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Tumor suppressor gene variants identified as cancer ‘double whammy’ for leukemia patients


Jun J. Yang, Ph.D., identified 22 high-risk germline variations related to high-risk acute lymphoblastic leukemia that will increase danger of relapse or improvement of second cancers. Credit: Seth Dixon / St. Jude Children’s Research Hospital

Newly identified germline variations in a key tumor suppressor gene predispose people to develop leukemia as youngsters and depart them with a 1-in-Four probability of creating a second cancer later. St. Jude Children’s Research Hospital scientists led the research, which seems at this time within the Journal of Clinical Oncology.Researchers sequenced the TP53 tumor suppressor gene in three,858 youngsters with acute lymphoblastic leukemia (ALL) and identified 22 high-risk germline variations. The variants have been related to lowered gene exercise and have been 5 occasions extra frequent in pediatric ALL patients than people with out the illness. Germline variations are often inherited and carried within the DNA of each cell, not simply within the DNA of tumor cells.

The 26 patients on this research who carried the high-risk TP53 variants have been additionally virtually 4 occasions extra probably than different pediatric ALL patients to die of their illness or associated problems.

“These germline variations are a double whammy for carriers,” stated corresponding writer Jun J. Yang, Ph.D., an affiliate member of the St. Jude Department of Pharmaceutical Sciences and Department of Oncology. “Not solely is their danger of creating very excessive, they’re additionally extra more likely to relapse or develop a second .”

The affiliation between the high-risk variants and second cancers is so vital that St. Jude researchers are exploring methods to assist patients and households handle their danger, Yang stated. “Maybe these patients should avoid certain ALL therapies in order to reduce their risk of developing another cancer,” he stated. “I believe this finding may change treatment and follow-up for these high-risk patients.”

ALL is the most typical childhood cancer. In most instances, the precise trigger is unknown. This research means that the high-risk TP53 variants are accountable for about zero.7 % of instances. The patients on this research embrace a cross-section of the U.S. inhabitants. They have been enrolled in medical trials of the Children’s Oncology Group, a medical analysis cooperative.The high-risk variants have been commonest within the high-risk leukemia subtype hypodiploid ALL. About 65 % of patients who carried high-risk TP53 on this research had the hypodiploid subtype of ALL. In reality, the ALL-associated high-risk TP53 gene variants have been first identified in hypodiploid ALL in earlier analysis from Charles Mullighan, M.D., M.B.B.S., of St. Jude, and others. Mullighan is a co-author of this research and a member of the St. Jude Department of Pathology.

This research expanded on the preliminary studies and revealed numerous novel TP53 pathogenic variants which might be associated to the danger of creating ALL. Researchers reported that one other 27 TP53 variants have been identified on this research, a few of which can nonetheless show to be pathogenic, Yang stated.

Inherited variations in TP53 are an indicator of Li-Fraumeni syndrome. This uncommon dysfunction runs in households and predisposes people to totally different cancers. Until just lately, leukemia had not been generally related to the syndrome.Li-Fraumeni syndrome may partially clarify the excessive price of second cancers skilled by pediatric ALL survivors with the high-risk TP53 variants, researchers famous. “The ALL treatment might have added to that risk but we do not know for sure,” Yang stated. Five with the high-risk variants included on this research developed second cancers, together with strong tumors and different leukemias.


Explore additional:
Hereditary cancer syndromes focus of JAMA Oncology collection

More info:
Maoxiang Qian et al. TP53 Germline Variations Influence the Predisposition and Prognosis of B-Cell Acute Lymphoblastic Leukemia in Children, Journal of Clinical Oncology (2018). DOI: 10.1200/JCO.2017.75.5215



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