Novel genetic causes of childhood cancer predisposition

Childhood cancer predisposition syndromes (CPS) refer to rare diseases increasing the risk of developing pediatric cancer. Genomic studies have estimated that about 8-18% of children with cancer carry pathogenic variants in CPS genes. This broad diagnostic yield is caused by differences in study designs such as patient inclusion criteria, sequencing methods, number of genes analyzed, and the definition of positive findings. Moreover, the diagnosis of CPS can have important clinical implications for patients including adjusted diagnostic procedures, treatment, surveillance and genetic counselling.

With the ultimate goal of increasing our knowledge on pediatric cancer predisposition, my thesis focused on the study of childhood CPS, using cross- disciplinary methods including register-based, genetic and molecular studies.

In Study I, we compiled a broad pediatric CPS research panel with 881 genes and developed a ranking system that prioritizes genes with established or suspected evidence for their association with childhood cancer predisposition. This panel can be used as a tool for the discovery of known and novel childhood CPS in massively parallel sequencing studies of large pediatric cancer cohorts.

In Studies II - IV, we report the occurrence of cancer in congenital syndromes with previously unknown cancer associations. Specifically, we describe multiple ovarian tumors in a 13-year-old girl with Prader-Willi syndrome (Study II), neuroblastoma in two female patients with Marfan syndrome (Study III), and a soft tissue sarcoma in a 17-year-old boy with Limb-girdle Muscular Dystrophy Recessive 1 (Study IV). Through these reports, we encourage further studies about the possible implication of these rare diseases in cancer development.

In Studies II and V, we used the Swedish national registries to determine the cancer risk spectrum in some of the congenital syndromes mentioned above. In patients with Prader-Willi syndrome (Study II), although we did not find an increased risk of cancer overall, we observed a high frequency of pediatric cancer. Moreover, the low number of pediatric patients with cancer precluded further statistical testing. In individuals with muscular dystrophy (Study V), we found an increased risk of pediatric astrocytomas and other gliomas, as well as an increased risk of adult pancreatic and nonthyroid endocrine tumors. In myotonic dystrophy (Study V), pediatric patients had an increased risk of brain tumors, while adults presented an overall increased cancer risk, explained by various malignancies.

In Study VI, we identified a homozygous variant in the FLCN gene as the genetic cause of a novel multisystemic syndrome in a boy with global developmental delay, short stature, severe immunodeficiency, and leukemia at 1-year of age. We showed that the FLCN p.G15S variant leads to nuclear retention of TFE3/TFEB, resulting in altered expression of genes involved in the lysosomal biogenesis and autophagy pathways. Further, we hypothesize that the FLCN p.G15S variant is hypomorphic, leading to this rare autosomal recessive syndrome.

All in all, this thesis aimed to contribute to a better understanding of childhood CPS.

List of scientific papers

I. Assembling a gene panel for the discovery of novel pediatric cancer predisposition syndromes. Maya-González C, Tesi B, Poluha A, Lagerstedt-Robinson K, Nordgren A#, Taylan F#. [Submitted]

II. Register-based and genetic studies of Prader-Willi syndrome show a high frequency of gonadal tumors and a possible mechanism for tumorigenesis through imprinting relaxation. Maya-González C, Wessman S, Lagerstedt-Robinson K, Taylan F, Tesi B, Kuchinskaya E, McCluggage WG, Poluha A, Holm S, Nergårdh R, Díaz De Ståhl T, Höybye C, Tettamanti G, Delgado-Vega AM, Skarin Nordenvall A, Nordgren A. Frontiers in Medicine, 2023. DOI: 10.3389/fmed.2023.1172565. https://doi.org/10.3389/fmed.2023.1172565

III. Occurrence of cancer in Marfan syndrome: Report of two females with neuroblastoma and review of the literature. Maya-González C, Delgado-Vega AM, Taylan F, Lagerstedt Robinson K, Hansson L, Pal N, Fagman H, Puls F, Wessman S, Stenman J, Georgantzi K, Fransson S, Díaz De Ståhl T, Ek T, Palmer R, Tesi B, Kogner P#, Martinsson T#, Nordgren A#. American Journal of Medical Genetics Part A, 2024. DOI: 10.1002/ajmg.a.63812.
https://doi.org/10.1002/ajmg.a.63812

IV. Pediatric Soft Tissue Sarcoma in Limb-Girdle Muscular Dystrophy: Molecular Findings and Clinical Implications. Maya-González C, Díaz De Ståhl T, Wessman S, Taylan F, Tesi B, Lagerstedt- Robinson K, Tettamanti G, Dukic M, Poluha A, Ljungman G, Nordgren A. American Journal of Case Reports, 2024. DOI: 10.12659/AJCR.945715.
https://doi.org/10.12659/AJCR.945715

V. Cancer Risk in Patients With Muscular Dystrophy and Myotonic Dystrophy: A Register-Based Cohort Study. Maya-González C*, Tettamanti G*, Taylan F, Skarin Nordenvall A, Sejersen T, Nordgren A. Neurology, 2024. https://doi.org/10.1212/WNL.0000000000209883

VI. Biallelic variants in the FLCN gene lead to a novel syndrome with global developmental delay, short stature and immunodeficiency. Maya-González C, Boeckemeier L, Ten Berk de Boer E, Eisfeldt J, Pozzani F, Mhashal A, Campbell T, Bobeck J, Ekholm K, Bryceson Y, Orellana L, Lindqvist A, Nordgren A#, Taylan F#. [Manuscript]

* Shared first authors.

# Shared senior authors.