ファンコニ貧血

Histological variation is a prognostic feature of metastatic urothelial cancer1-3, but its evolutionary trajectory remains poorly defined. We developed a metastatic bladder cancer rapid autopsy programme enriched in histological subtypes4 to profile individuals with terminal disease. Here by reconstructing the evolutionary histories of patient tumours, we show that metastasis-to-metastasis seeding is the dominant pattern of cancer spread and that increased polyclonal migration predicts poor prognosis. The burden, heterogeneity and timing of genomic alterations differ markedly among histological subtypes. Plasmacytoid and neuroendocrine variants develop early driver alterations associated with shorter survival. Mutational signature analyses and experimental models demonstrated that plasmacytoid tumours uniquely use the Fanconi anaemia pathway to mitigate chemotherapy-induced genomic scarring. Single-nucleus profiling revealed mixed cell states in histological subtypes and an association between transcriptional heterogeneity and patient survival. Characterization of the tumour microenvironment uncovered distinct immune states across subtypes, with plasmacytoid tumours exhibiting immune-inflamed profiles, whereas squamous tumours are predominantly immunosuppressive. Last, we demonstrate that post-mortem cell-free DNA captures genomic and transcriptional heterogeneity of the subtypes, which provides a potential strategy for noninvasive assessment of tumour identity and aggressiveness. Our results provide new insights into how tumour heterogeneity shapes the evolutionary history of disease progression in bladder cancer histological subtypes.

Defects in the replication stress response are major drivers of cancer development and present key targetable vulnerabilities that can be exploited for anti-cancer therapy. Recent studies have identified CHAMP1 as a novel DNA damage repair factor with roles in double-strand break repair and the replication stress response. Mutations in CHAMP1 are associated with the neurodevelopmental disorder CHAMP1 Syndrome. More recently, children with CHAMP1 Syndrome have developed leukemia, suggesting that CHAMP1 mutations are a potential cancer risk factor. CHAMP1 is part of two DNA damage repair complexes: CHAMP1-POGZ-REV7 (Complex I) and CHAMP1-POGZ-HP1α (Complex II). Complex I promotes homologous recombination by removing the Shieldin complex from the ends of double strand breaks and allowing DSB end resection to occur. Complex II enriches heterochromatin content through the recruitment of the methyltransferase SETDB1 to DNA damage sites. Increased heterochromatin at stalled forks is associated with proper fork stability and restart, demonstrating the importance of CHAMP1 in maintaining genomic integrity. Loss of CHAMP1 leads to increased sensitivity to DNA damaging agents and increased dependence on other DNA damage repair pathways, such as the DNA damage checkpoint and the Fanconi Anemia pathway. CHAMP1 is overexpressed in breast and ovarian cancer cells with high levels of replication stress, providing a molecular mechanism for the tolerance of replication stress. These new findings on the relationship of CHAMP1 with well-established DNA damage repair pathways, suggest that targeting CHAMP1 could present a new synthetic lethality opportunity for cancer cells with high levels of replication stress.

BACKGROUND: Fanconi anemia (FA) is the most common inherited bone marrow failure syndrome. Iran, with a high rate of consanguineous marriage and considerable ethnic diversity, represents a high-risk context for FA. We established the Iranian Fanconi Anemia Registry (IRFAR) to provide the first registry-based description of FA in Iran. PROCEDURE: IRFAR is a prospective national registry established in April 2021 at Tehran University of Medical Sciences (ethics code: IR.TUMS.MEDICINE.REC.1400.146). Diagnosis required chromosomal breakage testing and/or molecular confirmation, reviewed by at least two board-certified pediatric hematologist-oncologists. Data were collected using a structured questionnaire covering demographic, perinatal, clinical, hematologic, and genetic domains. RESULTS: A total of 116 patients from 101 families were enrolled. The male-to-female ratio was 1.15:1 and the mean age at diagnosis was 6.1 years (SD 3.08). Parental consanguinity was present in 91.1% of families. Patients originated from 25 of Iran's 31 provinces, with the highest concentrations in Tehran, Fars, Isfahan, and Kerman. Persian (41.4%), Azari (25.0%), and Lur (14.7%) were the predominant ethnic groups. The most frequent congenital findings were skin pigmentation abnormalities (71.6%), short stature (55.2%), and upper limb anomalies (52.6%). Nearly half of the patients had undergone hematopoietic stem cell transplantation (HSCT). Four patients (3.4%) had malignancies at enrollment. Molecular data were available in 11 patients, with FANCA as the predominant complementation group (72.7%). CONCLUSIONS: IRFAR is the first national FA registry in Iran and among the earliest in the Middle East. The high consanguinity rate and geographic diversity highlight the need for expanded molecular testing, premarital genetic counseling, and multi-center expansion.

