{"doi":"10.1002/ajh.70093","title":"Germline Pathogenic Variants in <scp> <i>MUTYH</i> </scp> Are Associated With Inferior Survival After Hematopoietic Cell Transplantation in Patients With Hematologic Malignancies or Disorders","abstract":"Hematopoietic cell transplantation (HCT) is a curative option for many hematologic diseases but remains associated with high mortality and morbidity risks. Recent efforts have focused on identifying genomic biomarkers beyond the well-established HLA loci to improve patient outcomes [1, 2]. DNA damage response and repair (DDR) genes are of particular interest due to recipients' exposure to DNA damaging agents like ionizing radiation and alkylating agents. While individuals with biallelic DDR variants (e.g., Fanconi anemia [3], ataxia telangiectasia [4, 5]) are known to require modified regimens to mitigate toxicity, the impact of monoallelic germline DDR variants on HCT outcomes remains unknown. In this study, we evaluated the associations between germline DDR variants and post-HCT outcomes and explored whether these associations were affected by the type of conditioning regimen. We used exome sequencing data we generated for 2008 allogeneic HCT recipients with severe aplastic anemia (SAA; N = 683) [6], primary or secondary myelofibrosis (MF; N = 930) [7], or myelodysplastic syndrome (MDS; N = 395; including 79 therapy-related MDS patients) [8]. Pre-HCT blood samples and clinical data were provided by the Center for International Blood and Marrow Transplant Research (CIBMTR). Patients with clinically or genetically diagnosed inherited bone marrow failure syndromes (N = 146) were excluded [6, 8]. We curated germline variants (with variant allele fraction; VAF 40%–60%) in 129 DDR genes involved in seven repair pathways (Table S1), following the American College of Medical Genetics and Genomics/Association of Molecular Pathology (ACMG/AMP) guideline [9]. Only tier-1 pathogenic/likely pathogenic (PLP) variants were included, defined as loss-of-function (LOF) variants (frameshift, nonsense, and splicing) in genes where LOF is a recognized mechanism, or variants previously reported as PLP in ClinVar (Table S2). The primary outcome was overall survival (OS) post-HCT. Survival probabilities were estimated using Kaplan–Meier methods with log-rank tests for group comparisons. Multivariable Cox proportional hazards models were used to assess associations between PLP DDR variants and OS, adjusting for clinical covariates (age, sex, conditioning intensity, donor type, year of transplant, and Karnofsky Performance Status) and stratified on graft source and disease type. Competing risks models were used to evaluate transplant-related mortality (TRM) and disease relapse. The survival analysis included only genes with PLP variants affecting ≥ 10 patients. Details are available in online Supporting Information. The patient median age at HCT was 20.2 years for SAA, 58.4 years for MF, and 60 years for MDS. Fludarabine-Busulfan (Flu-Bu)-based regimen was frequent in MDS (50.6%) and MF (44.2%), while total body irradiation (TBI) was used far more often in SAA (58%) than in MF (12%) or MDS (7%). Reduced intensity or non-myeloablative conditioning (RIC/NMA) regimens were most common in SAA patients (61%) (Table 1). We identified 274 tier-1 PLP variants in 86 DDR genes (Table S2). All were monoallelic, except for two homozygous variants in PMS1 or CHEK2 found in two patients, both died in the first 30 days post-HCT. LOF variants included 105 frameshift, 80 nonsense, and 47 splicing variants. PLP DDR variants were detected in 20.3% of SAA, 23.9% of MF, and 15.4% of MDS patients. Among 423 positive patients, 9.7% had variants in ≥ 2 DDR genes. PLP variants occurred most frequently in CHEK2 (N = 65, 3.2%), enriched in MF patients (5.5% vs. 1.3% in SAA or MDS, p < 0.0001), followed by MUTYH (N = 40, 2%), POLQ (N = 34, 1.7%), and POLG in (N = 24, 1.2%), with comparable frequencies across disease cohorts (Figure S1). MUTYH and BRCA2 were the only DDR genes statistically significantly associated with inferior survival (5-year OS = 39% vs. 58% in MUTYH-positive vs. negative, p = 0.003; and 23% vs. 58% in BRCA2-positive vs. negative, p = 0.03) (Figure 1 & Table","journal":"American Journal of Hematology","year":2025,"id":576743,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9536,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":339797,"name":"Youjin Wang","orcid":"0000-0001-5841-4183","position":1,"is_corresponding":false},{"id":851384,"name":"Ashwin Koppayi","orcid":"0000-0001-9956-1374","position":2,"is_corresponding":false},{"id":54401,"name":"Sharon A. Savage","orcid":"0000-0001-6006-0740","position":3,"is_corresponding":false},{"id":438090,"name":"Lucy A. Godley","orcid":"0000-0003-1914-9158","position":4,"is_corresponding":false},{"id":453342,"name":"Kirsten M. Williams","orcid":"0000-0001-9372-5286","position":5,"is_corresponding":false},{"id":371918,"name":"Christopher C. Porter","orcid":"0000-0001-8774-0180","position":6,"is_corresponding":false},{"id":1421991,"name":"Kristine Jones","orcid":"0000-0002-4611-9838","position":7,"is_corresponding":false},{"id":264024,"name":"Belynda Hicks","orcid":"0000-0001-8014-4888","position":8,"is_corresponding":false},{"id":122974,"name":"Stephen R. Spellman","orcid":"0000-0002-7271-8252","position":9,"is_corresponding":false},{"id":875501,"name":"Meilun He","orcid":null,"position":10,"is_corresponding":false},{"id":1139895,"name":"Rasha Atshan","orcid":"0000-0003-2830-4930","position":11,"is_corresponding":false},{"id":1140782,"name":"Caidon Iwuagwu","orcid":"0009-0008-2250-9891","position":12,"is_corresponding":false},{"id":632864,"name":"Yung‐Tsi Bolon","orcid":"0000-0001-9414-6120","position":13,"is_corresponding":false},{"id":874794,"name":"Esteban Arrieta‐Bolaños","orcid":"0000-0002-3696-5803","position":14,"is_corresponding":false},{"id":278814,"name":"Jennifer N. Saultz","orcid":"0000-0003-0024-9466","position":15,"is_corresponding":false},{"id":1014764,"name":"Cara L. Benjamin","orcid":"0009-0005-2906-8775","position":16,"is_corresponding":false},{"id":83997,"name":"Stephanie J. Lee","orcid":"0000-0003-2600-6390","position":17,"is_corresponding":false},{"id":122972,"name":"Wael Saber","orcid":"0000-0002-6544-5815","position":18,"is_corresponding":false},{"id":1485564,"name":"Shahinaz M. Gadalla","orcid":"0000-0002-0108-2381","position":19,"is_corresponding":false},{"id":1138915,"name":"Maryam Rafati","orcid":"0000-0001-7118-3412","position":0,"is_corresponding":true}],"reference_count":21,"raw_metadata":null,"created_at":"2026-07-19T02:58:00.620755Z","pmid":"41042026","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}