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Quality of internet information according to language search on childhood Cancer (Preprint)

10.2196/preprints.25580 ◽

2020 ◽

Author(s):

Yunam Cuan-Baltazar ◽

Maria José Muñóz-Pérez ◽

Elena Soto Vega

Keyword(s):

Childhood Cancer ◽

Health Information ◽

Pediatric Cancer ◽

Information Quality ◽

Cancer Information ◽

The Internet ◽

Children With Cancer ◽

Internet Information ◽

Chi2 Test

BACKGROUND Background: Health information on the internet could vary its quality given that nowadays it is easy for everyone to spread information on the internet even if it is not reliable. Also, one factor that could influence the quality of the information is the language in which it is presented. Parents of children with cancer tend to search for their children´s disease on the internet, and this could affect the decisions the parents take concerning their children´s treatment OBJECTIVE Objective: The aim of this study was to compare the quality of pediatric cancer information on the internet provided in English and Spanish languages METHODS Methods: Three different quality engines were used, JAMA benchmarks, DISCERN and HONcode to assess English and Spanish websites. RESULTS Results: : DISCERN scores were significantly different between English and Spanish websites (Mann-Whitney U test, p<0.001), JAMA benchmarks show a difference between English and Spanish websites (Chi2 test, p=0.009), but HONcode was no different between groups. CONCLUSIONS Conclusions: English websites had a better information quality than Spanish websites.

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Genetic Predisposition to Childhood Cancer in the Genomic Era

Annual Review of Genomics and Human Genetics ◽

10.1146/annurev-genom-083118-015415 ◽

2019 ◽

Vol 20 (1) ◽

pp. 241-263 ◽

Cited By ~ 5

Author(s):

Sharon E. Plon ◽

Philip J. Lupo

Keyword(s):

Childhood Cancer ◽

Pediatric Cancer ◽

Association Studies ◽

Cancer Predisposition ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Pathogenic Variants ◽

Pediatric Cancer Patients ◽

Genes Encoding ◽

Genome Analyses

Developments over the past five years have significantly advanced our ability to use genome-scale analyses—including high-density genotyping, transcriptome sequencing, exome sequencing, and genome sequencing—to identify the genetic basis of childhood cancer. This article reviews several key results from an expanding number of genomic studies of pediatric cancer: ( a) Histopathologic subtypes of cancers can be associated with a high incidence of germline predisposition, ( b) neurodevelopmental disorders or highly penetrant cancer predisposition syndromes can result from specific patterns of variation in genes encoding the SMARC family of chromatin remodelers, ( c) genome-wide association studies with relatively small pediatric cancer cohorts have successfully identified single-nucleotide polymorphisms with large effect sizes and provided insight into population differences in cancer risk, and ( d) multiple exome or genome analyses of unselected childhood cancer cohorts have yielded a 7–10% incidence of pathogenic variants in cancer predisposition genes. This work supports the increasing use of genomic sequencing in the care of pediatric cancer patients and at-risk family members.

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Effective identification of cancer predisposition syndromes in children with cancer employing a questionnaire

Familial Cancer ◽

10.1007/s10689-021-00233-5 ◽

2021 ◽

Author(s):

Miriam Schwermer ◽

Astrid Behnert ◽

Beate Dörgeloh ◽

Tim Ripperger ◽

Christian P. Kratz

Keyword(s):

