Cancer risk and predisposition in families with childhood cancer

Abstract: BACKGROUND: Recent whole genome sequencing studies report that up to 6% of the childhood cancer population harbour a pathogenic variant. Identification of families with hereditary cancer may improve early detection of cancer as well as treatment outcome. AIMS: The overall aim of this thesis was to investigate familial cancer risk in relatives of children with cancer and assess the prevalence of pathogenic germline variants.METHODS: Pediatric cancer patients included in the Lund Childhood Cancer Genetic study provided blood samples after informed consent. The Swedish Population- and Cancer Register were used to identify relatives with cancer diagnoses up to the third degree of relation. The relative risk for relatives was calculated. Illumina HiSeq 2500 was used to sequence DNA from patient blood for 22 cancer predisposition genes.RESULTS: Study I: 41/528 families (7.8%) had multiple pediatric cancer cases up to the third degree of relation. Related children with cancer often had the same cancer diagnosis and were more likely to be female. Study II: We report an increased risk for adult cancer (SIR 1.07) and pediatric cancer (SIR 1.48) in 16,430 relatives of 757 children with cancer up to the third degree of relation. The results were unchanged when excluding 30 families of children with known germline pathogenic variants. Study III: Among 790 children with cancer, 3.8% carried one of the 22 most frequent pathogenic germline variants, resulting in 4.9% when correcting for diagnosis distribution. The prevalence of pathogenic variants for childhood cancer diagnoses was in line with recent whole genomic sequencing studies. CONCLUSIONS: Family members of children with cancer have an increased cancer risk compared to the general population, which is not explained by known pathogenic germline variants alone. This thesis supports the need for further studies on genomics as well as other potential causes of pediatric and familial cancer.