HLA匹配同胞供者和半倍体供者异基因造血干细胞移植治疗多次输血的重型再生障碍性贫血

目的 研究HLA匹配同胞供者和半倍体供者异基因造血干细胞移植(allo-HSCT)治疗多次输血的重型再生障碍性贫血(SAA)患者的疗效。方法 回顾性分析11例多次输血的SAA患者移植疗效与并发症发生率。11例患者中8例接受HLA匹配同胞供者HSCT，3例接受半倍体(母亲)HSCT。供、受者之间HLAA，B，DR抗原全相合者7例，1个位点不相合者3例，3个位点不相合者1例。结果 所有11例患者移植后均获得造血重建，其中3例患者发生Ⅰ-Ⅱ度急性移植物抗宿主病(aGVHD)，2例发生慢性局限型GVHD，2例发生移植物排斥，1例死亡，1例因自身造血功能恢复而生存；1例患者移植后5个月死于间质性肺炎。中位随访13个月(3～71个月)，9例患者生存(包括3例半倍体供者植入HSCT)，其中8例患者供体细胞持久植入。结论 HLA匹配同胞供者和半倍体供者allo-HSCT是治疗SAA的一种有效方法。     

HLA-matched unrelated donor hematopoietic cell transplantation after nonmyeloablative conditioning for patients with chronic myeloid leukemia.

We evaluated 10/10 HLA antigen-matched unrelated hematopoietic cell transplantation (HCT) after nonmyeloablative conditioning with fludarabine 3 x 30 mg/m2 and 2 Gy of total body irradiation as treatment for patients with chronic myeloid leukemia who were ineligible for conventional HCT. Data from 21 consecutive patients in first chronic phase (CP1; n = 12), accelerated phase (AP; n = 5), second CP (CP2; n = 3), and blast crisis (n = 1) were analyzed. Stem cell sources were bone marrow (n = 4) or granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cells (G-PBMCs; n = 17). The patient who underwent transplantation in blast crisis died on day 21 (too early to be evaluated for engraftment) from progressive disease. Sustained engraftment was achieved in 5 of 12 patients who underwent transplantation in CP1, 4 of 5 patients who underwent transplantation in AP, and 2 of 3 patients who underwent transplantation in CP2, whereas 9 patients rejected their grafts between 28 and 400 days after HCT. Specifically, 1 of 4 marrow recipients and 10 of 17 G-PBMC recipients achieved sustained engraftment. Graft rejections were nonfatal in all cases and were followed by autologous reconstitution with persistence or recurrence of chronic myeloid leukemia. Seven of 11 patients with sustained engraftment--including all 5 patients in CP1, 2 of 4 patients in AP, and neither of the 2 patients in CP2--were alive in complete cytogenetic remissions 118 to 1205 days (median, 867 days) after HCT. Two of the remaining 4 patients died of nonrelapse causes in complete (n = 1) or major (n = 1) cytogenetic remissions, and 2 died of progressive disease. Further efforts are directed at reducing the risk of graft rejection by exclusive use of G-PBMC and increasing the degree of pretransplantation immunosuppression.     

Severe hemolysis due to passenger lymphocyte syndrome after hematopoietic stem cell transplantation from an HLA-matched related donor

A 61-year-old white man (group A, Rh-positive) was allotransplanted for acute myelogenous leukemia from his HLA-matched related sister (group O, Rh-positive) in 2 separate infusions. Three days after the second graft infusion, the patient's front blood type converted to O Rh-positive, with a negative direct antiglobulin test and elevated anti-A1 titer. Severe hemolysis developed, and the patient expired 14 days posttransplantation.     

Fludarabine-based reduced intensity conditioning for stem cell transplantation of Fanconi anemia patients from fully matched related and unrelated donors.

