Fanconi Anemia - Molecular Biology


Fanconi Anemia (FA) is a rare autosomal recessive genetic disorder characterised clinically by progressive bone marrow failure, skeletal deformities and a predisposition to leukaemia. Affected children usually develop severe aplastic anemia by age 8 to 9 years. The condition is thought to caused by a defect in the processing of DNA damage, patient cells can show extreme chromosomal instability.

There are a number of Fanconi Anemia complementation groups. The two most frequent are group A and group C, which together account for 75-80% of cases. The genes of the Fanconi anemia complementation groups do not share sequence similarity; rather they are related by their assembly into a common nuclear protein complex.

See also: Fanconi Anaemia - clinical resources (16)

Literature Analysis

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Tag cloud generated 29 August, 2019 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (15)

How to use this data tableClicking on the Gene or Topic will take you to a separate more detailed page. Sort this list by clicking on a column heading e.g. 'Gene' or 'Topic'.

-Fanconi Anemia - Complementation Group D1
FANCD2 3p25.3 FA4, FAD, FACD, FAD2, FA-D2, FANCD Germline
-Fanconi Anemia - Complementation Group D2
PALB2 16p12.2 FANCN, PNCA3 Germline
-Fanconi Anemia - Complementation Group N
FANCA 16q24.3 FA, FA1, FAA, FAH, FA-H, FACA, FANCH Germline
-Fanconi Anemia - Complementation Group A
FANCC 9q22.32 FA3, FAC, FACC Germline
-Fanconi Anemia - Complementation Group C
BRIP1 17q23.2 OF, BACH1, FANCJ Germline
-Fanconi Anemia - Complementation Group J
FANCG 9p13.3 FAG, XRCC9 Germline
-Fanconi Anemia - Complementation Group G
FANCF 11p14.3 FAF Germline
-Fanconi Anemia - Complementation Group F
FANCI 15q26.1 KIAA1794 Germline
-Fanconi Anemia - Complementation Group I
FANCM 14q21.2 FAAP250, KIAA1596 Germline
-Fanconi Anemia - Complementation Group M
FANCE 6p21.31 FAE, FACE Germline
-Fanconi Anemia - Complementation Group E
FANCL 2p16.1 POG, PHF9, FAAP43 Germline
-Fanconi Anemia - Complementation Group L
FANCB Xp22.2 FA2, FAB, FACB, FAAP90, FAAP95 Germline
-Fanconi Anemia - Complementation Group B
BACH1 21q21.3 BACH-1, BTBD24 -BACH1 and Fanconi Anaemia
RAD51C 17q22 FANCO, R51H3, BROVCA3, RAD51L2 -RAD51C and Fanconi Anaemia

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

FA and Cancer Susceptibility: Latest Research Publications

Onishi S, Tajika M, Tanaka T, et al.
Superficial Esophageal Cancer in a Fanconi Anemia Patient That Was Treated Successfully by Endoscopic Submucosal Resection.
Intern Med. 2019; 58(4):529-533 [PubMed] Free Access to Full Article Related Publications
Fanconi anemia (FA) is a disorder of chromosomal fragility characterized by progression to aplastic anemia, myelodysplastic syndrome, and leukemia. FA patients are also predisposed to solid cancers. A case of FA in an adult patient who developed tongue and superficial esophageal cancers following hematopoietic stem cell transplantation is reported. This case was considered significant because it is the first reported case of superficial esophageal cancer in an FA patient that was treated successfully by endoscopic submucosal resection.

Itskoviz D, Tamary H, Krasnov T, et al.
Endoscopic findings and esophageal cancer incidence among Fanconi Anemia patients participating in an endoscopic surveillance program.
Dig Liver Dis. 2019; 51(2):242-246 [PubMed] Related Publications
BACKGROUND AND AIMS: The primary clinical characteristics of Fanconi Anemia (FA) include typical physical features, progressive bone marrow failure, and an increased incidence of neoplasms, including esophageal carcinoma. Currently, there are no data regarding endoscopic findings or the interval time to malignancy in these patients. Data about the contribution of Human Papilloma Virus (HPV) to esophageal carcinoma is conflicting. Our objective is to document the upper gastrointestinal (GI) findings at baseline, document cancer incidence, and evaluate the role of HPV among these cancers.
METHODS: We reviewed endoscopic and clinical data of FA subjects who participated in active surveillance before cancer diagnosis. Incident esophageal cancers were stained for HPV
RESULTS: Eight FA patients were included (men 62.5%; median age at first endoscopy 20 years, median endoscopies number: 5.5). At baseline, 8/8 had endoscopic evidence for reflux esophagitis. In 3/8 the reflux esophagitis was mild and in 5/8 it was moderate or severe. During the follow up time (median time 4.5 years 2/8 developed Barrett's esophagus and 2/8 patients had incident esophageal squamous cell carcinoma during follow up, at intervals of eight and eighteen months from the previous upper endoscopy. Both cancers stained negative for HPV
CONCLUSIONS: FA subjects have both an extremely high risk for esophageal cancer within short intervals and a very high prevalence of reflux esophagitis with various severities. Active surveillance programs in specialized centers including annual upper endoscopies should be considered in these patients.

