Cancer Risks in Fanconi Anemia: Experience of the German Fanconi Anemia (GEFA) Registry.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 995-995
Author(s):  
Philip S. Rosenberg ◽  
Blanche P. Alter ◽  
Wolfram Ebell
Keyword(s):  
Bone Marrow ◽  
Solid Tumors ◽  
Fanconi Anemia ◽  
North American ◽  
Cumulative Incidence ◽  
Age Of Onset ◽  
Bone Marrow Failure ◽  
Significant Risk ◽  
North American Population ◽  
Increased Risk

Abstract OBJECTIVE: Acute Myeloid Leukemia (AML) and solid tumors (ST) occur frequently in Fanconi Anemia (FA). Our objective was to characterize the age of onset of cancer and identify any neoplasms occurring in excess. METHODS: We analyzed data from the German Fanconi Anemia (GEFA) Registry, a retrospective cohort. For competing adverse events of bone marrow failure (BMF), AML, and ST, we determined cause-specific hazards and cumulative incidence curves. We calculated the ratio of observed to expected cancers (O/E ratio) in GEFA compared to age- and sex-matched persons from the general North American population. We studied outcomes after bone marrow transplantation (BMT) using survival analysis. RESULTS: In GEFA, 182 patients contributed 2548 person-years of observation prior to BMT; 63 had BMF as the first adverse event, 15 had AML, and 10 had ST. The cumulative incidence by age 50 was 48% for BMF and 29% for ST. The cumulative incidence by age 20 was 9% for AML. The hazard of BMF peaked at 4%/y at age 10. The hazard of AML increased to 1.6%/y at age 20. The hazard of ST increased from 1%/y at age 20, to 5%/y at age 40, to ~10%/y at age 50. The O/E ratio was 45 for all cancers, 24 for all solid tumors, and 926 for AML; these increased risks were statistically significant. Significantly elevated O/E ratios were observed for esophagus (6346), vulva (2436), oral cavity and pharynx (121), breast (34), and brain (23) cancers. Forty-eight patients had BMT prior to cancer. Subsequently, there were 20 deaths and 3 malignancies in 216 person-years. The 3 malignancies (tongue, liver, and esophagus) occurred 2, 16, and 17 years after mismatched, matched, and matched transplant at ages 13, 23, and 34, respectively. The age-specific hazard of ST was 3.8-fold higher in transplanted versus untransplanted patients; this increased risk was not significant (P = 0.11). During 2000–2004, none of 5 patients with matched, and 3 of 18 patients with mismatched donors, died during the period from 0 – 6 months. In patients with matched donors, acute and chronic GVH were significant risk factors for death beyond 6 months. CONCLUSIONS: Absolute and relative risks of cancer in GEFA are quantitatively similar to previously reported estimates from the North American Survey. Outcomes after transplantation in GEFA are comparable to the Hôpital St Louis Cohort. Our prior observation that FA patients who survive BMF are at extraordinary risk of specific ST has been replicated.

Cancer incidence in persons with Fanconi anemia

Blood ◽  
2003 ◽  
Vol 101 (3) ◽  
pp. 822-826 ◽  
Author(s):  
Philip S. Rosenberg ◽  
Mark H. Greene ◽  
Blanche P. Alter
Keyword(s):  
Bone Marrow ◽  
Solid Tumors ◽  
Fanconi Anemia ◽  
Solid Tumor ◽  
Cumulative Incidence ◽  
Bone Marrow Failure ◽  
Adverse Outcomes ◽  
Relative Risks ◽  
Autosomal Recessive Condition ◽  
Progressive Pancytopenia

Abstract Fanconi anemia (FA) is an autosomal recessive condition associated with congenital abnormalities, progressive pancytopenia, and a predisposition to leukemia and solid tumors. We studied a retrospective cohort of North American patients with FA. We calculated relative risks of cancer compared to the general population and cause-specific hazards of the first major adverse outcomes of FA: bone marrow transplantation (BMT) for marrow complications, acute myeloid leukemia (AML), solid tumors, or death from bone marrow failure. We also estimated the cumulative incidence of each adverse event in the presence of the competing risks. Among 145 patients with FA, 9 developed leukemia and 14 developed a total of 18 solid tumors. The ratio of observed to expected cancers (O/E ratio) was 50 for all cancers, 48 for all solid tumors, and 785 for leukemia; these increased risks were statistically significant. The highest solid tumor O/E ratios were 4317 for vulvar cancer, 2362 for esophageal cancer, and 706 for head and neck cancer. Cause-specific hazards of both death and AML peaked at 1%/y in teenage years; the hazard of BMT peaked at 4%/y at age 7. In contrast, the hazard of a solid tumor approached 8%/y by age 40 years. The cumulative incidence to age 48 was 10% for leukemia, 11% for death from marrow failure, 29% for a solid tumor, and 43% for BMT. The risk of a solid tumor may become even higher as death from aplastic anemia is reduced and as patients survive longer after BMT.