Reduced intensity conditioning has been suggested as a desirable therapeutic modality for the treatment of patients with malignant and nonmalignant indications, but it seems particularly attractive for patients with Fanconi anemia due to their increased sensitivity to chemoradiotherapy. Between November 1996 and September 2003, 7 patients (1 male and 6 female; age range, 3-31 years; median age, 9.5) were conditioned with a fludarabine-based protocol for stem cell transplantation without radiation. In vivo T-cell depletion was accomplished with anti-thymocytic globulin or Campath-1H (alemtuzumab). Graft-versus-host disease prophylaxis consisted of low-dose cyclosporine alone. Eight transplantations were carried out for 7 patients using bone marrow, peripheral blood, and/or cord blood as sources of stem cells. All patients received transplants from HLA-A, -B, -C, and -DR matched donors, 5 from family members and 2 from matched unrelated donors. One patient did not engraft her first matched unrelated donor and underwent a second transplantation from another matched unrelated donor, after which she engrafted well. All 7 patients are alive and well, fully reconstituted with donor cells, and with 100% performance status. In conclusion, fludarabine-based preparative protocols are well tolerated, facilitate rapid engraftment with minimal toxicity, and should be considered an essential component of choice for patients with Fanconi anemia.     

Association of human papillomavirus with Fanconi anemia promotes carcinogenesis in Fanconi anemia patients

Fanconi anemia (FA) is a rare recessive disorder associated with chromosomal fragility. FA patients are at very high risk of cancers, especially head and neck squamous cell carcinomas and squamous cell carcinomas caused by infection of human papillomaviruses (HPVs). By integrating into the host genome, HPV oncogenes E6 and E7 drive the genomic instability to promote DNA damage and gene mutations necessary for carcinogenesis in FA patients. Furthermore, E6 and E7 oncoproteins not only inhibit p53 and retinoblastoma but also impair the FANC/BRCA signaling pathway to prevent DNA damage repair and alter multiple signals including cell‐cycle checkpoints, telomere function, cell proliferation, and interference of the host immune system leading to cancer development in FA patients. In this review, we summarize recent advances in unraveling the molecular mechanisms of FA susceptibility to HPV‐induced cancers, which facilitate rational preventive and therapeutic strategies. Copyright © 2015 John Wiley & Sons, Ltd.     

单倍体相合造血干细胞移植治疗儿童重型再生障碍性贫血

背景：目前治疗儿童再生障碍性贫血的主要方法为强化免疫抑制治疗或干细胞移植,后者由于供者来源少而受到限制,HLA单倍体相合的异基因造血干细胞在白血病治疗中常见应用,在再生障碍性贫血治疗中较少应用。目的：探讨单倍体相合的造血干细胞移植联合胎盘来源的间充质干细胞移植治疗重型儿童再生障碍性贫血的疗效。方法：患儿,女,7岁,确诊重型再生障碍性贫血1年半,2012-07-09接受HLA单倍体相合的异基因骨髓及外周血单个核细胞联合胎盘来源间充质干细胞移植,供者为母亲。预处理采用氟达拉滨联合环磷酰胺和抗胸腺细胞球蛋白方案。结果与结论：移植后+9 d中性粒细胞>0.5×10⁹ L^-1,+12 d完成造血重建,+100 d查STR提示植入完成。移植后+8个月停用免疫抑制药物,未发生急、慢性移植物抗宿主病。患儿随访18个月,无病生存。结果表明,HLA单倍体相合的造血干细胞联合胎盘来源间充质细胞移植治疗儿童重型再生障碍性贫血是一种安全有效、值得探索的方法。中国组织工程研究杂志出版内容重点：干细胞;骨髓干细胞;造血干细胞;脂肪干细胞;肿瘤干细胞;胚胎干细胞;脐带脐血干细胞;干细胞诱导;干细胞分化;组织工程全文链接：     

Pharmacokinetics and pharmacodynamics of anti-thymocyte globulin in recipients of partially HLA-matched blood hematopoietic progenitor cell transplantation.