Mafessoni TP, Mazur CE, Amenábar JM
Salivary lactate dehydrogenase (LDH) as a tool for early diagnosis of oral cancer in individuals with Fanconi anemia.
Med Hypotheses. 2018; 119:29-31 [PubMed] Related Publications
Currently one of the greater challenges is the diagnosis and treatment of cancer. Many studies address the genetic and metabolic aspects to support in early diagnosis and increase the survival of individuals at high risk. Individuals with Fanconi anemia can be included in this high risk group because they have a predisposition to develop head and neck cancer. The use of salivary enzymes as biomarkers to detect the changes in oral tissue at the initial phase seems viable, because saliva is easy to obtain, it moisture oral mucosa and cells metabolic compounds can be found on it. Due to the metabolic characteristics of the cancer cell, an increase in Lactate Dehydrogenase (LDH) may indicate a carcinogenesis process. The hypothesis of this study is to use of salivary LDH as a tool in the early diagnosis of oral cancer on a high risk group such as Fanconi anemia's patients.

Feben C, Wainstein T, Kromberg J, et al.
Fanconi anaemia in South Africa: Past, present and future.
S Afr Med J. 2018; 108(5):393-398 [PubMed] Related Publications
Fanconi anaemia (FA) is an inherited genetic disorder characterised by somatic anomalies, bone marrow failure and an increased predisposition to solid tumours and haematological malignancies. South African (SA) black and Afrikaner individuals are at higher than average risk for this condition owing to genetic founder mutations in certain Fanconi-associated genes. This review explores the epidemiology, clinical presentation, diagnostic modalities and recommended care of affected patients, focusing on the founder population groups in SA. The early diagnosis of FA is important and provides improved opportunities for early intervention, but remains challenging.

Furquim CP, Pivovar A, Amenábar JM, et al.
Oral cancer in Fanconi anemia: Review of 121 cases.
Crit Rev Oncol Hematol. 2018; 125:35-40 [PubMed] Related Publications
Fanconi anemia (FA) is a rare autosomal recessive genetic disorder characterized by aplastic anemia, progressive pancytopenia, congenital anomalies, and increased risk of cancer development. After hematopoietic stem cell transplant (HSCT), patients have an estimated 500-fold increase in the risk of developing head and neck cancer compared to a non-affected, and the oral cavity is affected in one-third of cases. Thus, this study aimed to better understand the natural history of oral cavity cancer in patients affected by FA. After conducting a keyword search on MEDLINE, we found 121 cases of oral cavity cancer in patients who had been affected by FA. In conclusion, HSCT may increase the risks of oral cancer development, especially after 5 years after the transplant. In the normal population, the tongue is the most affected area. FA patients should be informed of the risks of oral malignant transformation and encouraged to be undergo medical surveillance.

Nalepa G, Clapp DW
Fanconi anaemia and cancer: an intricate relationship.
Nat Rev Cancer. 2018; 18(3):168-185 [PubMed] Related Publications
Fanconi anaemia (FA) is a genetic disorder that is characterized by bone marrow failure (BMF), developmental abnormalities and predisposition to cancer. Together with other proteins involved in DNA repair processes and cell division, the FA proteins maintain genome homeostasis, and germline mutation of any one of the genes that encode FA proteins causes FA. Monoallelic inactivation of some FA genes, such as FA complementation group D1 (FANCD1; also known as the breast and ovarian cancer susceptibility gene BRCA2), leads to adult-onset cancer predisposition but does not cause FA, and somatic mutations in FA genes occur in cancers in the general population. Carcinogenesis resulting from a dysregulated FA pathway is multifaceted, as FA proteins monitor multiple complementary genome-surveillance checkpoints throughout interphase, where monoubiquitylation of the FANCD2-FANCI heterodimer by the FA core complex promotes recruitment of DNA repair effectors to chromatin lesions to resolve DNA damage and mitosis. In this Review, we discuss how the FA pathway safeguards genome integrity throughout the cell cycle and show how studies of FA have revealed opportunities to develop rational therapeutics for this genetic disease and for malignancies that acquire somatic mutations within the FA pathway.

Nepal M, Che R, Zhang J, et al.
Fanconi Anemia Signaling and Cancer.
Trends Cancer. 2017; 3(12):840-856 [PubMed] Free Access to Full Article Related Publications
The extremely high cancer incidence associated with patients suffering from a rare human genetic disease, Fanconi anemia (FA), demonstrates the importance of FA genes. Over the course of human tumor development, FA genes perform critical tumor-suppression roles. In doing so, FA provides researchers with a unique genetic model system to study cancer etiology. Here, we review how aberrant function of the 22 FA genes and their signaling network contributes to malignancy. From this perspective, we will also discuss how the knowledge discovered from FA research serves basic and translational cancer research.

Singh T, Andi K
Fanconi anaemia and oral squamous cell carcinoma: management considerations.
N Z Med J. 2017; 130(1466):92-95 [PubMed] Related Publications
Fanconi anaemia (FA) is a rare multi-system genetic disorder where patients are susceptible to the development of oral malignancies. Clinicians involved in their management should be vigilant in detecting lesions early, and an individualised treatment plan should then be formulated. Although surgery forms the mainstay of oncological treatment, adjuvant therapy can be instituted with care. Unfortunately, prognosis is poor, and close long-term follow-up is required. This short report describes pertinent management considerations in relation to a case of oral squamous cell carcinoma.

