Donor-Derived Malignancy and Transplantation Morbidity: Risks of Patient and Donor Genetics in Allogeneic Hematopoietic Stem Cell Transplantation

Williams, Lacey S.; Williams, Kirsten M.; Gillis, Nancy; Bolton, Kelly; Damm, Frederik; Deuitch, Natalie T.; Farhadfar, Nosha; Gergis, Usama; Keel, Siobán B.; Michelis, Fotios V.; Panch, Sandhya R.; Porter, Christopher C.; Sucheston-Campbell, Lara; Tamari, Roni; Stefanski, Heather E.; Godley, Lucy A.; Lai, Catherine

doi:10.1016/j.jtct.2023.10.018

Cited by 7 publications

(3 citation statements)

References 78 publications

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“…There was no overt immunologic disease reported in the stem cell donor. Potential stem cell donors undergo extensive health check-ups; however, there is currently no standard screening for IEI- or hematologic malignancy-related mutations [ 27 , 28 ]. The clinical penetrance of disease associated with TIM-3 missense mutations, especially in heterozygous state, has, to our knowledge, not been studied.…”

Section: Discussionmentioning

confidence: 99%

Post-transplant Inflammatory Bowel Disease Associated with Donor-Derived TIM-3 Deficiency

Baldrich,

Althaus,

Menter

et al. 2024

J Clin Immunol

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Inflammatory bowel disease (IBD) occurring following allogeneic stem cell transplantation (aSCT) is a very rare condition. The underlying pathogenesis needs to be better defined. There is currently no systematic effort to exclude loss- or gain-of-function mutations in immune-related genes in stem cell donors. This is despite the fact that more than 100 inborn errors of immunity may cause or contribute to IBD. We have molecularly characterized a patient who developed fulminant inflammatory bowel disease following aSCT with stable 100% donor-derived hematopoiesis. A pathogenic c.A291G; p.I97M HAVCR2 mutation encoding the immune checkpoint protein TIM-3 was identified in the patient’s blood-derived DNA, while being absent in DNA derived from the skin. TIM-3 expression was much decreased in the patient’s serum, and in vitro-activated patient-derived T cells expressed reduced TIM-3 levels. In contrast, T cell-intrinsic CD25 expression and production of inflammatory cytokines were preserved. TIM-3 expression was barely detectable in the immune cells of the patient’s intestinal mucosa, while being detected unambiguously in the inflamed and non-inflamed colon from unrelated individuals. In conclusion, we report the first case of acquired, “transplanted” insufficiency of the regulatory TIM-3 checkpoint linked to post-aSCT IBD.

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Section: Discussionmentioning

confidence: 99%

Post-transplant Inflammatory Bowel Disease Associated with Donor-Derived TIM-3 Deficiency

Baldrich,

Althaus,

Menter

et al. 2024

J Clin Immunol

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Section: Discussionmentioning

confidence: 99%

“…We identified several AR inherited PVs in donors and patients, including those responsible for Fanconi Anemia in a homozygous state and solid tumors in a heterozygous state [21,24,25,37,38] . FA mutation carriers do not exhibit the AR disorder; however, there is evidence that heterozygous Fanconi Anemia gene carriers may be at increased risk of developing MDS and AML [38] . The identification of the donor FA association with recipient survival and our previous publications on exome and genome-wide significant associations with survival in DISCOVeRY-BMT provide strong evidence that non-HLA genetics is relevant to patient survival and replication of these findings in additional cohorts could have implications for patient clinical care and for counseling patients around outcomes following transplant [10,11,39] .…”

Section: Discussionmentioning

confidence: 99%

Pathogenic and likely pathogenic germline variation in patients with myeloid malignancies and their unrelated HLA-matched hematopoietic stem cell donors

Clay-Gilmour,

Cooper,

Wang

et al. 2024

J Transl Genet Genom

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Aims: The revised 2022 World Health Organization classification recognizes myeloid neoplasms with associated germline predisposition as a defined subcategory, underscoring the clinical significance of likely pathogenic (LPV) and pathogenic (PV) germline variation in these diseases. To better understand the role of LPV/PV in blood or marrow transplants (BMT), a curative therapy for myeloid neoplasms, we measure their frequency and association with mortality in two cohorts of donor-recipient pairs. Methods: LPV/PV frequencies in 665 cancer-related genes were measured using exomechip genotyping data in 1990 acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients and their unrelated donors, registered with the Center for International Blood and Marrow Transplant Research. Cox proportional hazard models were used to test variant association with recipient mortality one-year post-transplant. Results: Thirteen autosomal dominant (AD) LPV/PV in eight genes were found in 2.8% of patients and 2.2% of donors; those linked to autosomal recessive conditions appeared in 11.1% of patients and 11% of donors. The most common AD LPV/PV mutations in recipients were found in DDX41 (n = 18). For donors, the most frequent AD PVs occurred in CHEK2 (n = 21) and Fanconi Anemia (FA) genes (n = 7). DDX41 and CHEK2 variation did not correlate with patient survival, but patients with donors with an LPV/PVs in an FA gene had lower survival (HR = 2.38, 95%CI: 1.06-5.31, P = 0.035) than patients whose donors did not have an FA LPV/PV. Conclusion: We identified LPVs/PVs in cancer genes in donors and recipients and are the first to show an association of donor FA PVs with mortality after BMT.

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Risk assessment and genetic counseling for hematologic malignancies—Practice resource of the National Society of Genetic Counselors

Stewart,

Helber,

Bannon

et al. 2024

Journal of Genetic Counseling

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Hematologic malignancies (HMs) are a heterogeneous group of cancers impacting individuals of all ages that have been increasingly recognized in association with various germline predisposition syndromes. Given the myriad of malignancy subtypes, expanding differential diagnoses, and unique sample selection requirements, evaluation for hereditary predisposition to HM presents both challenges as well as exciting opportunities in the ever‐evolving field of genetic counseling. This practice resource has been developed as a foundational resource for genetic counseling approaches to hereditary HMs and aims to empower genetic counselors who encounter individuals and families with HMs in their practice.

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Donor-Derived Malignancy and Transplantation Morbidity: Risks of Patient and Donor Genetics in Allogeneic Hematopoietic Stem Cell Transplantation

Cited by 7 publications

References 78 publications

Post-transplant Inflammatory Bowel Disease Associated with Donor-Derived TIM-3 Deficiency

Post-transplant Inflammatory Bowel Disease Associated with Donor-Derived TIM-3 Deficiency

Pathogenic and likely pathogenic germline variation in patients with myeloid malignancies and their unrelated HLA-matched hematopoietic stem cell donors

Risk assessment and genetic counseling for hematologic malignancies—Practice resource of the National Society of Genetic Counselors

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