Polyclonal anti-thymocyte globulin (ATG) administered before allogeneic blood hematopoietic progenitor cell transplantation reduces the risks of graft rejection and graft-versus-host disease, but may delay posttransplant immune reconstitution caused by delayed clearance of ATG from the blood. We studied graft-versus-host disease, infections, and the kinetics of immune reconstitution in 28 patients with very poor-risk hematologic malignancies who received lymphocyte-depleted, CD34(+) cell-enriched hematopoietic progenitor cell grafts from partially HLA-matched related donors (PMRD). The incidence of these clinical events was correlated with blood ATG levels in 19 transplant recipients who received rabbit ATG (r-ATG, thymoglobulin) during conditioning. Total r-ATG and the fraction of ATG antibodies that bind human cells (active ATG) were measured for up to 45 days posttransplantation using enzyme-linked immunosorbent assay and flow cytometry assays. Three patients received equine ATG (e-ATG; total dose of 60 mg/kg/day), 3 patients received 10 mg/kg r-ATG, and 22 patients received 6 mg/kg r-ATG during conditioning. All evaluable patients engrafted. Median numbers of blood CD4(+) and CD8(+) T cells at 100 days posttransplantation were 15 and 8 cells/microL, respectively. Acute graft-versus-host disease developed in 3 of 3 recipients of e-ATG and 1 of 25 recipients of r-ATG. Rapid T-cell reconstitution was seen only in younger patients. Overall mortality was 93% (26/28 patients) with poor immune reconstitution contributing to death in 21 of 28 patients. Recipients of 6 mg/kg r-ATG had peak levels of total and active r-ATG of 64+/-20 microg/mL and 9.2+/-5.8 microg/mL, respectively, with clearance of active r-ATG (t(1/2)6 days) to sub-therapeutic levels (<1 microg/mL) by a median of 15 days posttransplantation (range, 8-38 days). Delayed immune reconstitution is likely a consequence of ex vivo and in vivo purging of donor T cells in the graft coupled with inadequate thymic function rather than persistence of active r-ATG in the blood for months posttransplantation.     

Risk factors for late infections after allogeneic hematopoietic stem cell transplantation from a matched related donor.

After allogeneic hematopoietic stem cell transplantation (HSCT), early infections represent a major cause of morbidity and mortality but little information has been previously reported on late infections. Late infection incidence and risk factors were retrospectively determined in 196 long-term survivors after HLA matched related HSCT. Patients transplanted for aplastic anemia, chronic myelogenous leukemia (CML), and acute myelogenous leukemia (AML) were included. Median follow-up was 8 years. Thirty patients died beyond the first year, causes of death were relapse (n = 10) and infections (n = 19, associated with graft-versus-host disease [GVHD] in 16 patients). Late severe bacterial (LSB) and fungal infections occurred in 30 and 8 patients, yielding to an 8-year cumulative incidence of 15 (95%CI: 10-20) and 4% (95%CI: 1-6), respectively. The majority of viral infections were hepatitis C (HCV) and VZV (8-year cumulative incidence: 10 (95%CI: 5-14) and 27% (95%CI: 20-34), respectively. Three risk factors for LSB have been identified in multiple Cox analysis: CMV status (positive recipient and negative donor) (hazard ratio [HR]: 2.5, 95%CI: 1.1-5.9, P = .033), irradiation-based conditioning regimen (HR: 3.1, 95%CI: 1.2-7.8, P = .016), and extensive chronic GVHD (cGVHD; HR: 2.9, 95%CI: 1.3-6.9, P = .013). Extensive cGVHD was the only risk factor for non-HCV viral infections in patients transplanted for AML or CML (HR: 2.7, 95%CI: 1.4-5.1, P = .002). After HSCT, patients remain at high risk of infections even late after transplantation, in particular, with the above risk factors, and required a prolonged follow-up.     

Fluconazole coadministration concurrent with cyclophosphamide conditioning may reduce regimen-related toxicity postmyeloablative hematopoietic cell transplantation.

