scholarly journals FANCA Variants in Exons 27-30 Are Associated with Solid Tumors in Fanconi Anemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2192-2192
Author(s):  
Burak Altintas ◽  
Neelam Giri ◽  
Lisa J. McReynolds ◽  
Blanche P. Alter
Keyword(s):  
Bone Marrow ◽  
Solid Tumors ◽  
Fanconi Anemia ◽  
Solid Tumor ◽  
Cox Regression ◽  
Bone Marrow Failure ◽  
Large Deletion ◽  
Interaction Region ◽  
Small Indels ◽  
Large Deletions

Abstract Fanconi anemia (FA) is predominantly an autosomal recessive inherited bone marrow failure syndrome (IBMFS) characterized by congenital anomalies, bone marrow failure (BMF) and an increased cancer risk. It is caused by pathogenic variants in more than 22 genes in the FA/BRCA DNA repair pathway. Approximately 60% of patients have biallelic variants in FANCA. We sought to identify phenotypic differences and clinical outcomes of patients with diverse FANCA variants. We analyzed data from 86 patients with variants in FANCA enrolled in the National Cancer Institute (NCI) IBMFS study (ClinicalTrials.gov identifier 00027274). FANCA variants were determined through review of genetic test reports or whole exome sequencing done as part of the study. The variants were plotted using the online tool ProteinPaint (https://proteinpaint.stjude.org, Figure 1A). Clinical data were extracted from review of medical records and/or evaluations at the NIH. We compared patients with: 1) hypomorphic (hypomorphic variant on one or both alleles) versus null genotype (null variants on both alleles), 2) single nucleotide variant (SNV)/small insertions/deletions (indels) on both alleles versus SNV/small indels on one allele plus large multi-exon deletion on the other allele versus large multi-exon deletions on both alleles. We further compared patients with one or biallelic variants involving the BRCA1 interaction region in the N-terminal domain, FAAP20-binding domain, and variants in exons 27 to 30 where we saw an accumulation of variants, with patients who did not have variants in these regions. We evaluated physical abnormalities that are part of VACTERL-H (Vertebral, Anal, Cardiac, Tracheo-esophageal fistula, Esophageal or duodenal atresia, Renal, upper Limb abnormalities, Hydrocephalus) association and PHENOS (skin Pigmentation abnormalities, small Head, small Eyes, central Nervous system, Otologic abnormalities, Short stature). We focused on the presence, severity and age at BMF, and development of cancers and age at first solid tumor. Frequencies were compared by Fisher's exact test, and a multiple Cox regression model was used to estimate hazard ratio of solid tumors in patients with variants in different regions of FANCA, adjusting for age and hematopoietic cell transplant status of patients with cancer. Analyses were performed using Excel and RStudio, p-value <0.05 was considered significant. The phenotypes, BMF and cancer outcomes were similar between patients with hypomorphic and null genotypes. Similarly, comparison between patients with SNV/small indels, SNV/small indel plus large deletion, and biallelic large deletions did not reveal significant associations. Comparison according the location of the variants on FANCA protein showed that VACTERL-H and VACTERL-H plus PHENOS were less common in patients with at least one SNV/small indel in the BRCA1 interaction region of FANCA compared with patients without variants in this region (2/33 vs 12/51, p= 0.04; 1/33 vs 11/51, p= 0.024, respectively). These associations were not observed when we included patients with large deletions encompassing the BRCA1 interaction region. Eighteen of the 86 patients developed solid tumors; 15/45 patients with an SNV/small indel and/or large deletion within or including exons 27-30 region developed solid tumors compared with 3/41 patients without variants in this region (p= 0.003). Cox regression analysis showed that patients with variants within or involving exons 27-30 were at higher risk of developing solid tumors compared with those without variants in this region (HR: 6.2, 95% CI: 1.36-28.2, Figure 1B). There was no difference between the age at first cancer or type of solid tumors in patients with and without the variant involving this region. The frequency, severity, and age of BMF were also similar between the groups. Our data highlight the possibility that variants involving exons 27-30 within the C-terminal domain of FANCA may be associated with solid tumor development. FANCA forms a homodimer through the interaction between C-terminal domains; variants in this region may affect dimerization and further protein function. Functional analysis and in vivo studies of individual variants in this region and effects of the variants in trans might provide new insights into oncogenesis in FA and may have implications in personalized cancer screening. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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.

scholarly journals Characterization of Pathogenic Variants and Clinical Phenotypes in 117 Japanese Fanconi Anemia Patients

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3860-3860
Author(s):  
Minako Mori ◽  
Asuka Hira ◽  
Kenichi Yoshida ◽  
Hideki Muramatsu ◽  
Yusuke Okuno ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Exome Sequencing ◽  
Molecular Diagnosis ◽  
Fanconi Anemia ◽  
Direct Sequencing ◽  
Bone Marrow Failure ◽  
Whole Genome ◽  
Aberrant Splicing ◽  
Large Deletions ◽  
Complementation Groups