Chao MM, Thomay K, Goehring G, et al.
Mutational Spectrum of Fanconi Anemia Associated Myeloid Neoplasms.
Klin Padiatr. 2017; 229(6):329-334 [PubMed] Related Publications
Individuals with Fanconi anemia (FA) have a high risk of developing myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), yet the secondary somatic mutations lending to these malignancies remain to be further elucidated. We employed a next-generation sequencing myeloid neoplasia gene panel to determine the mutational spectrum of FA-related MDS/AML. Ten of 16 patients showed missense, nonsense, insertion or duplication mutations in 13 genes. In contrast to findings in MDS in the general population, mutations in genes involved in RNA splicing were rarely affected. Mutations in

Bierings M, Bonfim C, Peffault De Latour R, et al.
Transplant results in adults with Fanconi anaemia.
Br J Haematol. 2018; 180(1):100-109 [PubMed] Related Publications
The outcomes of adult patients transplanted for Fanconi anaemia (FA) have not been well described. We retrospectively analysed 199 adult patients with FA transplanted between 1991 and 2014. Patients were a median of 16 years of age when diagnosed with FA, and underwent transplantation at a median age of 23 years. Time between diagnosis and transplant was shortest (median 2 years) in those patients who had a human leucocyte antigen identical sibling donor. Fifty four percent of patients had bone marrow (BM) failure at transplantation and 46% had clonal disease (34% myelodysplasia, 12% acute leukaemia). BM was the main stem cell source, the conditioning regimen included cyclophosphamide in 96% of cases and fludarabine in 64%. Engraftment occurred in 82% (95% confidence interval [CI] 76-87%), acute graft-versus-host disease (GvHD) grade II-IV in 22% (95% CI 16-28%) and the incidence of chronic GvHD at 96 months was 26% (95% CI 20-33). Non-relapse mortality at 96 months was 56% with an overall survival of 34%, which improved with more recent transplants. Median follow-up was 58 months. Patients transplanted after 2000 had improved survival (84% at 36 months), using BM from an identical sibling and fludarabine in the conditioning regimen. Factors associated with improved outcome in multivariate analysis were use of fludarabine and an identical sibling or matched non-sibling donor. Main causes of death were infection (37%), GvHD (24%) and organ failure (12%). The presence of clonal disease at transplant did not significant impact on survival. Secondary malignancies were reported in 15 of 131 evaluable patients.

Catucci I, Osorio A, Arver B, et al.
Individuals with FANCM biallelic mutations do not develop Fanconi anemia, but show risk for breast cancer, chemotherapy toxicity and may display chromosome fragility.
Genet Med. 2018; 20(4):452-457 [PubMed] Related Publications
PurposeMonoallelic germ-line mutations in the BRCA1/FANCS, BRCA2/FANCD1 and PALB2/FANCN genes confer high risk of breast cancer. Biallelic mutations in these genes cause Fanconi anemia (FA), characterized by malformations, bone marrow failure, chromosome fragility, and cancer predisposition (BRCA2/FANCD1 and PALB2/FANCN), or an FA-like disease presenting a phenotype similar to FA but without bone marrow failure (BRCA1/FANCS). FANCM monoallelic mutations have been reported as moderate risk factors for breast cancer, but there are no reports of any clinical phenotype observed in carriers of biallelic mutations.MethodsBreast cancer probands were subjected to mutation analysis by sequencing gene panels or testing DNA damage response genes.ResultsFive cases homozygous for FANCM loss-of-function mutations were identified. They show a heterogeneous phenotype including cancer predisposition, toxicity to chemotherapy, early menopause, and possibly chromosome fragility. Phenotype severity might correlate with mutation position in the gene.ConclusionOur data indicate that biallelic FANCM mutations do not cause classical FA, providing proof that FANCM is not a canonical FA gene. Moreover, our observations support previous findings suggesting that FANCM is a breast cancer-predisposing gene. Mutation testing of FANCM might be considered for individuals with the above-described clinical features.

Bogliolo M, Bluteau D, Lespinasse J, et al.
Biallelic truncating FANCM mutations cause early-onset cancer but not Fanconi anemia.
Genet Med. 2018; 20(4):458-463 [PubMed] Related Publications
PurposeMutations in genes involved in Fanconi anemia (FA)/BRCA DNA repair pathway cause cancer susceptibility diseases including familial breast cancer and Fanconi anemia (FA). A single FA patient with biallelic FANCM mutations was reported in 2005 but concurrent FANCA pathogenic mutations precluded assignment of FANCM as an FA gene. Here we report three individuals with biallelic FANCM truncating mutations who developed early-onset cancer and toxicity to chemotherapy but did not present congenital malformations or any hematological phenotype suggestive of FA.MethodsChromosomal breakages, interstrand crosslink sensitivity, and FANCD2 monoubiquitination were assessed in primary fibroblasts. Mutation analysis was achieved through Sanger sequencing. Genetic complementation of patient-derived cells was performed by lentiviral mediated transduction of wild-type FANCM complementary DNA followed by functional studies.ResultsPatient-derived cells exhibited chromosomal fragility, hypersensitivity to interstrand crosslinks, and impaired FANCD2 monoubiquitination. We identified two homozygous mutations (c.2586_2589del4; p.Lys863Ilefs*12 and c.1506_1507insTA; p.Ile503*) in FANCM as the cause of the cellular phenotype. Patient-derived cells were genetically complemented upon wild-type FANCM complementary DNA expression.ConclusionLoss-of-function mutations in FANCM cause a cancer predisposition syndrome clinically distinct from bona fide FA. Care should be taken with chemotherapy and radiation treatments in these patients due to expected acute toxicity.