In a previous study comparing fluconazole and itraconazole administered as antifungal prophylaxis in hematopoietic cell transplant (HCT) recipients, we found that fluconazole administration concurrent with cyclophosphamide (CY)-based conditioning was associated with fewer early toxicities compared to itraconazole. Fluconazole inhibits cytochrome P450 2C9, which is involved with the activation of CY, and so might provide protection from CY-related toxicities. To investigate this further, we compared CY and CY-metabolite data from patients who received fluconazole (n = 56) concurrent with CY-containing conditioning and in patients who did not (n = 17). The fluconazole group had greater exposure to CY, and lower peak serum concentration of CY-metabolite 4-hydroxycyclophosphamide. In a separate cohort, we examined outcomes in patients randomized to receive either fluconazole (n = 152) or placebo (n = 147) concurrent with CY-containing conditioning in a prior randomized trial. Patients who received fluconazole experienced less hepatic and renal toxicity, and had lower mortality. No difference in relapsed malignancy was apparent. These data support the hypothesis that fluconazole, when coadministered with CY, decreases CY-related toxicities by inhibiting cytochrome P450 2C9 metabolism.     

Effect of procarbazine and cyclophosphamide on chromosome breakage in Fanconi anemia cells: relevance to bone marrow transplantation

Fanconi anemia (FA) patients develop stem cell defect-based pancytopenia for which bone marrow transplantation offers the potential for correction. Recently, it has become apparent that the outcome of marrow transplantation in FA patients is poor because of the hypersensitivity of these patients to the pretransplantation conditioning regimen which includes immunosuppression with high doses of the difunctional alkylating agent cyclophosphamide. In an effort to devise a less toxic immunosuppressive regimen, we compared the clastogenic effect of cyclophosphamide with that of procarbazine in cells from FA patients and normal controls. Activation of the drugs was achieved by two alternative methods, either by injection into rats (the in vivo activation method) or by incubation with a rat-liver microsome system (the in vitro activation method). Increased sister chromatid exchange following treatment of cells with cyclophosphamide or procarbazine was used as an indicator for the presence of activated drug metabolites in the system. Although FA cells were hypersensitive to the clastogenic effect of cyclophosphamide, they were not more sensitive than normal cell to procarbazine-induced chromosome breakage. Procarbazine may thus be a safer drug than cyclophosphamide for conditioning FA patients for bone marrow transplantation.     

Nonmyeloablative unrelated donor hematopoietic cell transplantation to treat patients with poor-risk, relapsed, or refractory multiple myeloma.

The purpose of this study was to determine long-term outcome of unrelated donor nonmyeloablative hematopoietic cell transplantation (HCT) in patients with poor-risk multiple myeloma. A total of 24 patients were enrolled; 17 patients (71%) had chemotherapy-refractory disease, and 14 (58%) experienced disease relapse or progression after previous autologous transplantation. Thirteen patients underwent planned autologous transplantation followed 43-135 days later with unrelated transplantation, whereas 11 proceeded directly to unrelated transplantation. All 24 patients were treated with fludarabine (90 mg/m(2)) and 2 Gy of total body irradiation before HLA-matched unrelated peripheral blood stem cell transplantation. Postgrafting immunosuppression consisted of cyclosporine and mycophenolate mofetil. The median follow-up was 3 years after allografting. One patient experienced nonfatal graft rejection. The incidences of acute grades II and III and chronic graft-versus-host disease were 54%, 13%, and 75%, respectively. The 3-year nonrelapse mortality (NRM) was 21%. Complete responses were observed in 10 patients (42%); partial responses, in 4 (17%). At 3 years, overall survival (OS) and progression-free survival (PFS) rates were 61% and 33%, respectively. Patients receiving tandem autologous-unrelated transplantation had superior OS and PFS (77% and 51%) compared with patients proceeding directly to unrelated donor transplantation (44% and 11%) (PFS P value = .03). In summary, for patients with poor-risk, relapsed, or refractory multiple myeloma, cytoreductive autologous HCT followed by nonmyeloablative conditioning and unrelated HCT is an effective treatment approach, with low NRM, high complete remission rates, and prolonged disease-free survival.     

