Fanconi Anaemia
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What is Fanconi Anaemia ?

Fanconi Anaemia is a rare disorder found in children that involves the blood and bone marrow. The symptoms include severe aplastic anemia, hypoplasia of the bone marrow, and patchy discoloration of the skin. This is an autosomal recessive condition, affected children usually develop severe aplastic anemia by age 8 to 9 years. Treatment usually consists of bone marrow transplant. Fanconi Anaemia is not a cancer, though recent research has shown an association between Fanconi Anaemia and leukaemia. There are 8 types of Fanconi Anaemia; known as complementation groups A through to H.

Some definitions:

Anemia
below normal levels of erythrocytes (red blood cells)
Aplastic anemia
anemia that is resistant to treatment; often accompanied by deficiencies of other blood cells.
Hypoplasia
incomplete / under development of a part of the body.
Pancytopenia
deficiency of all types of blood cells.
Recessive
(genetics) if the required allele (a type of gene) is not present in both members of a pair of chromosomes then that allele is not expressed.
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Aplastic Anaemia
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Information Patients and Family (13 links)


Information for Health Professionals / Researchers (6 links)

See also: Molecular Biology of Fanconi Anaemia

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Trejo Bittar HE, Radder JE, Ranganathan S, et al.
Clear cell sarcoma of the kidney in a child with Fanconi anemia.
Pediatr Dev Pathol. 2014 Jul-Aug; 17(4):297-301 [PubMed] Related Publications
Patients with Fanconi anemia subgroup D1, attributable to biallelic mutations in BRCA2, have an increased risk of solid tumors. Tumors in the kidneys of these patients are almost exclusively Wilms tumor. We report the first recorded case, to our knowledge, of a Clear Cell Sarcoma of the Kidney in a patient with this cancer predisposition syndrome. We review different aspects of the need for careful clinical observation in patients of this complementation group, given their risk for malignancy.

Related: Kidney Cancer


Mulligan JM, Hill LA, Deharo S, et al.
Identification and validation of an anthracycline/cyclophosphamide-based chemotherapy response assay in breast cancer.
J Natl Cancer Inst. 2014; 106(1):djt335 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: There is no method routinely used to predict response to anthracycline and cyclophosphamide-based chemotherapy in the clinic; therefore patients often receive treatment for breast cancer with no benefit. Loss of the Fanconi anemia/BRCA (FA/BRCA) DNA damage response (DDR) pathway occurs in approximately 25% of breast cancer patients through several mechanisms and results in sensitization to DNA-damaging agents. The aim of this study was to develop an assay to detect DDR-deficient tumors associated with loss of the FA/BRCA pathway, for the purpose of treatment selection.
METHODS: DNA microarray data from 21 FA patients and 11 control subjects were analyzed to identify genetic processes associated with a deficiency in DDR. Unsupervised hierarchical clustering was then performed using 60 BRCA1/2 mutant and 47 sporadic tumor samples, and a molecular subgroup was identified that was defined by the molecular processes represented within FA patients. A 44-gene microarray-based assay (the DDR deficiency assay) was developed to prospectively identify this subgroup from formalin-fixed, paraffin-embedded samples. All statistical tests were two-sided.
RESULTS: In a publicly available independent cohort of 203 patients, the assay predicted complete pathologic response vs residual disease after neoadjuvant DNA-damaging chemotherapy (5-fluorouracil, anthracycline, and cyclophosphamide) with an odds ratio of 3.96 (95% confidence interval [Cl] =1.67 to 9.41; P = .002). In a new independent cohort of 191 breast cancer patients treated with adjuvant 5-fluorouracil, epirubicin, and cyclophosphamide, a positive assay result predicted 5-year relapse-free survival with a hazard ratio of 0.37 (95% Cl = 0.15 to 0.88; P = .03) compared with the assay negative population.
CONCLUSIONS: A formalin-fixed, paraffin-embedded tissue-based assay has been developed and independently validated as a predictor of response and prognosis after anthracycline/cyclophosphamide-based chemotherapy in the neoadjuvant and adjuvant settings. These findings warrant further validation in a prospective clinical study.