Chandrasekharappa SC, Chinn SB, Donovan FX, et al.
Assessing the spectrum of germline variation in Fanconi anemia genes among patients with head and neck carcinoma before age 50.
Cancer. 2017; 123(20):3943-3954 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Patients with Fanconi anemia (FA) have an increased risk for head and neck squamous cell carcinoma (HNSCC). The authors sought to determine the prevalence of undiagnosed FA and FA carriers among patients with HNSCC as well as an age cutoff for FA genetic screening.
METHODS: Germline DNA samples from 417 patients with HNSCC aged <50 years were screened for sequence variants by targeted next-generation sequencing of the entire length of 16 FA genes.
RESULTS: The sequence revealed 194 FA gene variants in 185 patients (44%). The variant spectrum was comprised of 183 nonsynonymous point mutations, 9 indels, 1 large deletion, and 1 synonymous variant that was predicted to effect splicing. One hundred eight patients (26%) had at least 1 rare variant that was predicted to be damaging, and 57 (14%) had at least 1 rare variant that was predicted to be damaging and had been previously reported. Fifteen patients carried 2 rare variants or an X-linked variant in an FA gene. Overall, an age cutoff for FA screening was not identified among young patients with HNSCC, because there were no significant differences in mutation rates when patients were stratified by age, tumor site, ethnicity, smoking status, or human papillomavirus status. However, an increased burden, or mutation load, of FA gene variants was observed in carriers of the genes FA complementation group D2 (FANCD2), FANCE, and FANCL in the HNSCC patient cohort relative to the 1000 Genomes population.
CONCLUSIONS: FA germline functional variants offer a novel area of study in HNSCC tumorigenesis. FANCE and FANCL, which are components of the core complex, are known to be responsible for the recruitment and ubiquitination, respectively, of FANCD2, a critical step in the FA DNA repair pathway. In the current cohort, the increased mutation load of FANCD2, FANCE, and FANCL variants among younger patients with HNSCC indicates the importance of the FA pathway in HNSCC. Cancer 2017;123:3943-54. © 2017 American Cancer Society.

Nolan M, Courtney R, Sexton P, et al.
Aggressive Recurrence of Oral Squamous Cell Carcinoma in a patient with Fanconi's Anaemia (FA).
Ir Med J. 2017; 110(3):533 [PubMed] Related Publications
Fanconi's Anaemia is a rare autosomal recessive disease for which the incidence of head and neck cancer can be increased 700-fold1. We report a case of a 31-year old Caucasian male with FA who initially presented in July 2007 with oral squamous cell carcinoma for which he received radical surgery and radiotherapy. He was disease-free until August 2015 when he presented with an extremely aggressive recurrence.

Cheung RS, Taniguchi T
Recent insights into the molecular basis of Fanconi anemia: genes, modifiers, and drivers.
Int J Hematol. 2017; 106(3):335-344 [PubMed] Free Access to Full Article Related Publications
Fanconi anemia (FA), the most common form of inherited bone marrow failure, predisposes to leukemia and solid tumors. FA is caused by the genetic disruption of a cellular pathway that repairs DNA interstrand crosslinks. The impaired function of this pathway, and the genetic instability that results, is considered the main pathogenic mechanism behind this disease. The identification of breast cancer susceptibility genes (for example, BRCA1/FANCS and BRCA2/FANCD1) as being major players in the FA pathway has led to a surge in molecular studies, resulting in the concept of the FA-BRCA pathway. In this review, we discuss recent advances in the molecular pathogenesis of FA from three viewpoints: (a) new FA genes, (b) modifier pathways that influence the cellular and clinical phenotypes of FA and (c) non-canonical functions of FA genes that may drive disease progression independently of deficient DNA repair. Potential therapeutic approaches for FA that are relevant to each will also be proposed.

Pivovar A, Furquim CP, Bonfim C, Torres-Pereira CC
Mouth examination performance by children's parents and by adolescents in Fanconi anemia.
Pediatr Blood Cancer. 2017; 64(11) [PubMed] Related Publications
BACKGROUND: Fanconi anemia (FA) is a rare genetic syndrome characterized by increased risk of developing malignant neoplasms, particularly oral squamous cell carcinoma. This study aims to ascertain the extent to which adolescents and guardians/parents of children with FA are aware of their oral cancer risks and assess their ability to perform mouth examination (ME).
PROCEDURE: A cross-sectional study was conducted among patients with FA (between 6 and 16 years) and their parents. A total of 45 patients, 19 children and 26 adolescents, participated in the study. Among children less than 12 years of age, caregivers performed ME and adolescents between 12 and 16 years of age performed mouth self-examination (MSE). All parents were given a self-reporting questionnaire to collect sociodemographic data, information about health-related behaviors, and oral cancer awareness. Performance was evaluated using criteria for mucosal visualization and retracting ability. Subsequently, a dentist clinically examined all patient participants.
RESULTS: Performance evaluation indicated that the examination quality was unsatisfactory in both groups. Statistical significance was found between ability to perform ME by marital status (P < 0.036), where divorced parents had more difficulty performing ME than nondivorced parents.
CONCLUSION: Oral mucosa surveillance performed by parents and adolescents seems to be inaccurate. However, as an oral examination is a relatively inexpensive form of secondary prevention, it merits attention to teaching the technique to patients with FA and their caregivers.

Türke C, Horn S, Petto C, et al.
Loss of heterozygosity in FANCG, FANCF and BRIP1 from head and neck squamous cell carcinoma of the oral cavity.
Int J Oncol. 2017; 50(6):2207-2220 [PubMed] Related Publications
Recent advances have been made in the understanding of Fanconi anemia (FA), a hereditary disease that increases the risk for head and neck squamous cell carcinomas (HNSCC) by 500- to 700-fold. FA patients harbour germline mutations in genes of cellular DNA repair pathways that are assumed to facilitate the accumulation of mutations during HNSCC development. Mutations in these FA genes may also contribute to HNSCC in general. In the present study, we analysed three FA genes; FANCF, FANCG and BRIP1, that are involved in the repair of DNA inter strand cross-links, in HNSCC and their potential role for patient survival. We measured loss of heterozygosity (LOH) mutations at eight microsatellite loci flanking three FA genes in 54 HNSCC of the oral cavity and corresponding blood samples. Survival analyses were carried out using mutational data and clinical variables. LOH was present in 17% (FANCF region), 41% (FANCG region) and 11% (BRIP1 region) of the patients. Kaplan-Meier survival curves and log-rank tests indicated strong clinical predictors (lymph node stages with decreased survival: p=2.69e-12; surgery with improved survival: p=0.0005). LOH in the FANCF region showed a weaker association with decreased overall survival (p=0.006), which however, did not hold in multivariate analyses. LOH may predominantly indicate copy number gains in FANCF and losses in FANCG and BRIP1. Integration of copy number data and gene expression proved difficult as the available sample sets did not overlap. In conclusion, LOH in FA genes appears to be a common feature of HNSCC development seen here in 57% of patients and other mutation types may increase this mutation frequency. We suggest larger patient cohorts would be needed to test the observed association of LOH in FANCF and patient survival comprehensively.

