Congenital heart disease, genetic syndromes, and childhood cancer

Abstract

Childhood cancer is a diverse group of rare diseases and remains a significant global concern, despite substantial improvements in survival outcomes. Yet, little is known about its etiology. Certain congenital disorders, including congenital heart disease (CHD) and neurocutaneous syndromes, have been implicated as potential risk factors, but the intricate relationships between these disorders and childhood cancer are poorly understood. Notably, the survival outcomes of children grappling with both CHD and cancer have been underexplored, and there is a dearth of knowledge regarding risk factors for the de novo occurrence of cancer-linked neurocutaneous syndromes.

To address these knowledge gaps, this thesis endeavored to deepen the comprehension of childhood cancer etiology, survival, and the occurrence of cancer-linked neurocutaneous syndromes. Employing high-quality, nationwide Nordic administrative and healthcare register data, four studies were conducted.

Studies I and II, cohort studies based on the Swedish child population born between 1973 and 2014, explored potential risk factors for childhood cancer. Study I unveiled a moderate association between CHD and risk of childhood non-Hodgkin’s lymphoma and hepatoblastoma. Notably, severe CHD had a more pronounced effect on childhood lymphoma. Study II identified robust associations between neurocutaneous syndromes, particularly neurofibromatosis type 1 (NF1) and tuberous sclerosis complex (TSC), and childhood central nervous system tumors. Certain perinatal characteristics, including high birth weight, preterm birth, low 5-minute Apgar score, large head circumference, and being large for gestational age, exhibited weak associations with childhood cancer, independent of neurocutaneous syndromes.

Study III, a cohort study based on the child population of Denmark and Sweden born between 1973 and 2014 and diagnosed with cancer before age 20, focused on childhood cancer survival. The study revealed that CHD was linked to higher five-year mortality, particularly following lymphoma and neuroblastoma diagnoses. Despite positive trends in recent decades, lymphoma mortality remained disproportionately high among children with CHD.

Study IV, a case-control study based on the Swedish child population born between 1960 and 2014, investigated the occurrence of de novo neurocutaneous syndromes in relation to parental occupational exposures. The study included all diagnosed cases of de novo neurocutaneous syndromes matched to neurocutaneous syndrome-free population controls by birth year and sex. Distinct associations were observed for maternal and paternal exposures, indicating increased de novo NF1 risk in offspring of parents exposed to several agents. Maternal exposures generally showed stronger associations. Aliphatic and alicyclic hydrocarbon solvents, chlorinated hydrocarbon solvents, iron, benzo(a)pyrene, polycyclic aromatic hydrocarbons, man-made mineral fibers, and welding fume in either parent were associated with increased offspring NF1 risk. Aromatic hydrocarbon solvents, quartz dust, stone and concrete, asbestos, and bitumen fumes were also associated with elevated NF1 risk, but only in offspring of exposed mothers. Paternal exposure to formaldehyde, trichloroethane, toluene, wood dust, chromium, nickel, lead, and volatile sulfur compounds was linked to increased offspring NF1 risk. No associations were observed for de novo TSC.

In conclusion, this thesis sheds light on potential risk factors for childhood cancer incidence and mortality, as well as the de novo occurrence of cancerlinked NF1. Children with CHD emerged as a vulnerable population, necessitating consideration for cancer screening, and raising concerns about their treatment modalities. Neurocutaneous syndromes, while strongly associated with childhood cancer, did not account for the weak associations between perinatal characteristics and childhood cancer, suggesting the involvement of other biological mechanisms. Differentially associated maternal and paternal occupational chemical exposures with de novo risk of NF1 prompt further inquiries into underlying mechanisms.