Preemptive Bone Marrow Transplantation and Event-Free Survival in Fanconi Anemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3624-3624
Author(s):  
Nicholas Economou Khan ◽  
Philip S. Rosenberg ◽  
Blanche P. Alter
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Fanconi Anemia ◽  
Marrow Transplantation ◽  
Standard Care ◽  
Bone Marrow Failure ◽  
Event Free Survival ◽  
Free Survival ◽  
Increased Risk ◽  
The Mean

Abstract Background: Fanconi anemia (FA) is a primarily autosomal recessive bone marrow failure and cancer predisposition syndrome associated with mutations in the FA/BRCA DNA damage response pathway. The median age at diagnosis of FA is 7 years; the diagnosis is often made due to recognition of characteristic birth defects. Over half of patients with FA develop severe bone marrow failure (BMF) by age 50 years, one in ten develop acute myeloid leukemia (AML), and one in four develop a solid tumor (ST) as their first event. Successful allogeneic bone marrow transplantation (BMT) is potentially curative of FA's hematologic manifestations but introduces risks of transplant-related mortality (TRM) and morbidity. We hypothesized that preemptive bone marrow transplantation (PE-BMT) for individuals diagnosed prior to the development of BMF, AML, or ST, would increase event-free survival (EFS) if the risks associated with transplantation were sufficiently low. Methods: We developed a mathematical decision model (Markov) of EFS with the assumption that successful PE-BMT would eliminate the risks of BMF and AML, but would introduce a procedural risk of TRM. We modeled the EFS of PE-BMT at variable ages at decision ranging from birth to 30 years, and without and with an increase in the rate of ST following BMT above the level in untransplanted patients with FA. We developed our model using empirical estimates of the age-specific conditional probabilities of BMF, AML, and ST (Alter et al, BJH, 2010), and a 4.4-fold estimated increased risk of ST following BMT (Rosenberg et al, Blood, 2005). We tested the sensitivity of the model over a range of values for TRM and an increased risk of ST following BMT, and evaluated the model using TreeAge Pro 2014 (TreeAge Software, Inc, Williamstown MA, http://www.treeage.com). Results: Children diagnosed at age 7 years receiving standard care could expect to live an additional 16 years before experiencing BMF, ST, or AML, and thus survive free of an event until an average age of 23 years. If those children instead received PE-BMT with a 10% risk of TRM, they could expect to survive an additional 29 years and be cancer-free until an average age of 36 years. However, if PE-BMT were to increase the rate of ST 4.4-fold, PE-BMT would only increase the mean EFS by 2 years over standard care, until an average age of 25 years. PE-BMT would increase the mean EFS at all ages if TRM was ≤10% and the risk of ST was the same as in untransplanted patients. PE-BMT would decrease the mean EFS when performed after age 9 years if there was 10% TRM and a 4.4-fold increased rate of ST. PE-BMT at age 18 years with 10% TRM would increase the mean EFS if it did not affect the trajectory to ST, but would decrease the mean EFS if it modestly increased the rate of ST (≥2.2-fold). Conclusions: PE-BMT in patients with FA may provide an event-free survival benefit so long as the risk of TRM appears to be low (≤10%) and the regimen has little or no impact on the development of ST. The decision was particularly sensitive to the increase in ST following BMT. Our model suggests that older ages at decision, higher risks of TRM, and greater relative risks of ST following transplant would lead to PE-BMT being a less desirable strategy. Our estimates of event-free survival may be used to inform shared decision making between providers and families, with attention paid to patient values and the morbidity associated with BMT. Disclosures No relevant conflicts of interest to declare.

