Germline Predisposition to Pediatric Cancer, from Next Generation Sequencing to Medical Care

Abstract

Knowledge about genetic predisposition to pediatric cancer is constantly expanding. The categorization and clinical management of the best-known syndromes has been refined over the years. Meanwhile, new genes for pediatric cancer susceptibility are discovered every year. Our current work shares the results of genetically studying the germline of 170 pediatric patients diagnosed with cancer. Patients were prospectively recruited and studied using a custom panel, OncoNano V2. The well-categorized predisposing syndromes incidence was 9.4%. Likely pathogenic variants for predisposition to the patient’s tumor were identified in an additional 5.9% of cases. Additionally, a high number of pathogenic variants associated with recessive diseases was detected, which required family genetic counseling as well. The clinical utility of the Jongmans MC tool was evaluated, showing a high sensitivity for detecting the best-known predisposing syndromes. Our study confirms that the Jongmans MC tool is appropriate for a rapid assessment of patients; however, the updated version of Ripperger T criteria would be more accurate. Meaningfully, based on our findings, up to 9.4% of patients would present genetic alterations predisposing to cancer. Notably, up to 20% of all patients carry germline pathogenic or likely pathogenic variants in genes related to cancer and, thereby, they also require expert genetic counseling. The most important consideration is that the detection rate of genetic causality outside Jongmans MC et al. criteria was very low.

Diagnostic Strategies and Algorithms for Investigating Cancer Predisposition Syndromes in Children Presenting with Malignancy

“…Knowledge about the prevalence of CPSs in children presenting with malignancy is critical to appropriately designing the optimal pathway to screen this population. The proportion of childhood cancer secondary to germline genetic predisposition, which was estimated to be around 4% in the ‘90s [ 14 ], grew to approximately 10% in broad sequencing studies performed in the last 10 years, probably due to the identification of previously unrecognized CPSs and the advancement of the available technologies for genetic sequencing [ 3 , 12 , 13 , 15 , 16 , 17 , 18 , 19 , 20 ]. The 10 main studies analyzing the prevalence of CPS-associated variants in children and adolescents diagnosed with cancer are shown in Table 1 .…”

“…Interestingly, this proportion did not vary substantially among different studies even if performed in diverse populations and settings. Important exceptions characterized by a lower diagnostic yield are the cohorts described by Wang et al [ 15 ] and the cohort described by Von Stedingk et al [ 19 ]. The study by Wang included 3006 childhood cancer survivors, showing only a 5.8% prevalence of pathogenic or likely pathogenic variants (PV or LPV) for CPSs.…”

Genetic Disorders with Predisposition to Paediatric Haematopoietic Malignancies—A Review

“…Specific features which should be taken into consideration are congenital anomalies, facial dysmorphisms, intellectual disability, aberrant growth, skin anomalies, haematological disorders, and immune deficiency. Gargallo et al evaluated Jongmans et al’s tool in relation to pathogenic mutations and found a sensitivity of 94% and a specificity of 77% in their cohort [ 3 ]. Jongmans et al’s criteria modification by Ripperger et al (with an added category of genetic tumour analysis which may reveal a defect suggesting a germline predisposition and expanded list of cancer types associated with CPS, presented in Figure 1 ) was found to have 100% sensitivity in this cohort [ 3 , 101 ].…”

“…Gargallo et al evaluated Jongmans et al’s tool in relation to pathogenic mutations and found a sensitivity of 94% and a specificity of 77% in their cohort [ 3 ]. Jongmans et al’s criteria modification by Ripperger et al (with an added category of genetic tumour analysis which may reveal a defect suggesting a germline predisposition and expanded list of cancer types associated with CPS, presented in Figure 1 ) was found to have 100% sensitivity in this cohort [ 3 , 101 ]. Schwermer et al also reported a significant impact of the CPS questionnaire on diagnosis improvement.…”

“…The past decade, with large-scale genomic analyses, gave a possibility for better understanding of genetic disorders with predisposition to paediatric cancer. However, the prevalence of cancer predisposition mutations among children is still incompletely known and is reported in 7–10% of paediatric cancer patients [ 3 , 4 , 5 ]. Germline mutations are genetic variants that occur in gametes and are present in every cell of an offspring.…”