Han B, Shen Y, Zhang P, et al.
Overlooked FANCD2 variant encodes a promising, portent tumor suppressor, and alternative polyadenylation contributes to its expression.
Oncotarget. 2017; 8(14):22490-22500 [PubMed] Free Access to Full Article Related Publications
Fanconi Anemia (FA) complementation group D2 protein (FANCD2) is the center of the FA tumor suppressor pathway, which has become an important field of investigation in human aging and cancer. Here we report an overlooked central player in the FA pathway, FANCD2 variant 2 (FANCD2-V2), which appears to perform more potent tumor suppressor-function compared to the known variant of FANCD2, namely, FANCD2-V1. Detailed analysis of the FANCD2 gene structure indicated a proximal and distal polyadenylation site (PAS), associated with V2 and V1 transcripts accordingly. RNA polymerase II Chromatin immunoprecipitation (ChIP) targeting the two PAS-regions determined lesser binding of RNA pol II to DNA fragments in the distal PAS region in non-malignant cells compared to malignant cells. Conversely, the opposite occurred in the proximal PAS region. Moreover, RNA immunoprecipitation (RIP) identified that U2 snRNP, a major component of RNA splicing complex that interacts with the 3'end of an intron, showed greater binding to the last intron of the FANCD2-V1 transcript in malignant cells compared to the non-malignant cells. Importantly, our data showed that in human tissue samples, the ratio of V2 /V1 expression in lung, bladder, or ovarian cancer correlates inversely with the tumor stages/grades. Therefore, these findings provide a previously unrecognized central player FANCD2-V2 and thus novel insights into human tumorigenesis, and indicate that V2/V1 can act as an effective biomarker in assisting the recognition of tumor malignance.

Ebens CL, MacMillan ML, Wagner JE
Hematopoietic cell transplantation in Fanconi anemia: current evidence, challenges and recommendations.
Expert Rev Hematol. 2017; 10(1):81-97 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Hematopoietic cell transplantation for Fanconi Anemia (FA) has improved dramatically over the past 40 years. With an enhanced understanding of the intrinsic DNA-repair defect and pathophysiology of hematopoietic failure and leukemogenesis, sequential changes to conditioning and graft engineering have significantly improved the expectation of survival after allogeneic hematopoietic cell transplantation (alloHCT) with incidence of graft failure decreased from 35% to <10% and acute graft-versus-host disease (GVHD) from >40% to <10%. Today, five-year overall survival exceeds 90% in younger FA patients with bone marrow failure but remains about 50% in those with hematologic malignancy. Areas covered: We review the evolution of alloHCT contributing to decreased rates of transplant related complications; highlight current challenges including poorer outcomes in cases of clonal hematologic disorders, alloHCT impact on endocrine function and intrinsic FA risk of epithelial malignancies; and describe investigational therapies for prevention and treatment of the hematologic manifestations of FA. Expert commentary: Current methods allow for excellent survival following alloHCT for FA associated BMF irrespective of donor hematopoietic cell source. Alternative curative approaches, such as gene therapy, are being explored to eliminate the risks of GVHD and minimize therapy-related adverse effects.

Furquim CP, Soares GM, Ribeiro LL, et al.
The Salivary Microbiome and Oral Cancer Risk: a Pilot Study in Fanconi Anemia.
J Dent Res. 2017; 96(3):292-299 [PubMed] Free Access to Full Article Related Publications
Fanconi anemia (FA) is a rare genetic disease characterized by chromosomal instability and impaired DNA damage repair. FA patients develop oral squamous cell carcinoma (OSCC) earlier and more frequently than the general population, especially after hematopoietic stem cell transplantation (HSCT). Although evidence of an etiological role of the local microbiome and carcinogenesis has been mounting, no information exists regarding the oral microbiome of FA patients. The aim of this study was to explore the salivary microbiome of 61 FA patients regarding their oral health status and OSCC risk factors. After answering a questionnaire and receiving clinical examination, saliva samples were collected and analyzed using 16S rRNA sequencing of the V3-V4 hypervariable region. The microbial profiles associated with medical and clinical parameters were analyzed using general linear models. Patients were young (mean age, 22 y) and most had received HSCT ( n = 53). The most abundant phyla were Firmicutes [mean relative abundance (SD), 42.1% (10.1%)] and Bacteroidetes [(25.4% (11.4%)]. A history of graft-versus-host disease (GVHD) ( n = 27) was associated with higher proportions of Firmicutes (43.8% × 38.5%, P = 0.05). High levels of gingival bleeding were associated with the genera Prevotella (22.25% × 20%), Streptococcus (19.83% × 17.61%), Porphyromonas (3.63% × 1.42%, P = 0.03), Treponema (1.02% × 0.28%, P = 0.009), Parvimonas (0.28% × 0.07%, P = 0.02) and Dialister (0.27% × 0.10%, P = 0.04). Finally, participants transplanted over 11 y ago showed the highest levels of Streptococcus (18.4%), Haemophilus (12.7%) and Neisseria (6.8%). In conclusion, FA patients that showed poor oral hygiene harbored higher proportions of the genera of bacteria compatible with gingival disease. Specific microbial differences were associated with a history of oral GVHD and a history of oral mucositis.