scholarly journals CDK-Mediated Phosphorylation of FANCD2 Promotes Mitotic Fidelity

2020 ◽  
Author(s):  
Juan A. Cantres-Velez ◽  
Justin L. Blaize ◽  
David A. Vierra ◽  
Rebecca A. Boisvert ◽  
Jada M. Garzon ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Bone Marrow ◽  
Fanconi Anemia ◽  
Genetic Disease ◽  
Regulatory Mechanism ◽  
Bone Marrow Failure ◽  
Chromosome Instability ◽  
S Phase ◽  
Rare Genetic Disease ◽  
Increased Risk

AbstractFanconi anemia (FA) is a rare genetic disease characterized by increased risk for bone marrow failure and cancer. The FA proteins function together to repair damaged DNA. A central step in the activation of the FA pathway is the monoubiquitination of the FANCD2 and FANCI proteins under conditions of cellular stress and during S-phase of the cell cycle. The regulatory mechanisms governing S-phase monoubiquitination, in particular, are poorly understood. In this study, we have identified a CDK regulatory phospho-site (S592) proximal to the site of FANCD2 monoubiquitination. FANCD2 S592 phosphorylation was detected by LC-MS/MS and by immunoblotting with a S592 phospho-specific antibody. Mutation of S592 leads to abrogated monoubiquitination of FANCD2 during S-phase. Furthermore, FA-D2 (FANCD2-/-) patient cells expressing S592 mutants display reduced proliferation under conditions of replication stress and increased mitotic aberrations, including micronuclei and multinucleated cells. Our findings describe a novel cell cycle-specific regulatory mechanism for the FANCD2 protein that promotes mitotic fidelity.Author SummaryFanconi anemia (FA) is a rare genetic disease characterized by high risk for bone marrow failure and cancer. FA has strong genetic and biochemical links to hereditary breast and ovarian cancer. The FA proteins function to repair DNA damage and to maintain genome stability. The FANCD2 protein functions at a critical stage of the FA pathway and its posttranslational modification is defective in >90% of FA patients. However, the function, and regulation of FANCD2, particularly under unperturbed cellular conditions, remains remarkably poorly characterized. In this study, we describe a novel mechanism of regulation of the FANCD2 protein during S-phase of the cell cycle. CDK-mediated phosphorylation of FANCD2 on S592 promotes the ubiquitination of FANCD2 during S-phase. Disruption of this phospho-regulatory mechanism results in compromised mitotic fidelity and an increase in mitotic chromosome instability.

scholarly journals Bone marrow transplantation for Fanconi anemia

Blood ◽  
1995 ◽  
Vol 86 (7) ◽  
pp. 2856-2862 ◽  
Author(s):  
E Gluckman ◽  
AD Auerbach ◽  
MM Horowitz ◽  
KA Sobocinski ◽  
RC Ash ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Fanconi Anemia ◽  
Marrow Transplantation ◽  
Bone Marrow Failure ◽  
Unrelated Donor ◽  
Bone Marrow Transplants ◽  
Transplant Outcome ◽  
Factors Associated ◽  
Increased Risk

Fanconi anemia is a genetic disorder associated with diverse congenital abnormalities, progressive bone marrow failure, and increased risk of leukemia and other cancers. Affected persons often die before 30 years of age. Bone marrow transplantation is an effective treatment, but there are few data regarding factors associated with transplant outcome. We analyzed outcomes of HLA-identical sibling (N = 151) or alternative related or unrelated donor (N = 48) bone marrow transplants for Fanconi anemia performed between 1978 and 1994 and reported to the International Bone Marrow Transplant Registry. Fanconi anemia was documented by cytogenetic studies in all cases. Patient, disease, and treatment factors associated with survival were determined using Cox proportional hazards regression. Two-year probabilities (95% confidence interval) of survival were 66% (58% to 73%) after HLA-identical siblings transplants and 29% (18% to 43%) after alternative donor transplants. Younger patient age (P .0001), higher pretransplant platelet counts (P = .04), use of antithymocyte globulin (P = .005), and use of low-dose (15 to 25 mg/kg) cyclophosphamide plus limited field irradiation (P = .009) for pretransplant conditioning and cyclosporine for graft-versus-host disease prophylaxis (P = .002) were associated with increased survival. Bone marrow transplants are effective therapy for Fanconi anemia. The adverse impact of increasing age and lower pretransplant platelet count on transplant outcome favors earlier intervention, especially when there is an HLA-identical sibling donor.