Fanconi anemia (FA) is a rare inherited disorder of bone marrow failure that presents with progressive pancytopenia, multiple congenital abnormalities, and an increased predisposition to various malignancies. We describe a 19-year-old male who reported generalized weakness, shortness of breath on exertion, and a dry cough persisting for 1 month. He had undergone three blood transfusions within the preceding 3 months. Clinical examination revealed marked pallor without evidence of jaundice, cyanosis, clubbing, or lymphadenopathy. Laboratory investigations showed pancytopenia, while bone marrow biopsy demonstrated normocellular marrow with trilineage hematopoiesis and mild hemophagocytosis. Radiological assessment identified bilateral ectopic kidneys, and serum ferritin levels were significantly elevated (2753.93 ng/mL). These findings raised a strong clinical suspicion of FA, which was subsequently confirmed through comprehensive genetic testing. This case underscores the importance of considering FA in young adults with unexplained pancytopenia and congenital anomalies, highlighting the need for an integrated, multidisciplinary diagnostic and management approach.

Mesenchymal stem cells (MSCs) inevitably undergo replicative senescence during in vitro expansion, leading to progressive loss of therapeutic efficacy. However, the global landscape of alternative splicing (AS) during this process and its relationship with transcriptional regulation remain uncharacterized. Here, we performed splicing-aware transcriptomic profiling of human umbilical cord derived MSCs across four passage points (P2, P8, P10, P12; n = 11). Using stringent AND criteria (FDR < 0.05, |ΔPSI| ≥ 0.05), we identified 112 differential splicing events (DSEs) affecting 96 genes. Skipped exon (SE) events predominated (82/112, 73.2%), with DSEs peaking at P8 (83 events), indicating that splicing reprogramming is an early senescence event. Only four genes overlapped between the 699 differentially expressed genes (DEGs) and 96 DSE genes (COL12A1, ITGA7, MYOCD, TNS3), indicating that splicing and transcriptional changes affect largely distinct gene sets. Functional enrichment revealed that DEGs converged on ECM remodeling and immune/inflammatory pathways, whereas DSE genes were significantly enriched in DNA repair pathways (Fanconi anemia, homologous recombination), and splicing factor genes showed a 5.6-fold enrichment trend among DSEs (p = 0.054). PTC-50nt rule based classification showed that in-frame changes constituted the predominant category (58.5%), with NMD_risk at only 14.6% and NMD_rescue at 26.8%. The core spliceosome component SF3B1 harbored a predicted NMD-targeting event (745 bp exon inclusion, dPSI = + 0.122), while the SR protein SRSF4 experienced a predicted NMD-rescue event (dPSI = - 0.098). Splicing factor expression profiling revealed that PTBP1 exhibited an early sharp decline at P8 (- 20.2%) followed by partial recovery, with divergent regulation of SRSF and HNRNP families. Multi-layer convergence analysis resolved the senescent MSC output into two separable molecular programs, ECM remodeling and immune modulation, driven predominantly at the transcriptional level. This study provides the first systematic characterization of the alternative splicing landscape during human MSC replicative senescence, revealing that splicing changes are largely gene-level distinct from transcriptional changes, that in-frame changes rather than NMD dominate the predicted functional consequences, and that splicing factors and DNA repair genes are preferentially affected. These findings integrate alternative splicing into the regulatory landscape of MSC senescence and establish a molecular foundation for developing splicing-aware quality control strategies in ATMP manufacturing.