Lakhi NA, Mizejewski GJ
Alpha-fetoprotein and Fanconi Anemia: Relevance to DNA Repair and Breast Cancer Susceptibility.
Fetal Pediatr Pathol. 2017; 36(1):49-61 [PubMed] Related Publications
Elevations of serum alpha-fetoprotein (sAFP) have been reported in fetal and infant states of anemia. Fanconi anemia (FA) belongs to a family of genetic instability disorders which lack the capability to repair DNA breaks. The lesion occurs at a checkpoint regulatory step of the G2 to mitotic transition, allowing FA cells to override cell-cycle arrest. FA DNA repair pathways contain complementation groups known as FANC proteins. FANC proteins form multi-protein complexes with BRCA proteins and are involved in homologous DNA repair. An impaired cascade in these events imparts an increased breast cancer susceptibility to female FA patients. Elevations of sAFP have availed this fetal protein to serve as a biomarker for FA disease. However, the origin of the synthesis of sAFA has not been determined in FA patients. We hypothesize that hematopoietic multipotent progenitor stem cells in the bone marrow are the source of sAFP production in FA patients.

Brégnard C, Guerra J, Déjardin S, et al.
Upregulated LINE-1 Activity in the Fanconi Anemia Cancer Susceptibility Syndrome Leads to Spontaneous Pro-inflammatory Cytokine Production.
EBioMedicine. 2016; 8:184-194 [PubMed] Free Access to Full Article Related Publications
Fanconi Anemia (FA) is a genetic disorder characterized by elevated cancer susceptibility and pro-inflammatory cytokine production. Using SLX4(FANCP) deficiency as a working model, we questioned the trigger for chronic inflammation in FA. We found that absence of SLX4 caused cytoplasmic DNA accumulation, including sequences deriving from active Long INterspersed Element-1 (LINE-1), triggering the cGAS-STING pathway to elicit interferon (IFN) expression. In agreement, absence of SLX4 leads to upregulated LINE-1 retrotransposition. Importantly, similar results were obtained with the FANCD2 upstream activator of SLX4. Furthermore, treatment of FA cells with the Tenofovir reverse transcriptase inhibitor (RTi), that prevents endogenous retrotransposition, decreased both accumulation of cytoplasmic DNA and pro-inflammatory signaling. Collectively, our data suggest a contribution of endogenous RT activities to the generation of immunogenic cytoplasmic nucleic acids responsible for inflammation in FA. The additional observation that RTi decreased pro-inflammatory cytokine production induced by DNA replication stress-inducing drugs further demonstrates the contribution of endogenous RTs to sustaining chronic inflammation. Altogether, our data open perspectives in the prevention of adverse effects of chronic inflammation in tumorigenesis.

Park S, Park JW, Pitot HC, Lambert PF
Loss of Dependence on Continued Expression of the Human Papillomavirus 16 E7 Oncogene in Cervical Cancers and Precancerous Lesions Arising in Fanconi Anemia Pathway-Deficient Mice.
MBio. 2016; 7(3) [PubMed] Free Access to Full Article Related Publications
Fanconi anemia (FA) is a rare genetic disorder caused by defects in DNA damage repair. FA patients often develop squamous cell carcinoma (SCC) at sites where high-risk human papillomaviruses (HPVs) are known to cause cancer, including the cervix. However, SCCs found in human FA patients are often HPV negative, even though the majority of female FA patients with anogenital cancers had preexisting HPV-positive dysplasia. We hypothesize that HPVs contribute to the development of SCCs in FA patients but that the continued expression of HPV oncogenes is not required for the maintenance of the cancer state because FA deficiency leads to an accumulation of mutations in cellular genes that render the cancer no longer dependent upon viral oncogenes. We tested this hypothesis, making use of Bi-L E7 transgenic mice in which we temporally controlled expression of HPV16 E7, the dominant viral oncogene in HPV-associated cancers. As seen before, the persistence of cervical neoplastic disease was highly dependent upon the continued expression of HPV16 E7 in FA-sufficient mice. However, in mice with FA deficiency, cervical cancers persisted in a large fraction of the mice after HPV16 E7 expression was turned off, indicating that these cancers had escaped from their dependency on E7. Furthermore, the severity of precancerous lesions also failed to be reduced significantly in the mice with FA deficiency upon turning off expression of E7. These findings confirm our hypothesis and may explain the fact that, while FA patients have a high frequency of infections by HPVs and HPV-induced precancerous lesions, the cancers are frequently HPV negative. IMPORTANCE  : Fanconi anemia (FA) patients are at high risk for developing squamous cell carcinoma (SCC) at sites where high-risk human papillomaviruses (HPVs) frequently cause cancer. Yet these SCCs are often HPV negative. FA patients have a genetic defect in their capacity to repair damaged DNA. HPV oncogenes cause an accumulation of DNA damage. We hypothesize, therefore, that DNA damage induced by HPV leads to an accumulation of mutations in patients with FA deficiency and that such mutations allow HPV-driven cancers to become independent of the viral oncogenes. Consistent with this hypothesis, we found that cervical cancers arising in HPV16 transgenic mice with FA deficiency frequently escape from dependency on the HPV16 oncogene that drove its development. Our report provides further support for vaccination of FA patients against HPVs and argues for the need to define mutational profiles of SCCs arising in FA patients in order to inform precision medicine-based approaches to treating these patients.