Identifying Unexpected Inherited Marrow Failure Syndromes in Adults Presenting with Aplastic Anemia, MDS or Solid Tumors

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5071-5071
Author(s):  
Curtis Lachowiez ◽  
Gabrielle Meyers
Keyword(s):  
Bone Marrow ◽  
Genetic Counseling ◽  
Aplastic Anemia ◽  
Solid Tumors ◽  
Early Recognition ◽  
Bone Marrow Failure ◽  
Family Members ◽  
Blood Dyscrasia ◽  
Solid Organ ◽  
Increased Risk

Abstract The inherited marrow failure syndromes, most importantly Fanconi Anemia (FA) and the Telomere Diseases, are associated not only with marrow failure, but with endocrinopathies, pulmonary fibrosis, cirrhosis and solid organ malignancies. While these disorders classically present in childhood with physical traits and blood count abnormalities, in reality, there is a wide spectrum of clinical findings in these syndromes. Patients may present with solid organ malignancies, pulmonary or liver abnormalities, aplastic anemia (AA) or myelodysplastic syndrome (MDS). Such presentations in adults require a high index of suspicion on behalf of the clinician during the initial stages of diagnosis, as prompt recognition of an inherited marrow failure disorder is imperative to creating an optimal treatment course. Early recognition allows for institution of surveillance programs for solid tumors, routine blood and bone marrow monitoring for the development of AA or MDS, and imparts a certain prognosis. It also allows for screening of additional family members (most important siblings who may be considered as bone marrow donors) and genetic counseling for families affected by these disorders. Treatment is often directed at the underlying bone marrow failure, and as highlighted by the recently published experience at the NIH (Townsley DM et al, NEJM 2016; 374), specific drugs may impact the disease trajectory. While FA and the other inherited marrow failure syndromes are thought of as primarily diseases of the young, patients can present at older ages. We have therefore established a screening program for patients presenting with MDS under the age of 60, AA patients under the age of 65, and head and neck cancers under the age of 60. Patients presenting with these findings are subject to screening with telomere length testing and blood breakage testing to screen for inherited marrow failure syndromes. With this testing approach, we have identified eight patients with unrecognized inherited bone marrow defects (see Table). Five patients met the criteria for a Telomere Disease, and three patients were diagnosed with FA. Of this subset of patients, only two (20%) had physical characteristics of an inherited bone marrow disorder. In these eight patients, the treatment approach was modulated significantly, including reducing conditioning for BMT, utilizing danazol as first line treatment for AA, and aggressive cancer/endocrinopathy screening. The importance of recognizing an inheritable syndrome cannot be understated. Treatment options for these patients vary widely compared to the standard approach for acquired MDS and AA. Family members of these patients need to be screened for defects if they are potential bone marrow donors, family members are potentially at increased risk for malignancy and marrow failure, and their offspring are at increased risk of inheritance of the mutated gene. Thus, patients and their family members should be engaged in genetic counselling and encouraged to pursue screening for the inherited marrow failure disorder. Affected individuals should then undergo a comprehensive surveillance program consisting of genetic counseling, and screening for associated endocrine, genitourinary, gastrointestinal, ophthalmologic and hematologic pathology in addition to screening for solid tumors. Thus, the approach to the congenital/inherited marrow failure syndromes is bimodal. For cases that present in childhood, early recognition can lead to institution of surveillance for malignancy, blood dyscrasia, and marrow failure as well as family counseling via a genetic specialist. Similarly, recognition of delayed presentations is equally paramount, as the adult who presents with MDS, AML, or aplastic anemia is still at increased risk for solid tumors and a more aggressive transformation to a hematologic malignancy. Additionally, identifying a family member with an inheritable condition allows for screening and surveillance of unaffected, or phenotypically silent relatives, with implications ranging from simple counseling and screening, to pre-emptive treatment. Disclosures No relevant conflicts of interest to declare.

