Portal de Periódicos da CAPES

Variants at 6q21 implicate PRDM1 in the etiology of therapy-induced second malignancies after Hodgkin's lymphoma

2011; Nature Portfolio; Volume: 17; Issue: 8 Linguagem: Inglês

10.1038/nm.2407

1546-170X

Timothy Best, Dalin Li, Andrew D. Skol, Tomas Kirchhoff, Sarah Jackson, Yutaka Yasui, Ravi Bhatia, Louise C. Strong, Susan M. Domchek, Katherine L. Nathanson, Olufunmilayo I. Olopade, R. Stephanie Huang, Thomas M. Mack, David V. Conti, Kenneth Offit, Wendy Cozen, Leslie L. Robison, Kenan Onel,

Cancer-related molecular mechanisms research

Patients undergoing radiation treatment for Hodgkins's lymphoma are at increased risk of developing secondary malignancies with time. This genome-wide analysis identifies genetic polymorphisms associated with increased risk of secondary malignancies in treated children. The risk alleles result in decreased radiation-mediated induction of PRDM1, a tumor suppressor transcription factor, leading to impaired repression of oncogenic drivers such as MYC. Survivors of pediatric Hodgkin's lymphoma are at risk for radiation therapy–induced second malignant neoplasms (SMNs). We identified two variants at chromosome 6q21 associated with SMNs in survivors of Hodgkin's lymphoma treated with radiation therapy as children but not as adults. The variants comprise a risk locus associated with decreased basal expression of PRDM1 (encoding PR domain containing 1, with ZNF domain) and impaired induction of the PRDM1 protein after radiation exposure. These data suggest a new gene-exposure interaction that may implicate PRDM1 in the etiology of radiation therapy-induced SMNs.