Barnum JL, Petryk A, Zhang L, et al.
Endocrinopathies, Bone Health, and Insulin Resistance in Patients with Fanconi Anemia after Hematopoietic Cell Transplantation.
Biol Blood Marrow Transplant. 2016; 22(8):1487-1492 [PubMed] Free Access to Full Article Related Publications
A number of endocrinopathies have been described after hematopoietic cell transplantation (HCT), but data are limited in patients with Fanconi anemia (FA). We report several endocrine-based disorders in a cohort of 44 patients with FA after HCT compared with both 74 patients who received HCT for hematologic malignancies and with 275 healthy controls. Endocrinopathies assessed included hypothyroidism, hypogonadism, short stature, dyslipidemia, insulin resistance, abnormalities in body composition, and bone health. Most (86%) patients with FA had at least 1 endocrinopathy, with 11% having 3 or more. Hypothyroidism was seen in 57%, hypogonadism in 27%, short stature in 50%, and reduced total body and lumbar spine bone mineral density (BMD) (height adjusted Z-score < -1) in 57% and 21%, respectively. Vitamin D deficiency was seen in 71%. Short stature was associated with younger age at HCT and gonadal failure was associated with older age at HCT. Insulin resistance was associated with increased percent fat mass and increased android/gynoid ratio by dual energy X-ray absorptiometry. Hypothyroidism, short stature, and reduced total body BMD were more prevalent in patients with FA compared with patients with hematologic malignancies. We recommend an assessment before transplantation and close follow-up afterwards to ensure proper clinical management. Future studies should continue to explore the impact of HCT on endocrinopathies in FA patients.

Esteban-Jurado C, Franch-Expósito S, Muñoz J, et al.
The Fanconi anemia DNA damage repair pathway in the spotlight for germline predisposition to colorectal cancer.
Eur J Hum Genet. 2016; 24(10):1501-5 [PubMed] Free Access to Full Article Related Publications
Colorectal cancer (CRC) is one of the most common neoplasms in the world. Fanconi anemia (FA) is a very rare genetic disease causing bone marrow failure, congenital growth abnormalities and cancer predisposition. The comprehensive FA DNA damage repair pathway requires the collaboration of 53 proteins and it is necessary to restore genome integrity by efficiently repairing damaged DNA. A link between FA genes in breast and ovarian cancer germline predisposition has been previously suggested. We selected 74 CRC patients from 40 unrelated Spanish families with strong CRC aggregation compatible with an autosomal dominant pattern of inheritance and without mutations in known hereditary CRC genes and performed germline DNA whole-exome sequencing with the aim of finding new candidate germline predisposition variants. After sequencing and data analysis, variant prioritization selected only those very rare alterations, producing a putative loss of function and located in genes with a role compatible with cancer. We detected an enrichment for variants in FA DNA damage repair pathway genes in our familial CRC cohort as 6 families carried heterozygous, rare, potentially pathogenic variants located in BRCA2/FANCD1, BRIP1/FANCJ, FANCC, FANCE and REV3L/POLZ. In conclusion, the FA DNA damage repair pathway may play an important role in the inherited predisposition to CRC.

Panneerselvam J, Wang H, Zhang J, et al.
BLM promotes the activation of Fanconi Anemia signaling pathway.
Oncotarget. 2016; 7(22):32351-61 [PubMed] Free Access to Full Article Related Publications
Mutations in the human RecQ helicase, BLM, causes Bloom Syndrome, which is a rare autosomal recessive disorder and characterized by genomic instability and an increased risk of cancer. Fanconi Anemia (FA), resulting from mutations in any of the 19 known FA genes and those yet to be known, is also characterized by chromosomal instability and a high incidence of cancer. BLM helicase and FA proteins, therefore, may work in a common tumor-suppressor signaling pathway. To date, it remains largely unclear as to how BLM and FA proteins work concurrently in the maintenance of genome stability. Here we report that BLM is involved in the early activation of FA group D2 protein (FANCD2). We found that FANCD2 activation is substantially delayed and attenuated in crosslinking agent-treated cells harboring deficient Blm compared to similarly treated control cells with sufficient BLM. We also identified that the domain VI of BLM plays an essential role in promoting FANCD2 activation in cells treated with DNA crosslinking agents, especially ultraviolet B. The similar biological effects performed by ΔVI-BLM and inactivated FANCD2 further confirm the relationship between BLM and FANCD2. Mutations within the domain VI of BLM detected in human cancer samples demonstrate the functional importance of this domain, suggesting human tumorigenicity resulting from mtBLM may be at least partly attributed to mitigated FANCD2 activation. Collectively, our data show a previously unknown regulatory liaison in advancing our understanding of how the cancer susceptibility gene products act in concert to maintain genome stability.

Thirthagiri E, Klarmann KD, Shukla AK, et al.
BRCA2 minor transcript lacking exons 4-7 supports viability in mice and may account for survival of humans with a pathogenic biallelic mutation.
Hum Mol Genet. 2016; 25(10):1934-1945 [PubMed] Free Access to Full Article Related Publications
The breast cancer gene, BRCA2, is essential for viability, yet patients with Fanconi anemia-D1 subtype are born alive with biallelic mutations in this gene. The hypomorphic nature of the mutations is believed to support viability, but this is not always apparent. One such mutation is IVS7+2T>G, which causes premature protein truncation due to skipping of exon 7. We previously identified a transcript lacking exons 4-7, which restores the open-reading frame, encodes a DNA repair proficient protein and is expressed in IVS7+2T>G carriers. However, because the exons 4-7 encoded region contains several residues required for normal cell-cycle regulation and cytokinesis, this transcript's ability to support viability can be argued. To address this, we generated a Brca2 knock-in mouse model lacking exons 4-7 and demonstrated that these exons are dispensable for viability as well as tumor-free survival. This study provides the first in vivo evidence of the functional significance of a minor transcript of BRCA2 that can play a major role in the survival of humans who are homozygous for a clearly pathogenic mutation. Our results highlight the importance of assessing protein function restoration by premature truncating codon bypass by alternative splicing when evaluating the functional significance of variants such as nonsense and frame-shift mutations that are assumed to be clearly pathogenic. Our findings will impact not only the assessment of variants that map to this region, but also influence counseling paradigms and treatment options for such mutation carriers.

