AluY-mediated germline deletion, duplication and somatic stem cell reversion in <i>UBE2T</i> defines a new subtype of Fanconi anemia

Fanconi anemia (FA) is a rare inherited disorder clinically characterized by congenital malformations, progressive bone marrow failure and cancer susceptibility. At the cellular level, FA is associated with hypersensitivity to DNA-crosslinking genotoxins. Eight of 17 known FA genes assemble the FA E3 ligase complex, which catalyzes monoubiquitination of FANCD2 and is essential for replicative DNA crosslink repair. Here, we identify the first FA patient with biallelic germline mutations in the ubiquitin E2 conjugase UBE2T. Both mutations were aluY-mediated: a paternal deletion and maternal duplication of exons 2-6. These loss-of-function mutations in UBE2T induced a cellular phenotype similar to biallelic defects in early FA genes with the absence of FANCD2 monoubiquitination. The maternal duplication produced a mutant mRNA that could encode a functional protein but was degraded by nonsense-mediated mRNA decay. In the patient's hematopoietic stem cells, the maternal allele with the duplication of exons 2-6 spontaneously reverted to a wild-type allele by monoallelic recombination at the duplicated aluY repeat, thereby preventing bone marrow failure. Analysis of germline DNA of 814 normal individuals and 850 breast cancer patients for deletion or duplication of UBE2T exons 2-6 identified the deletion in only two controls, suggesting aluY-mediated recombinations within the UBE2T locus are rare and not associated with an increased breast cancer risk. Finally, a loss-of-function germline mutation in UBE2T was detected in a high-risk breast cancer patient with wild-type BRCA1/2. Cumulatively, we identified UBE2T as a bona fide FA gene (FANCT) that also may be a rare cancer susceptibility gene.</p

CHROMOSOMAL LOCUS 19P13 AS POTENTIAL HOTSPOT FOR ABERRANT GENE EXPRESSION IN RELAPSED PAEDIATRIC ACUTE LYMPHOBLASTIC LEUKEMIA.

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Gene expression profiling: a possible tool in the prediction of outcome in paediatric acute lymphoblastic leukaemia?

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Gene expression profiling: a possible tool in the prediction of outcome in pediatric acute lymphoblastic leukemia

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Genotypes of the glutathione S-transferase superfamilydo not correlate with outcome of childhood acute lymphoblastic leukemia

Several studies implicate GST polymorphisms in de novo cancer as well as cancers that are secondary to chemotherapy. In all cases, GST deficiency, rather than high GST activity, has been associated with an increased risk of cancer. However, because of its activity, GST has been associated with cancer-drug resistance, while GST deficiency of GSTT1 and GSTM1 could positively influence chemotherapeutic efficacy in some patients.1 In the case of childhood acute lymphoblastic leukemia (ALL), conflicting results have been reported on the associations between GSTM1 and GSTT1 genotypes and outcome.2,3 Stanulla et al.4 recently showed a two-fold and 2.8-fold reduction in risk of relapse, respectively, relative to the presence of the GSTM1 or GSTT1. These findings encouraged the evaluation of the GST genotypes contribution to therapeutic outcome in larger, well-characterized ALL patient populations prospectively enrolled in the same protocol treatmen