Israeli Fanconi Anemia Registry

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4125-4125
Author(s):  
Hannah Tamary ◽  
Blanche P. Alter ◽  
Daniella Nishri ◽  
Philip S Rosenberg
Keyword(s):  
Bone Marrow ◽  
Solid Tumors ◽  
Fanconi Anemia ◽  
Congenital Abnormality ◽  
Bone Marrow Failure ◽  
Epidemiological Data ◽  
Quantitative Model ◽  
Complementation Group ◽  
Adverse Outcomes ◽  
Complementation Groups

Abstract Using epidemiological data from retrospective cohorts of patients with Fanconi Anemia (FA) in North America and Germany a quantitative model to estimate bone marrow failure (BMF) and cancer risk was previously generated. To evaluate generalizability to another population, and to determine the risks for adverse outcomes in Israel, we created an Israeli FA registry and used the model to evaluate complications. We reviewed patient charts of 66 patients with FA diagnosed in Israel between 1964–2005. The data base included demographic information, as well as data describing the congenital abnormalities, FA complementation groups, BMT course and malignancies. Thirty six (36) patients were of Jewish origin [Ashkenzi 7, Sephardic 23, mixed 6] and 30 of Arabic origin. The first adverse event was bone marrow failure (BMF) in 35 patients (53%), hematological malignancy in 7 (11%) and 2 solid tumors in each of 3 patients (5%). The cause-specific hazard of BMF peaked at 10.5%/year at age 10 years (95% CI: 6.7–14.1%/year). The hazard of AML/ALL and MDS were stable at 0.9%/year (95% CI: 0.42–1.85%/year) and 1.4%/year (95% CI: 0.76–2.49%/year) respectively. The cumulative incidence of each outcome to age 32 was 70% for BMF, 13% for AML/ALL, and 17% for solid tumor. A five item congenital abnormality score was significantly associated with the risk of BMF (P = 0.009). The ratio of observed to expected cancer was 71 for all cancers [50 for solid tumors, 175 for leukemia] and >11,000 for myelodysplastic syndrome. Significantly elevated ratios of observed to expected cancers were observed for head and neck squamous cell carcinoma in 2 patients (986-fold), tumor of larynx (13,238-fold), vulva (3,701-fold), cervix (244-fold) and breast (88-fold). The complementation group was known in 41 patients [A 25 (63%), C 9 (22%), G 6 (15%), and D1 1 (2%)]. However, associations between complementation groups and specific outcomes were not significant. Despite the different ethnic background and the smaller number of FA patients in the Israeli cohort the risk estimates compared with the US and German cohorts were similar. As previously suggested the congenital abnormality score was significantly associated with the risk of BMF; an extraordinary risk of developing AML/MDS and later specific solid tumors was also found.

Individualized risks of first adverse events in patients with Fanconi anemia

Blood ◽  
2004 ◽  
Vol 104 (2) ◽  
pp. 350-355 ◽  
Author(s):  
Philip S. Rosenberg ◽  
Yi Huang ◽  
Blanche P. Alter
Keyword(s):  
Fanconi Anemia ◽  
Cumulative Incidence ◽  
Congenital Abnormality ◽  
Risk Group ◽  
Bone Marrow Failure ◽  
Significant Risk ◽  
Risk Groups ◽  
Hematopoietic Stem ◽  
Prognostic Groups ◽  
Autosomal Recessive Condition

Abstract Fanconi anemia (FA) is an autosomal recessive condition associated with bone marrow failure (BMF) leading to death or hematopoietic stem cell transplantation, acute myeloid leukemia (AML), and solid tumors (STs). It is unclear which patients are most likely to develop each outcome. From a cohort of 144 North American patients with FA, we calculated individualized risks of each outcome, given the presence or absence of readily diagnosed congenital abnormalities that occur frequently in FA. Abnormal radii and a 5-item congenital abnormality score were significant risk factors for BMF. The cumulative incidence of BMF by age 10 years varied from 18% in the lowest BMF risk group to 83% in the highest. Because of competing risks, patients in the lowest BMF risk group were most likely to live long enough to develop AML or ST, and, conversely, patients in the highest BMF risk group were least likely to live long enough to develop AML or ST. By age 40, the cumulative incidence of ST ranged from 0.6% to 29% in the highest and lowest BMF risk groups, respectively. Abnormal radii are the strongest predictor of early BMF in FA; a congenital abnormality score separates patients with normal radii into distinct prognostic groups. (Blood. 2004;104:350-355)

scholarly journals Bone marrow transplantation for Fanconi anemia

Blood ◽  
1995 ◽  
Vol 86 (7) ◽  
pp. 2856-2862 ◽  
Author(s):  
E Gluckman ◽  
AD Auerbach ◽  
MM Horowitz ◽  
KA Sobocinski ◽  
RC Ash ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Fanconi Anemia ◽  
Marrow Transplantation ◽  
Bone Marrow Failure ◽  
Unrelated Donor ◽  
Bone Marrow Transplants ◽  
Transplant Outcome ◽  
Factors Associated ◽  
Increased Risk