Abstract Objective: Fanconi anemia (FA) is the most common inherited bone marrow failure syndrome associated with multiple congenital abnormalities and predisposition to malignancies, resulting from mutations in one of the 22 known FA genes (FANCA to W). The proteins encoded by these genes participate in DNA repair pathway (the FA pathway) for endogenous aldehyde damage. Compared to the situation in the US or Europe, the number of Japanese FA patients with genetic diagnosis was relatively limited. In this study, we reveal the genetic subtyping and the characteristics of mutated FA genes in Japanese population and clarify the genotype-phenotype correlations. Results: We studied 117 Japanese FA patients from 103 families (1996 to 2018). The diagnosis of FA was confirmed on the basis of chromosomal breakage tests and clinical features. Molecular diagnosis was obtained in 107 (91.5%) of the 117 patients through direct sequencing of FANCA and FANCG, MLPA analysis for FANCA, targeted exome sequencing (targeted-seq), and whole exome sequencing (WES) analysis (Figure 1). To provide genetic subtyping for the 10 unclassified cases, we tried to apply various technologies. Array CGH revealed large deletions in two FA-B and one FA-T cases. Whole genome sequencing and RNA-sequencing analysis identified splicing site or aberrant splicing mutations among three cases (one FA-B, one FA-C, and one FA-N). Collectively, 113 (97%) of Japanese 117 FA patients were successfully subtyped and a total of 219 mutated alleles were identified. FA-A and FA-G accounted for the disease in 58% and 25% of FA patients, respectively, whereas each of the other complementation groups accounted for less than 5% of FA cases. FANCB was the third most common complementation group (n=4) and only one FA-C case was identified in Japanese FA patients. In the 68 FA-A patients, we identified 130 mutant alleles that included 55 different FANCA variants (17 nucleotide substitutions, 16 small deletions/insertions, 12 large deletions, 1 large duplication and 9 splice site mutation). FANCA c.2546delC was the most prevalent (41/130 alleles; 32%). In the 29 FA-G patients, 57 mutant alleles were identified and seven different FANCG variants were detected. FANCG c.307+1G>C and 1066C>T accounted for most of FANCG mutant alleles (49/57; 88%) in the Japanese FA-G patients. The three hotspot mutations (FANCA c.2546delC, FANCG c.307+1G>C and c.1066C>T) existed at low prevalence (0.04-0.1%) in the whole-genome reference panel of 3554 Japanese individuals (3.5KJPN, Tohoku Megabank). Consistent with the paucity of the FA-C patients as opposed to the previous report (Blood 2000), the FANCC IVS4+4A mutation was absent in the 3.5KJPN database. We were able to examine the hematological outcomes in a subset of our cases (52 FA-A and 23 FA-G). Interestingly, the FA-G patients developed bone marrow failure (BMF) at a significantly younger age than FA-A patients (median age at onset of BMF: 3.1 years vs 5 years). Furthermore, the patients with the FANCA c.2546delC mutation had an increased risk of developing myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), compared to FA-A patients without the mutation. In the rare complementation groups of FA, two FA-B cases with complete loss of FANCB gene and one FA-I patient with N-terminal premature termination codons revealed severe somatic abnormalities, consistent with VACTERL-H association. Two FANCD1 (BRCA2) patients and one FANCN (PALB2) patients did not experience bone marrow failure but developed early-onset malignancies (immature teratoma, T-lymphoblastic lymphoma, adenosquamous lung carcinoma, Wilms tumor). Conclusion: This is the largest series of subtyped Japanese FA patients to date and the results would be useful for future clinical management. To provide molecular diagnosis for FA in Japan, we suggest to start with PCR-direct sequencing of the three common mutations (FANCA c.2546delC, FANCG c.307+1G>C and FANCG c.1066C>T) along with MLPA assay for FANCA. These analyses would enable the identification of about 50% of the mutant alleles. For the rest of the cases, WES or targeted-seq analysis should be useful, however, large deletions and aberrant splicing need to be kept in mind. Disclosures Takaori-Kondo: Pfizer: Honoraria; Novartis: Honoraria; Celgene: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Janssen Pharmaceuticals: Honoraria.

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.

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.

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.

Oxandrolone for the treatment of bone marrow failure in Fanconi anemia

2013 ◽  
Vol 61 (1) ◽  
pp. 11-19 ◽  
Author(s):  
Susan R. Rose ◽  
Mi-Ok Kim ◽  
Leslie Korbee ◽  
Kimberly A. Wilson ◽  
M. Douglas Ris ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Fanconi Anemia ◽  
Bone Marrow Failure

scholarly journals ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR ADULT PATIENTS WITH FANCONI ANEMIA.

2016 ◽  
Vol 8 ◽  
pp. 2016054 ◽  
Author(s):  
Hosein Kamranzadeh fumani ◽  
Mohammad Zokaasadi ◽  
Amir Kasaeian ◽  
Kamran Alimoghaddam ◽  
Asadollah Mousavi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Fanconi Anemia ◽  
Bone Marrow Failure ◽  
Term Survival ◽  
Hematopoietic Stem

Background & objectives: Fanconi anemia (FA) is a rare genetic disorder caused by an impaired DNA repair mechanism which leads to an increased tendency toward malignancies and progressive bone marrow failure. The only curative management available for hematologic abnormalities in FA patients is hematopoietic stem cell transplantation (HSCT). This study aimed to evaluate the role of HSCT in FA patients.Methods: Twenty FA patients with ages of 16 or more who underwent HSCT between 2002 and 2015 enrolled in this study. All transplants were allogeneic and the stem cell source was peripheral blood and all patients had a full HLA-matched donor.Results: Eleven patients were female and 9 male (55% and 45%). Mean age was 24.05 years. Mortality rate was 50% (n=10) and the main cause of death was GVHD. Survival analysis showed an overall 5-year survival of 53.63% and 13 year survival of 45.96 % among patients.Conclusion: HSCT is the only curative management for bone marrow failure in FA patients and despite high rate of mortality and morbidity it seems to be an appropriate treatment with an acceptable long term survival rate for adolescent and adult group.

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