Medical School ◽

Comparative Effectiveness Research ◽

Comparative Effectiveness ◽

Cancer Predisposition ◽

Effectiveness Research ◽

Newly Diagnosed ◽

Children With Cancer ◽

Hannover Medical School ◽

Cancer Predisposition Syndrome ◽

Time Periods

AbstractApproximately 10% of children with newly diagnosed cancer have a cancer predisposition syndrome (CPS). The optimal diagnostic approach to identify them among children diagnosed with cancer is unknown. Objective: To determine whether the use of a one-page questionnaire can improve the CPS diagnosis among children with an oncologic condition. Design: Comparative effectiveness research. Setting: Referral center for children with cancer. Results: 739 children diagnosed with an oncologic condition between 2012 and 2019. All children with a newly diagnosed oncologic condition presenting to Hannover Medical School between January 1st 2017 and December 31st 2019 were prospectively evaluated with a CPS questionnaire. Children in whom the questionnaire suggested the need of a genetic workup were further evaluated. All children diagnosed with an oncologic condition between January 1st 2012 and December 31st 2016 served as control. The CPS diagnoses established during both time periods were evaluated and compared. A CPS was diagnosed in 27 out of 287 children (9.4%) during the questionnaire period versus 24 out of 452 children (5.3%) during the control period (P = 0.032). Conclusion: The CPS questionnaire appears to significantly improve the diagnosis of children with CPS among children with a newly diagnosed oncologic condition.

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National Childhood Cancer Plan Prepared by the National Center of Pediatric Hematology, Oncology and Immunology and the National Society of Pediatric Hematologists and Oncologists as a New Successful Strategy

Journal of Global Oncology ◽

10.1200/jgo.18.78000 ◽

2018 ◽

Vol 4 (Supplement 2) ◽

pp. 166s-166s

Author(s):

K. Kirgizov ◽

G. Muftakhova ◽

G. Serik ◽

S. Kogan ◽

S. Varfolomeeva ◽

...

Keyword(s):

Childhood Cancer ◽

Cancer Registry ◽

Pediatric Cancer ◽

Cancer Control ◽

National Society ◽

Close Collaboration ◽

Children With Cancer ◽

Multicenter Studies ◽

Educational Activities ◽

Pediatric Hematology

Background and context: More than 4000 cases of pediatric cancer registered in Russia annually. Overall survival for pediatric cancer is about 80% and improved from 10% during last 25 years. Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology (Center) and the National Society of Pediatric Hematologists and Oncologists (NSPHO) played a major role in this movement. Aim: Build new childhood cancer control plan based on close collaboration of 86 centers and departments of pediatric oncology. Strategy/Tactics: Plan is based on close collaboration between leading Center and NSPHO (representative of all centers) and supported by the government and the Ministry of Health. Plan developed as the result of analysis of strengths, weaknesses, threats and possible opportunities. Strengths: unique standards (guidelines and protocols) for pediatric cancer for all country with the financial governmental support, strong society (NSPHO), availability of modern technologies and rapid improvement of rehabilitation for children with cancer. Weaknesses: absence of national pediatric cancer registry, lack of high quality oncology nursing, comparable low publication activity. Opportunities: building of the national pediatric cancer registry, increasing of number of multicenter studies, implementation of the new technologies (cellular and gene therapy) and active educational activities based on international collaboration. Program/Policy process: Dmitry Rogachev Center in charge of pediatric hematology, oncology and immunology for Russia and NSPHO is key society. Strategy: scientific analysis and continuous improving of standards (guidelines and protocols) based on multicenter studies; building the morphologically-based national pediatric hematology/oncology registry; continuous development of professional standards for education and quality control; capacity building; scientific and educational activities (national meetings, schools for healthcare professionals, regional educational programs, Russian CME accreditation, outreach programs). Outcomes: Sixty guidelines were prepared, this work is continuing. Morphologic study for more than 13,000 children was made in Dmitry Rogachev Center (all suspicious cases controlled). New standards prepared and discussed. National telemedicine network formed (consulting, case registration, database updates, etc.). More than 5000 cases were consulted through this system in 2017. CME educational seminars (on/off-line) organized. About 12 regions of Russia visited annually with preparation of the report with proposals for improvement of regional service for children with cancer. What was learned: Success is based on close collaboration between Center, Society and Government (all aspects of pediatric cancer control from diagnostics to education covered). This experience could be implemented in the countries with post-Soviet model of healthcare.

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