Comparable outcomes after nonmyeloablative hematopoietic cell transplantation with unrelated and related donors.

We sought to determine whether patients with hematologic malignancies treated by nonmyeloablative hematopoietic cell transplantation (HCT) at a single institution between December 1997 and June 2006 had worse outcomes with grafts from unrelated donors (URDs) (n = 184) compared with HLA-identical related donors (n = 221). The nonmyeloablative preparative regimen consisted of 2 Gy of total body irradiation (TBI) with (78%) or without (22%) fludarabine, along with posttransplantation mycophenolate mofetil (MMF) and cyclosporine (CSa). After adjusting for the HCT comorbidity index, relapse risk, patient age, stem cell source, preparative regimen, previous cytomegalovirus (CMV) infection, and sex mismatch of donor and recipient in multivariate analysis, we found no statistically significant differences between unrelated and related HCT recipients in terms of risk of nonrelapse mortality (NRM; hazard ratio [HR] = 0.98; 95% confidence interval = 0.6-1.6; P = .94), relapse (HR = 1.04; 95% confidence interval = 0.7-1.5; P = .82), or overall mortality (HR = 0.99; 95% confidence interval = 0.7-1.4; P = .94). Overall rates of severe acute and extensive chronic graft-versus-host disease (aGVHD, cGVHD) also were not significantly different between the 2 groups. We conclude that within the limitations of a retrospective study, these results indicate that candidates for nonmyeloablative HCT without suitable related donors may expect similar outcomes with grafts from URDs.     

Haploidentical haematopoietic stem cell transplantation for the treatment of severe aplastic anaemia patients with high-risk factors who lack an HLA-matched sibling donor

This study aimed to analyse the efficacy of haploidentical donor (HID) haematopoietic stem cell transplantation as a first-line treatment for severe aplastic anaemia (SAA) with high-risk factors (infection or very severe aplastic anaemia,VSAA) in patients who lack an HLA-matched sibling donor (MSD). The patients with infection were treated with anti-infection therapy, and allogeneic haematopoietic stem cell transplantation (HSCT) was carried out after the infection being effectively controlled was in accordance with the stable infection (SI) standard. A total of 44 SAA patients receiving MSD transplantation (n = 19) and HID transplantation (n = 25) were included in this study. There was no significant difference in neutrophil engraftment between the two groups [MSD vs. HID, 19 (11–38) vs. 22 (15–47).P = 0.241], and the difference in platelet engraftment was statistically significant [MSD vs. HID, 11(7–33) vs. 20 (12–69), P = 0.034]. The HID group exhibited a higher incidence of grade II–IV acute graft-versus-host disease (aGVHD) (HID vs. MSD, 48.0% vs10.5%, P = 0.034)and a higher incidence of chronic GVHD (cGVHD) than the MSD group (64.0% vs. 21.1%, P = 0.026). There was no significant difference between overall survival (OS) following HID and MSD transplantation (84.0% vs. 89.5%, P = 0.664) and failure-free survival (FFS)(80.0% vs. 84.2%, P = 0.965). The interval from diagnosis to transplantation (> 50d) and ECOG (> 2) were independent factors associated with OS and FFS. HID HSCT may be an effective and safe option for SAA patients with high-risk factors who lack an MSD.     

Advance care planning in patients undergoing hematopoietic cell transplantation.