Villalona-Calero MA, Duan W, Zhao W, et al.
Veliparib Alone or in Combination with Mitomycin C in Patients with Solid Tumors With Functional Deficiency in Homologous Recombination Repair.
J Natl Cancer Inst. 2016; 108(7) [PubMed] Free Access to Full Article Related Publications
BACKGROUND: BRCA germline mutations are being targeted for development of PARP inhibitors. BRCA genes collaborate with several others in the Fanconi Anemia (FA) pathway. We screened cancer patients' tumors for FA functional defects then aimed to establish the safety/feasibility of administering PARP inhibitors as monotherapy and combined with a DNA-breaking agent.
METHODS: Patients underwent FA functional screening for the presence (or lack) of tumor FancD2 nuclear foci formation on their archival tumor material, utilizing a newly developed method (Fanconi Anemia triple-stain immunofluorescence [FATSI]), performed in a Clinical Laboratory Improvement Amendments-certified laboratory. FATSI-negative patients were selected for enrollment in a two-arm dose escalation trial of veliparib, or veliparib/mitomycin-C (MMC).
RESULTS: One hundred eighty-five of 643 (28.7%) screened patients were FATSI-negative. Sixty-one received veliparib or veliparib/MMC through 14 dose levels. Moderate/severe toxicities included fatigue (DLT at veliparib 400mg BID), diarrhea, and thrombocytopenia. Recommended doses are 300mg BID veliparib and veliparib 200mg BID for 21 days following 10mg/m(2) MMC every 28 days. Six antitumor responses occurred, five in the combination arm (3 breast, 1 ovarian, 1 endometrial [uterine], and 1 non-small cell lung cancer). Two patients have received 36 and 60 cycles to date. BRCA germline analysis among 51 patients revealed five deleterious mutations while a targeted FA sequencing gene panel showed missense/nonsense mutations in 29 of 49 FATSI-negative tumor specimens.
CONCLUSIONS: FATSI screening showed that a substantial number of patients' tumors have FA functional deficiency, which led to germline alterations in several patients' tumors. Veliparib alone or with MMC was safely administered to these patients and produced clinical benefit in some. However, a better understanding of resistance mechanisms in this setting is needed.

Matsuzaki K, Borel V, Adelman CA, et al.
FANCJ suppresses microsatellite instability and lymphomagenesis independent of the Fanconi anemia pathway.
Genes Dev. 2015; 29(24):2532-46 [PubMed] Free Access to Full Article Related Publications
Microsatellites are short tandem repeat sequences that are highly prone to expansion/contraction due to their propensity to form non-B-form DNA structures, which hinder DNA polymerases and provoke template slippage. Although error correction by mismatch repair plays a key role in preventing microsatellite instability (MSI), which is a hallmark of Lynch syndrome, activities must also exist that unwind secondary structures to facilitate replication fidelity. Here, we report that Fancj helicase-deficient mice, while phenotypically resembling Fanconi anemia (FA), are also hypersensitive to replication inhibitors and predisposed to lymphoma. Whereas metabolism of G4-DNA structures is largely unaffected in Fancj(-/-) mice, high levels of spontaneous MSI occur, which is exacerbated by replication inhibition. In contrast, MSI is not observed in Fancd2(-/-) mice but is prevalent in human FA-J patients. Together, these data implicate FANCJ as a key factor required to counteract MSI, which is functionally distinct from its role in the FA pathway.

Risitano AM, Marotta S, Calzone R, et al.
Twenty years of the Italian Fanconi Anemia Registry: where we stand and what remains to be learned.
Haematologica. 2016; 101(3):319-27 [PubMed] Free Access to Full Article Related Publications
The natural history of Fanconi anemia remains hard to establish because of its rarity and its heterogeneous clinical presentation; since 1994, the Italian Fanconi Anemia Registry has collected clinical, epidemiological and genetic data of Italian Fanconi Anemia patients. This registry includes 180 patients with a confirmed diagnosis of Fanconi anemia who have either been enrolled prospectively, at diagnosis, or later on. After enrollment, follow-up data were periodically collected to assess the clinical course, possible complications and long-term survival; the median follow up was 15.6 years. The main goal of the study was to describe the natural history of Fanconi anemia, focusing on the following variables: family history, disease presentation, development of hematological manifestations, development of malignancies, occurrence of hematopoietic stem cell transplantation and survival. Typical morphological and/or hematological abnormalities and/or growth retardation were the most common manifestations at diagnosis; the majority of patients (77%) exhibited hematological abnormalities at the initial presentation, and almost all (96%) eventually developed hematological manifestations. More than half of the patients (57%) underwent a bone-marrow transplant. The occurrence of cancer was quite rare at diagnosis, whereas the cumulative incidence of malignancies at 10, 20 and 30 years was 5%, 8% and 22%, respectively, for hematological cancers and 1%, 15% and 32%, respectively, for solid tumors. Overall survival at 10, 20 and 30 years were 88%, 56% and 37%, respectively; the main causes of death were cancer, complications of the hematological presentation and complications of transplantation. These data clearly confirm the detrimental outcome of Fanconi anemia, with no major improvement in the past decades.

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