According to a new study which appears in the Journal of Clinical Oncology, newly identified germline variations in a key tumour suppressor gene TP53 influence individuals to develop leukaemia as children and leave them with a 25% chance of developing second cancer later.
Researchers sequenced the TP53 tumour suppressor gene in 3,858 children with acute lymphoblastic leukaemia (ALL) and identified 22 high-risk germline variations. The variants were associated with reduced gene activity and were five times more frequent in paediatric ALL patients than individuals without the disease.
Germline variations are usually inherited and carried in the DNA of every cell, not just in the DNA of tumour cells. The 26 patients in the study who carried the high-risk TP53 variants were also almost four times more likely than other paediatric ALL patients to die of the disease or related complications.
The association between the high-risk variants and second cancers is so significant. Maybe the patients should avoid certain ALL therapies in order to reduce their risk of developing another cancer. The finding might change treatment and follow-up for these high-risk patients. ALL is the most common childhood cancer.
The study suggests that the high-risk TP53 variants are responsible for about 0.7% of cases. The study included a cross-section of the U.S. population and they were enrolled in clinical trials of the Children's Oncology Group, a clinical research cooperative. The high-risk variants were most common in the high-risk leukaemia subtype hypodiploid ALL.
Approximately 65% of patients who carried high-risk TP53 variant had the hypodiploid subtype of ALL. In fact, in previous research, the ALL-associated high-risk TP53 gene variants were identified in hypodiploid ALL. Five patients with the high-risk variants developed second cancers, including solid tumours and other leukaemia.
The present study expanded on the initial reports and revealed a large number of novel TP53 pathogenic variants that are related to the risk of developing ALL. Researchers reported that another 27 TP53 variants were identified in the study, some of which may still prove to be pathogenic.
Inherited variations in TP53 are a hallmark of Li-Fraumeni syndrome. Until recently, leukaemia had not been commonly associated with the syndrome. Li-Fraumeni syndrome might partially explain the high rate of second cancers experienced by pediatric ALL survivors with the high-risk TP53 variants, researchers noted.