Assessment of Cancer Predisposition Syndromes in a National Cohort of Children With a Neoplasm

Abstract

ImportanceTo improve diagnostics of cancer predisposition syndromes (CPSs) in children with cancer, it is essential to evaluate the effect of CPS gene sequencing among all children with cancer and compare it with genetic testing based on clinical selection. However, a reliable comparison is difficult because recent reports on a phenotype-first approach in large, unselected childhood cancer cohorts are lacking.ObjectiveTo describe a national children’s cancer center’s experience in diagnosing CPSs before introducing routine next-generation sequencing.Design, Setting, and ParticipantsThis retrospective cohort study was conducted at the National Retinoblastoma Treatment Center (Amsterdam, the Netherlands) and the Princess Máxima Center for Pediatric Oncology (Utrecht, Netherlands) and included Dutch pediatric patients with a new diagnosis of neoplasm between June 1, 2018, and December 31, 2019. Follow-up was at least 18 months after neoplasm diagnosis. Data analysis was conducted from July 2021 to February 2022.ExposuresAs part of routine diagnostics, pediatric oncologists and ophthalmologists checked for characteristics of CPSs and selected children for referral to clinical geneticists and genetic testing.Main Outcomes and MeasuresDetected cancer predisposition syndromes.ResultsA total of 824 patients (median [range] age at diagnosis 7.5 [0-18.9] years; 361 girls [44%]) were assessed, including 335 children with a hematological neoplasm (41%) and 489 (59%) with a solid tumor. In 71 of 824 children (8.6%), a CPS was identified, of which most (96%) were identified by a phenotype-driven approach. Down syndrome and neurofibromatosis type 1 were the most common CPSs diagnosed. In 42 of 71 patients (59%), a CPS was identified after these children developed a neoplasm. The specific type of neoplasm was the most frequent indicator for genetic testing, whereas family history played a minor role.Conclusions and RelevanceIn this cohort study of children with a neoplasm, the prevalence of CPSs identified by a phenotype-driven approach was 8.6%. The diagnostic approach for identifying CPSs is currently shifting toward a genotype-first approach. Future studies are needed to determine the diagnostic value, as well as possible disadvantages of CPS gene sequencing among all children with cancer compared with the phenotype-driven approach.

Morbidity and healthcare use among mothers of children with cancer: A population‐based study

“…Studies that did find an increased risk of cancer in first degree relatives of children with cancer noted that there may be an interplay between genetic susceptibility and environmental factors in the etiology of tumors, but that hereditary cancer syndromes could not entirely account for this increased risk. Indeed, recent studies indicate that the rates of children with cancer considered to have an underlying cancer predisposition may be higher than previously thought, reaching approximately 10% 34–36 . However, this prediction is limited by the fact that this is a rapidly evolving field as the numbers of recognized cancer predisposition genes and syndromes, as well as imaging and laboratory techniques to identify these genes are constantly growing and improving 34–36 .…”

“…Indeed, recent studies indicate that the rates of children with cancer considered to have an underlying cancer predisposition may be higher than previously thought, reaching approximately 10%. [34][35][36] However, this prediction is limited by the fact that this is a rapidly evolving field as the numbers of recognized cancer predisposition genes and syndromes, as well as imaging and laboratory techniques to identify these genes are constantly growing and improving. [34][35][36] In our exposed mothers cohort, the three most common cancer diagnoses were breast (36.6%), thyroid (12.2%), and gastrointestinal (11.0%).…”

“…[34][35][36] However, this prediction is limited by the fact that this is a rapidly evolving field as the numbers of recognized cancer predisposition genes and syndromes, as well as imaging and laboratory techniques to identify these genes are constantly growing and improving. [34][35][36] In our exposed mothers cohort, the three most common cancer diagnoses were breast (36.6%), thyroid (12.2%), and gastrointestinal (11.0%). The health administrative data used in our study did not capture the presence or absence of a known All-cause mortality/death 0.8 (0.6-1.2) .24…”

Simultaneous Occurrence of Multiple Neoplasms in Children with Cancer Predisposition Syndromes: Collaborating with Abnormal Genes

“…Minimizing the risk of adverse events, with the development of another metachronous cancer as one of the most important side effects, can improve healthcare delivery [31][32][33]. Very often, patients with CPSs are at higher risk of developing several cancers, not just one type [1,16], so preventive management is essential to avoid increasing the already elevated risk of cancer in these cases. The question "How should we guide treatment?"…”

Diagnostic yield and clinical impact of germline sequencing in children with CNS and extracranial solid tumors—a nationwide, prospective Swedish study

“…A recent retrospective study of a phenotype-first approach for ChiCaP diagnostics demonstrated a diagnostic yield of 8.6%. 11 However, phenotype-first approaches require robust clinical screening tools to identify patients with ChiCaP syndromes. 12 …”