Few data are available on the prevalence of advance care planning (ACP) in patients undergoing hematopoietic cell transplantation (HCT). We surveyed adult patients pre-HCT to ascertain completion of various elements of ACP. We also reviewed medical records for documentation of discussions regarding ACP and for the presence of written advance directives. Evaluable surveys were returned by 155 of 335 patients (46%) who underwent HCT during the study period; we obtained permission for medical record review from 137 of these 155 survey respondents (88%). We found that 69% of the respondents reported having designated a health care proxy, 44% had completed a living will, 61% had prepared an estate will, and 63% had discussed their wishes regarding life support with family and friends. In contrast, only 16% had discussed their wishes regarding life support with their clinicians. Documentation of discussions between clinicians and patients regarding most elements of ACP was rare. Written advance directives were present in the charts of 54 patients (39%). ACP was more common in older, college-educated, and allogeneic transplant patients. Even though ACP was more prevalent among this sample than in the general population, its use still could be enhanced, given the high risks of decisional incapacity and death that HCT patients face.     

以FCA预处理的造血干细胞移植治疗SAA的临床研究

目的探讨以氟达拉滨（Flu）、低剂量环磷酰胺（CTX）和抗胸腺细胞球蛋白（ATG）为预处理的FCA方案异基因造血干细胞移植治疗重型再生障碍性贫血（SAA）的疗效及安全性。方法用FCA预处理方案预处理移植治疗SAA-Ⅰ型和SAA-Ⅱ型患者各2例,其中同胞供者人类白细胞抗原（HLA）低分辨配型（6/6位点）全相合的骨髓联合外周血造血干细胞移植3例、非血缘关系高分辨HLA配型（10/10位点）全相合的外周血造血干细胞移植1例。同胞供者的预处理方案：Flu30mg·m-2d-1×5d,CTX50～60mg·kg-1d-1×5d,ATG3mg·kg-1d-1×3d。非血缘关系的预处理方案：CTX20mg·kg-1d-1×2d,ATG5mg·kg-1d-1×3d,Flu30mg·m-2d-1×4d。移植物抗宿主病（GVHD）的预防：均采用低剂量环孢素A（CsA）联合低剂量短程甲氨蝶呤（MTX）,非血缘关系移植加用霉酚酸酯（MMF）0.5gbid,＋1d～＋28d。观察移植并发症、输血量、造血重建、嵌合体和生存状态。结果 4例患者均获得造血干细胞的成功植入,移植后中性粒细胞绝对值（ANC）〉0.5×109/L的时间为＋10d～＋15d,血小板（PLT）〉20×109/L的时间为＋10d～＋20d,移植后输注红细胞3～6U,血小板4～10U,随访7～42个月,完全供者嵌合体,血液学完全缓解;患者1出现广泛型慢性移植物抗宿主病（cGVHD）,死于多脏器功能衰竭,其余3例无病生存,其中非血缘关系移植的患者4发生轻度局限型cGVHD和巨细胞病毒血症,经过治疗很快控制。结论 Flu、低剂量CTX和ATG的FCA预处理方案的异基因造血干细胞移植治疗SAA的疗效肯定,患者耐受性好,值得推广。     

Donor-recipient combinations of group A and B KIR haplotypes and HLA class I ligand affect the outcome of HLA-matched, sibling donor hematopoietic cell transplantation

The influence of donor and recipient killer immunoglobulin-like receptor (KIR) genotype on the outcome of hematopoietic cell transplantation between human leukocyte antigen (HLA)-matched siblings was investigated. Transplants were divided into four groups according to the combination of group A and B KIR haplotypes in the transplant donor and recipient. Overall survival of myeloid patients varied with KIR genotype combination. Best survival was associated with the donor lacking and the recipient having group B KIR haplotypes; poorest survival was associated with the donor having and the recipient lacking group B KIR haplotypes. The latter combination was also associated with increased relapse and acute graft-versus-host disease (GVHD). However, its detrimental effects were seen only for transplants where the recipient and donor were homozygous for the C1 KIR ligand and therefore lacked the C2 ligand. Presence of the Bw4 ligand was also associated with increased acute GVHD. In contrast presence of both KIR3DL1 and its cognate Bw4 ligand was associated with decreased nonrelapse mortality. Analysis of the KIR genes individually revealed KIR2DS3 as a protective factor for chronic GVHD. The results suggest how simple assessments of KIR genotype might inform the selection of donors for hematopoietic cell transplantation.     

