Prevalence of germline pathogenic variants in 22 cancer susceptibility genes in Swedish pediatric cancer patients

Abstract

Up to 10% of pediatric cancer patients harbor pathogenic germline variants in one or more cancer susceptibility genes. A recent study from the US reported pathogenic variants in 22 out of 60 analyzed autosomal dominant cancer susceptibility genes, implicating 8.5% of pediatric cancer patients. Here we aimed to assess the prevalence of germline pathogenic variants in these 22 genes in a population-based Swedish cohort and to compare the results to those described in other populations. We found pathogenic variants in 10 of the 22 genes covering 3.8% of these patients. The prevalence of TP53 mutations was significantly lower than described in previous studies, which can largely be attributed to differences in tumor diagnosis distributions across the three cohorts. Matched family history for relatives allowed assessment of familial cancer incidence, however, no significant difference in cancer incidence was found in families of children carrying pathogenic variants compared to those who did not.

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

“…Meanwhile, considering that an additional 5.9% of the patients carried likely pathogenic variants, a few of which might be involved in susceptibility to the disease, this figure might be higher. The results obtained were consistent with previously published data [ 4 , 5 , 6 ]. Recent results from the MSK-IMPACT cohort also pointed the same way [ 46 ].…”

“…Environmental factors, involved in tumor onset during adult ages, are not so relevant in childhood [ 3 ]. However, the incidence and spectrum of mutations predisposing to cancer among children and adolescents are only partially understood [ 4 , 5 , 6 ]. Narod and colleagues claimed, in 1991, that 10% of children with cancer had a genetic predisposition [ 7 ].…”

Population-based whole-genome sequencing with constrained gene analysis identifies predisposing germline variants in children with central nervous system tumors

“…Family cancer incidence did not differ significantly between children with or without predisposing germline alterations, which is in line with findings in comparable cohorts 3,35 . The introduced novel pedigree-based family cancer incidence score, which weighs both the number of relatives registered with and without cancer and their relation to the proband, also did not differ between families of probands harboring pathogenic CPS gene variants.…”

Redefining germline predisposition in children with molecularly characterized ependymoma: a population-based 20-year cohort

“…The gene, which is centromeric to NF2 and SMARCB1 on chromosome 22q11.21, was recently uncovered as a germline predisposition gene in schwannomatosis [ 50 ]. Pathogenic LZTR1 germline variants have been reported in children with different cancer types, including high-grade glioma [ 13 ], but have not been evaluated in the majority of the existing large pan-childhood cancer germline sequencing studies [ 10 , 11 , 16 – 18 ]. Although monozygosity of 22q has been reported in ~ 40% of RELA-fusion positive supratentorial ependymoma (ST-EPN-RELA) [ 52 ], the rarity of pathogenic somatic NF2 variants in the majority of intracranial ependymoma suggests a different tumor suppressor gene to be located on chromosome 22 [ 51 , 53 , 54 ].…”

“…Moreover, their lack of population-based study design may have introduced selection bias. As illustrated by the pathogenic NF2 deletion detected in our cohort, limiting bioinformatic analyses solely to SNVs, as done in one of the reviewed sequencing studies [ 18 ], may miss pathogenic alterations. Also affecting the generalizability of the combined estimate is the fact that the two cohorts contributing 65% (112/173) of the total ependymoma sample size were limited to intracranial ependymoma, likely resulting in underreporting of NF2 -associated cases [ 10 , 13 ].…”