Abstract Fanconi anemia is a genetic disorder associated with diverse congenital abnormalities, progressive bone marrow failure, and increased risk of leukemia and other cancers. Affected persons often die before 30 years of age. Bone marrow transplantation is an effective treatment, but there are few data regarding factors associated with transplant outcome. We analyzed outcomes of HLA-identical sibling (N = 151) or alternative related or unrelated donor (N = 48) bone marrow transplants for Fanconi anemia performed between 1978 and 1994 and reported to the International Bone Marrow Transplant Registry. Fanconi anemia was documented by cytogenetic studies in all cases. Patient, disease, and treatment factors associated with survival were determined using Cox proportional hazards regression. Two-year probabilities (95% confidence interval) of survival were 66% (58% to 73%) after HLA-identical siblings transplants and 29% (18% to 43%) after alternative donor transplants. Younger patient age (P .0001), higher pretransplant platelet counts (P = .04), use of antithymocyte globulin (P = .005), and use of low-dose (15 to 25 mg/kg) cyclophosphamide plus limited field irradiation (P = .009) for pretransplant conditioning and cyclosporine for graft-versus-host disease prophylaxis (P = .002) were associated with increased survival. Bone marrow transplants are effective therapy for Fanconi anemia. The adverse impact of increasing age and lower pretransplant platelet count on transplant outcome favors earlier intervention, especially when there is an HLA-identical sibling donor.

scholarly journals A Clinical, Genomic and Proteomic Approach for the Characterization of Fanconi Anemia in Adolescent and Young Adult (AYA) Patients : A Single Center Study of 55 Patients from a National Bone Marrow Failure Referral Center

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2594-2594
Author(s):  
Taimoor Hussain ◽  
Ayodele Alaiya ◽  
Majed Dasouki ◽  
Hazzaa Alzahrani ◽  
Afnan Al-Sabbagh ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Young Adult ◽  
Solid Tumors ◽  
Fanconi Anemia ◽  
Peripheral Blood ◽  
Proteomic Analysis ◽  
Bone Marrow Failure ◽  
Adolescent And Young Adult ◽  
Proteomic Approach

