Short tandem repeat and human leukocyte antigen mutations or losses confound engraftment and typing analysis in hematopoietic stem cell transplants

Pereira, Shalini; Vayntrub, Tamara; Hiraki, Debra D.; Cherry, Athena M.; Arai, Sally; Dvorak, Christopher C.; Grumet, F. Carl

doi:10.1016/j.humimm.2011.03.003

Cited by 15 publications

(17 citation statements)

References 23 publications

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“…Somatic changes can also occur in HLA genes and when they do they can result in a unique functional class of mutations with potential for providing a selective advantage to malignant clones by allowing escape from immune surveillance. The 15 cases of acquired HLA mutations in our cohort, together with an additional 16 published cases with similar findings (4–10, 15, 16), clearly establish HLA mutations as recurrent phenomena in patients with leukemia and lymphoma, however, these do not appear to be frequent events. Cases identified pretransplant described by other investigators include six examples of full or partial HLA haplotype loss (5–10) and three with mutations in specific HLA‐A (4) or HLA‐B (9, 10) alleles.…”

Section: Discussionsupporting

confidence: 83%

Somatic mutations in the HLA genes of patients with hematological malignancy

et al. 2012

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Somatic mutations and genomic alterations are frequent events in the clonal evolution of hematologic malignancies. Recent studies have reported copy neutral loss of heterozygosity (LOH) for the mismatched human leukocyte antigen (HLA) haplotype in patients relapsed after haploidentical hematopoietic cell transplantation (HCT) for a hematologic malignancy. Herein, we report 15 cases of somatic mutations in the HLA genes of patients with a variety of hematologic diseases, including acute myelogenous leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, myelodysplastic syndrome, and non-Hodgkin's lymphoma, encountered at our institute over the past decade. While two of the cases were identified in patient relapse specimens collected post-HCT, 13 cases were found in peripheral blood specimens submitted for HLA typing prior to transplantation. Ten patients exhibited acquired LOH for all or part of one HLA haplotype. Five other cases involved somatic mutations in the nucleotide sequences of common HLA-A or HLA-B alleles. Since they are not systematically evaluated prior to HCT, acquired mutations in HLA genes are likely under reported. Beyond the implications for accurate HLA typing and donor selection, alternations that result in the loss of HLA expression may allow escape from immune surveillance and adversely impact transplant outcome.

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Section: Discussionsupporting

confidence: 83%

Somatic mutations in the HLA genes of patients with hematological malignancy

et al. 2012

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“…Our laboratory has recently undertaken to get both blood and a buccal swab on all new stem cell transplant recipients. Given current understanding of the potential for allelic loss that may affect clinical laboratory studies (HLA typing [10] and engraftment studies [11]), the use of a temporally separated or other somatic cell sample should be used for verification. Additionally, the targeted use of a cytogenetics array for malignancies such as CLL known for genetic instability would be useful to interrogate immunologically relevant regions.…”

Section: Discussionmentioning

confidence: 99%

Leukemia specific loss of heterozygosity of MHC in a CLL patient: Disease state impacts timing of confirmatory typing

et al. 2013

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“…Therefore, a 3 --4% LOH incidence can be calculated as a minimal estimate, which is very close to the recently reported rate. 16 aUPD involving 6p21 in pretransplant samples may thus be more frequent than expected. The risk of HLA allele misassignment would even be higher if aUPD does not involve the entire major histocompatibility complex thereby leading to only partial HLA homozygosity, such as observed in patient CJ.…”

Section: Discussionmentioning

confidence: 82%

“…Very recently three cases of LOH leading to HLA homozygosity have been described representing about 4% of patients suffering of myeloid malignancies tested in this center. 16 Although mechanisms contributing to the LOH were not addressed in this study, we predict that aUPD may account for these LOH cases. In our study, the actual frequency of LOH among AML patients is difficult to assess precisely, because the six cases have been detected in five different laboratories with four of them in the last year and two in previous years.…”

Section: Discussionmentioning

confidence: 85%

Pretransplant HLA mistyping in diagnostic samples of acute myeloid leukemia patients due to acquired uniparental disomy

Dubois¹,

Sloan‐Béna

Cesbron

et al. 2012

Leukemia

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Although acquired uniparental disomy (aUPD) has been reported in relapse acute myeloid leukemia (AML), pretransplant aUPD involving chromosome 6 is poorly documented. Such events could be of interest because loss of heterozygosity (LOH) resulting from aUPD in leukemic cells may lead to erroneous results if HLA typing for hematopoietic stem cell donor searches is performed on blood samples drawn during blastic crisis. We report here six AML patients whose HLA typing was performed on DNA extracted from peripheral blood obtained at diagnosis. We observed LOH involving the entire HLA region (three patients), HLA-A, B, C (two patients) and HLA-A only (one patient). An array-comparative genomic hybridization showed that copy number was neutral for all loci, thus revealing partial aUPD of chromosome 6p21. When HLA typing was performed on remission blood samples both haplotypes were detected. A 3 --4% LOH incidence was estimated in AML patients with high blast counts. Based on DNA mixing experiments, we determined by PCR sequence-specific oligonucleotide hybridization on microbeads arrays a detection threshold for HLA-A, B, DRB1 heterozygosity in blood samples with o80% blasts. Because aUPD may be partial, any homozygous HLA result should be confirmed by a second typing performed on buccal swabs or on blood samples from the patient in remission.

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Short tandem repeat and human leukocyte antigen mutations or losses confound engraftment and typing analysis in hematopoietic stem cell transplants

Cited by 15 publications

References 23 publications

Somatic mutations in the HLA genes of patients with hematological malignancy

Somatic mutations in the HLA genes of patients with hematological malignancy

Leukemia specific loss of heterozygosity of MHC in a CLL patient: Disease state impacts timing of confirmatory typing

Pretransplant HLA mistyping in diagnostic samples of acute myeloid leukemia patients due to acquired uniparental disomy

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