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Down Syndrome and Malignancies: A Unique Clinical Relationship: A Paper from the 2008 William Beaumont Hospital Symposium on Molecular Pathology

https://doi.org/10.2353/jmoldx.2009.080132Get rights and content

The patterns of malignancies in Down syndrome (DS) are unique and highlight the relationship between chromosome 21 and cancer. DS children have a ∼10- to 20-fold higher risk for developing acute lymphoblastic leukemia and acute myeloid leukemia (AML), as compared with non-DS children, although they do not have a uniformly increased risk of developing solid tumors. DS children with acute lymphoblastic leukemia frequently experience higher levels of treatment-related toxicity and inferior event-free survival rates, as compared with non-DS children. DS children also develop AML with unique features and have a 500-fold increased risk of developing the AML subtype, acute megakaryocytic leukemia (AMkL; M7). Nearly 10% of DS newborns are diagnosed with a variant of AMkL, the transient myeloproliferative disorder, which can resolve spontaneously without treatment; event-free survival rates for DS patients with AMkL ranges from 80% to 100%, in comparison with <30% for non-DS children with AMkL. In addition, somatic mutations of the GATA1 gene have been detected in nearly all DS TMD and AMkL cases and not in leukemia cases in non-DS children. GATA1 mutations are key factors linked to both leukemogenesis and the high cure rates of DS AMkL patients. Identifying the mechanisms that account for the high event-free survival rates of DS AMkL patients may ultimately improve AML treatment as well. Examining leukemogenesis in DS children may identify factors linked to the general development of childhood leukemia and lead to potential new therapeutic strategies to fight this disease.

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Supported by grants (RO1 CA120772), from the National Cancer Institute, Leukemia Research Life, BPCT Golf Charity, The Elana Fund, Justin's Gift Charity, Children's Research Center of Michigan, St. Baldrick's Foundation, and The Ring Screw Textron Chair in Pediatric Cancer Research.

This article is partly based on material presented by the authors at the William Beaumont Hospital 17th Annual Symposium on Molecular Pathology: Clinical Applications of Genomic Medicine, which took place on September 10 to 12, 2008, in Troy, MI.

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