Genome-wide Association Studies Reveal Novel Locus With Sex-/Therapy-Specific Fracture Risk Effects in Childhood Cancer Survivors

Abstract

doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.

Osteoporosis in Childhood Cancer Survivors: Physiopathology, Prevention, Therapy and Future Perspectives

“…Even though the evidence is currently very limited, genetics also seems to influence bone density in children with cancer. Te Winkel et al observed that variations in genes involved in folate metabolism negatively affect bone mass density in ALL patients at diagnosis [ 61 ], as well as the finding that a polymorphism of corticotrophin-releasing hormone receptor-1 gene is related to low bone density in male ALL survivors [ 6 ]. Furthermore, in 2020, Im and collaborators performed genome-wide association studies of fracture risk after cancer diagnosis in patients from the Childhood Cancer Survivor Study (CCSS), identifying a genetic locus (HAGHL, 16p13.3) for fracture risk [ 6 ].…”

“…Te Winkel et al observed that variations in genes involved in folate metabolism negatively affect bone mass density in ALL patients at diagnosis [ 61 ], as well as the finding that a polymorphism of corticotrophin-releasing hormone receptor-1 gene is related to low bone density in male ALL survivors [ 6 ]. Furthermore, in 2020, Im and collaborators performed genome-wide association studies of fracture risk after cancer diagnosis in patients from the Childhood Cancer Survivor Study (CCSS), identifying a genetic locus (HAGHL, 16p13.3) for fracture risk [ 6 ]. A few years earlier, it was demonstrated by multivariate analyses that CCS carrying SNPs in the ESR1 (estrogen receptor type 1) or LRP5 (low-density lipoprotein receptor) genes had an impairment in bone mass at an early adult age [ 62 ].…”

“…The main long-term adverse consequence is the alteration of the endocrine system’s function and activity, which affects about 20–50% of CCS [ 3 ]. In CCS, there have been reports of obesity and metabolic syndrome development, impairment of the hypothalamic–pituitary axis, fertility, and bone metabolism, with osteopenia onset and, consequently, an increase in fracture risk [ 3 , 4 , 5 , 6 , 7 , 8 , 9 ]. Radiotherapy and chemotherapy are the main causes of the alteration of physiologic cellular and tissue functions, determining an increase in inflammatory processes, senescent cells number, DNA mutations, and an accumulation of reactive oxygen species (ROS) [ 10 , 11 ].…”

“…It should be underlined that genetic susceptibility may also play an important role in the BMD loss and fragility fracture occurrence in cancer-treated children. A recent genome-wide analysis of BMD in acute lymphoblastic leukemia (ALL) CCS identified complex genetic variants (epistatic interactions), including novel single-nucleotide polymorphisms (SNPs) that potentially modify the effects of specific cancer therapies on BMD [ 6 ].…”

Long-Term Effects of Pediatric Acute Lymphoblastic Leukemia Chemotherapy: Can Recent Findings Inform Old Strategies?

“…These effects put survivors at increased risk of failure to achieve potential peak bone mass and increase their fracture vulnerability in adulthood (59). The prevalence of low bone mineral density (BMD) indicates that osteoporosis occurs in almost 10% of cancer survivors with a median age of 32 years, the exact prevalence of osteoporosis among adult Americans aged 60 to 80 (60). Progression into osteonecrosis can be symptomatic, characterized by severe pain, joint damage, and articular collapse, or remain asymptomatic (61).…”