造血干细胞移植治疗再生障碍性贫血的现状

文题释义：预处理：指在移植前对患者进行的放、化疗和免疫抑制治疗。再生障碍性贫血预处理的重点为免疫抑制,常采用非清髓和减低剂量预处理。 移植物抗宿主病：是异基因造血干细胞移植最常见的并发症,分为急性和慢性2种类型。目前认为移植物含有免疫活性细胞、供受者之间存在组织不相容性、受者不排斥植入的细胞是发生移植物抗宿主病3个必备条件。 背景：异基因造血干细胞移植治疗再生障碍性贫血的研究近年来取得很大的进步,但是移植后移植物抗宿主病、移植失败等仍是患者非复发死亡的主要原因,严重影响患者生存。 目的：总结异基因造血干细胞移植治疗再生障碍性贫血的现状及进展。 方法：中文检索词为“再生障碍性贫血,同胞全合异基因造血干细胞移植,无关供者造血干细胞移植,单倍体造血干细胞移植,脐血造血干细胞移植”,英文检索词为“aplastic anemia,matched sibling donor hematopoietic stem cell transplantation,unrelated donor hematopoietic stem cell transplantation,haploidentical hematopoietic stem cell transplantation,cord blood transplantation”,由第一作者检索1990年1月至2019年9月在PubMed、中国知网、万方、维普等数据库中发表的与造血干细胞移植治疗再生障碍性贫血相关的文献,最终选择55篇文献进行分析。 结果与结论：同胞全合异基因造血干细胞移植仍是目前首选的移植方式;对于无同胞全合供者的重型再生障碍性贫血患儿,一线治疗可以选择无关供者相合异基因造血干细胞移植;缺乏全合供者时,单倍体移植和脐血移植亦为不错的选择。 ORCID: 0000-0003-3931-8385(黄东平) 中国组织工程研究杂志出版内容重点：干细胞;骨髓干细胞;造血干细胞;脂肪干细胞;肿瘤干细胞;胚胎干细胞;脐带脐血干细胞;干细胞诱导;干细胞分化;组织工程     

Risk of cancer in heterozygous relatives of patients with Fanconi anemia

PurposeFanconi anemia (FA) is a cancer-prone inherited bone marrow failure syndrome caused by biallelic pathogenic variants in one of >22 genes in the FA/BRCA DNA repair pathway. A major concern is whether the risk of cancer is increased in individuals with a single pathogenic FA gene variant.MethodsWe evaluated the risk of cancer in the relatives of patients with FA in the National Cancer Institute Inherited Bone Marrow Failure Syndrome cohort. We genotyped all available relatives and determined the rates, types of cancer and the age of patients at cancer diagnosis. We calculated the observed-to-expected (O/E) cancer ratios using data from the Surveillance, Epidemiology, and End Results Program adjusted for age, sex, and birth cohort.ResultsThe risk of cancer was not increased among all FA relatives and FA heterozygotes (O/E ratios of 0.78 and 0.79, respectively). In particular, the risk of cancer was not increased among FANCA or FANCC heterozygotes (O/E ratios of 0.92 and 0.71, respectively). Relatives did not have typical FA cancers, and age at cancer diagnosis was not younger than expected.ConclusionUnderstanding the risk of cancer in individuals with single pathogenic FA variants is critical for counseling and management. We did not find increased risk of cancer in these individuals. These findings do not extend to the known cancer predisposition autosomal dominant FA genes, namely BRCA1, BRCA2, PALB2, BRIP1, and RAD51C.     

Novel inactivating mutations of FANCC in Brazilian patients with Fanconi anemia

We have identified three novel FANCC mutations, a truncating single base insertion in exon 4 (c.455_456dupA), a point mutation in exon 13 (c.1390C>T), and a splice site mutation leading to deletion of exon 9, in two Brazilian FA-C patients, each a compound heterozygote. Using complementation analyses, we confirmed that two of these mutations inactivate the function of the FANCC protein.