The Investigation of Relationship Between Fok1 and Col1A1 Gene Polymorphisms and Development of Treatment-Related Bone Complications in Children with Acute Lymphoblastic Leukemia

Abstract

In acute lymphoblastic leukemia (ALL), various clinical risk factors and genetic predispositions contribute to the development of bone complications during and after chemotherapy. In this study, we aimed to investigate whether vitamin D receptor (VDR) Fok1 and collagen protein Col1A1 Sp1-binding site gene polymorphisms, which are important in bone mineral and matrix formation, have effects on the development of bone abnormalities in childhood ALL survivors. Materials and Methods: Fifty children with ALL who were treated with the ALL Berlin-Frankfurt-Muenster-95 protocol between 1998 and 2008 and were followed for at least 7 years were enrolled. The control group consisted of 96 healthy children. VDR Fok1 and Col1A1 Sp1-binding site gene polymorphisms were analyzed by polymerase chain reaction and restriction fragment length polymorphism. Bone mineral density (BMD) and markers of bone metabolism were all noted. All patients who presented with pain in the joints were examined for bone pathologies while on chemotherapy or during long-term follow-up. Results: Low BMD (16%), osteoporosis (12%), and osteonecrosis (8%) were present in a total of 18 patients (36%). The frequency of osteonecrosis and total bone abnormalities was significantly higher in children aged ≥10 years (p=0.001). The risk of low BMD and osteonecrosis was higher in those with vitamin D deficiency. Only the Col1A1 Sp1-binding site gene polymorphism showed a significant association in ALL patients with osteonecrosis. Conclusion: The development of therapy-induced bone mineral loss and osteonecrosis in children with ALL is frequent and the risk is especially higher in children aged ≥10 years and with vitamin D deficiency. The association between Col1A1 Sp1-binding site gene polymorphisms and osteonecrosis has to be assessed in a larger group of ALL survivors.

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“…Donmez, et al [13] found osteopenia in 23.1% and osteoporosis in 7.7% of patients in their survey. In another study from Turkey, reported low BMD in 32%, osteoporosis in 24% and osteonecrosis in 16% of patients [14]. We found low BMD in 50% and osteoporosis in 12% of patients in our study.…”

“…Vitanza, et al [15] found that the overall difference in BMD after six years from cessation of chemotherapy among three age groups patients defined as ages under five years group 1, ages five to 10 years group 2 and ages above 10 years at the time of diagnosis, significant difference was found between group 1 and group 3. Similar to Vitanza, et al [15] study, Erdem, et al [14] found that the rate of osteonecrosis and bone changes were significantly higher in patients aged above 10 years. As summarized above, varying results were obtained on factors affecting to BMD in different studies.…”

Serum Biomarkers Related to Glucocorticoid‐Induced Osteonecrosis of the Femoral Head: A Prospective Nested Case‐Control Study

“…It has been reported that collagen types II and V are associated with non‐traumatic ONFH, but few studies have investigated the relationship between type I collagen and osteonecrosis. Recently, a prospective study involving 50 children with acute lymphoblastic leukemia who received GC therapy showed a significant association between collagen protein Col1A1 Sp1‐binding site gene polymorphisms and development of osteonecrosis in a long‐term follow‐up . Although osteonecrosis affected different areas, including the femoral head in two patients, and the sacroiliac joints and lumbar spine in one patient each, the study provided preliminary but compelling evidence for a possible correlation between type I collagen and osteonecrosis.…”

Understanding the role of genetics in childhood acute lymphoblastic leukemia (Review)

“…In addition, the vitamin D receptor (VDR) Fok1, as well as the collagen protein Col1A1 Sp1-binding site gene polymorphisms, which play a role in bone mineral and matrix formation, were previously investigated for their role in bone complications due to therapy in 50 pediatric patients with ALL, who were treated with the ALL Berlin-Frankfurt-Muenster-95 protocol between 1998 and 2008. A higher risk of therapy-induced bone mineral loss and osteonecrosis was found in patients aged ≥10 years and with vitamin D deficiency (56).…”