Abstract Introduction: Fanconi Anemia (FA) is an autosomal recessive disorder characterized by bone marrow failure (BMF), constitutional anomalies and high risk of developing cancer. Distinguishing FA from severe aplastic anemia (SAA) can be challenging especially in asyndromic patients. We undertook a clinical and laboratory cohort study of adolescent and young adult (AYA) patients with a diagnosis of FA treated at our institution to characterize the clinical features in our population, and conducted a prospective translational study to explore integration of a genomic and proteomic approach for improved diagnosis and molecular characterization of FA. Methods: Data on FA patients was obtained from an institutionally approved BMF database and hematopoietic stem cell transplant (HSCT) database. Further data was obtained from a register of chromosomal breakage (CB) analysis results. Index cases were identified if they were older than 14 years of age at the time of diagnosis or under the care of adult hematology with a clinical diagnosis of FA based on the presence of BMF and abnormal CB, or clinical phenotype with the presence of homozygous FA related genes. Family pedigrees were constructed based on history. In addition, patients presenting with BMF were enrolled onto an institutionally approved study investigating proteomic biomarkers and genomics of BMF syndromes. Consented peripheral blood samples and/or extracted DNA were subject to either panel based next generation sequencing (NGS) testing as part of the Saudi Genome Project or subjected to whole exome sequencing (WES) by external lab. For proteomic analysis, peripheral blood plasma (PBP) samples from 6 patients with FA, 10 SAA patients and 7 normal controls were subjected to expression proteomics using liquid chromatography tandem mass spectrometry (LC-MS/MS). Result: Patients and clinical features: 55 patients (26 M, 29 F) in 30 families were identified. While 18 patients (32%) were referred with a diagnosis/suspicion of FA, in 26 (47%) FA was diagnosed at our institution. The most frequent anomaly was short stature (14 patients, 25%), skin changes (7, 12%), urogenital abnormalities (7, 12%), dysmorphism/craniofacial abnormalities (7, 12%), hands anomalies (4, 7%); 12 (22%) had no recorded anomalies. 18 patients (33%) developed a malignancy either before or after diagnosis of FA: solid tumors in 5 (9%), AML and/or MDS in 15 (27%); 3 (5%) of these patients had both solid tumors and AML/MDS. Diagnostic Tests: 35 patients (63.6%) had a positive CB analysis with diepoxybutane (DEB) or mitomycin-C (MMC) testing; in 5 patients (9%) DEB testing was borderline and 3 (5%) had a normal CBA but had a diagnostic phenotype+/- family history and presence of a homozygous mutation in a known FA related gene. 14 patients had cytogenetic abnormalities and abnormalities involving chromosome 1 were the most frequent (50%). Mutation Analysis: Mutational analysis was available for 12 (22%) cases; homozygous mutations in FA genes were identified in 10 patients (18%) in 7 families (23% of families): FANCA (5 patients/3 families); BRIP1 (2/2); FANCP (1/1); FANCD2 (2/1). In one case, post matched sibling (HSCT) blood sample revealed a known pathogenic heterozygous c.2632G>C,p.Glu878Gln mutation in FANCA, suggesting a carrier donor. Proteomic analysis: Over 1650 unique PBP protein species were identified of which 605 were significantly differentially expressed (≥ 2 to ∞ - fold change & p < 0.001) between SAA /FA/ normal control subjects (Fig 1a). DNMT3A, Kinase Insert Domain Receptor (KDR) and TGFB-1 was found to be highly expressed in SAA versus FA, while ATM and APOB were highly expressed in FA versus SAA (Fig.1b). Treatment outcomes: 36 out of 55 patients (65%) received HSCT. Actuarial survival of HSCT (n=37) and non-HSCT (n=14) patients was 70% and 77%, respectively. Treatment details were not available on 6 (11%). CONCLUSION: We report the first characterization of AYA patients with FA in Saudi Arabia. Our report emphasizes the need for a high index of suspicion of a diagnosis of FA in BMFs. CB may be falsely negative in cases, and panel based and/or WES based NGS testing increases diagnostic accuracy; in this cohort, mutations in FANCA were the most frequent (50%). Occurrence of hematological and solid tumors is a significant risk in these AYA patients. We also report proteomic panels as potential biomarkers that distinguish FA from SAA and may provide mechanistic insights. Disclosures No relevant conflicts of interest to declare.

scholarly journals Serial Cancer Development Three Times in a Patient with Fanconi Anemia

2021 ◽  
pp. 1168-1174
Author(s):  
Katsuya Yanagisawa ◽  
Toshimichi Horiuchi ◽  
Akemi Matsuo ◽  
Hiroshi Kuraishi ◽  
Hidetoshi Satomi ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Solid Tumors ◽  
Fanconi Anemia ◽  
Cell Lung Cancer ◽  
Bone Marrow Failure ◽  
Nonsmall Cell Lung Cancer ◽  
Cancer Development ◽  
Hematopoietic Stem ◽  
Anal Squamous Cell Carcinoma ◽  
Increased Risk

Fanconi anemia (FA) is characterized clinically by bone marrow failure, congenital malformations, sensitivity to DNA cross-linking agents, and increased risk of malignancy. Hematological cancer is the best-described malignancy in patients with FA, but the susceptibility to the development of solid tumors is also well documented, especially after hematopoietic stem cell transplantation (HSCT). With regard to the development of solid tumors in patients with FA, head and neck, esophageal, and anal squamous cell carcinoma are well known, but reports of lung cancer are extremely rare. Here, we describe an FA patient with a history of HSCT that developed 3 serial cancers – oral, esophageal, and nonsmall cell lung cancer – over a period of 6 years. The third lesion was nonsmall cell lung cancer and its location corresponded closely to the field of irradiation treatment for prior esophageal cancer. The occurrence of lung cancer in patients with FA is uncommon, but FA patients should be screened regularly and serially. Our case also indicated the importance of the irradiated field as a location for subsequent cancer development.

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