Related: Breast Cancer Cyclophosphamide Epirubicin Fluorouracil


Meyer S, Tischkowitz M, Chandler K, et al.
Fanconi anaemia, BRCA2 mutations and childhood cancer: a developmental perspective from clinical and epidemiological observations with implications for genetic counselling.
J Med Genet. 2014; 51(2):71-5 [PubMed] Related Publications
Fanconi anaemia (FA) is an inherited condition characterised by congenital and developmental abnormalities and a strong cancer predisposition. In around 3-5% of cases FA is caused by biallelic mutations in the BRCA2 gene. Individuals heterozygous for BRCA2 mutations have an increased risk of inherited breast and ovarian cancer. We reviewed the mutation spectrum in BRCA2-associated FA, and the spectrum and frequency of BRCA2 mutations in distinct populations. The rarity of FA due to biallelic BRCA2 mutations supports a fundamental role of BRCA2 for prevention of malignant transformation during development. The spectrum of malignancies seen associated with FA support the concept of a tissue selectivity of BRCA2 mutations for development of FA-associated cancers. This specificity is illustrated by the distinct FA-associated BRCA2 mutations that appear to predispose to specific brain or haematological malignancies. For some populations, the number of FA-patients with biallelic BRCA2 disruption is smaller than that expected from the carrier frequency, and this implies that some pregnancies with biallelic BRCA2 mutations do not go to term. The apparent discrepancy between expected and observed incidence of BRCA2 mutation-associated FA in high-frequency carrier populations has important implications for the genetic counselling of couples with recurrent miscarriages from high-risk populations.

Related: BRCA2 Cancer Prevention and Risk Reduction


Mitchell R, Wagner JE, Hirsch B, et al.
Haematopoietic cell transplantation for acute leukaemia and advanced myelodysplastic syndrome in Fanconi anaemia.
Br J Haematol. 2014; 164(3):384-95 [PubMed] Article available free on PMC after 01/02/2015 Related Publications
Acute leukaemia or advanced myelodysplastic syndrome (MDS ≥ 5% blasts) in Fanconi anaemia (FA) patients is associated with a poor prognosis. We report 21 FA patients with acute leukaemia or advanced MDS who underwent haematopoietic cell transplantation (HCT) at the University of Minnesota between 1988 and 2011. Six patients had biallelic BRCA2 mutations. Eight patients received pre-transplant cytoreduction, with 3 achieving complete remission. HCT donor source included human leucocyte antigen-matched sibling (n = 2) or alternative donors (n = 19). Neutrophil engraftment was 95% for the entire cohort, and the incidence of acute graft-versus-host disease was 19%. 5-year overall survival (OS) was 33%, with a relapse rate of 24%, with similar OS in patients with biallelic BRCA2 mutations. Our study supports the use of HCT in the treatment of FA patients with acute leukaemia or advanced MDS, however, the role of chemotherapy prior to HCT remains unclear for this population. FA patients with biallelic BRCA2 are unique and may benefit from higher dose chemotherapy relative to other complementation groups.

Related: Leukemia Childhood Leukaemia Leukemia - Molecular Biology


Peffault de Latour R, Porcher R, Dalle JH, et al.
Allogeneic hematopoietic stem cell transplantation in Fanconi anemia: the European Group for Blood and Marrow Transplantation experience.
Blood. 2013; 122(26):4279-86 [PubMed] Related Publications
Although allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative treatment for patients with Fanconi anemia (FA), published series mostly refer to single-center experience with limited numbers of patients. We analyzed results in 795 patients with FA who underwent first HSCT between May 1972 and January 2010. With a 6-year median follow-up, overall survival was 49% at 20 years (95% confidence interval, 38-65 years). Better outcome was observed for patients transplanted before the age of 10 years, before clonal evolution (ie, myelodysplastic syndrome or acute myeloid leukemia), from a matched family donor, after a conditioning regimen without irradiation, the latter including fludarabine. Chronic graft-versus-host disease and secondary malignancy were deleterious when considered as time-dependent covariates. Age more than 10 years at time of HSCT, clonal evolution as an indication for transplantation, peripheral blood as source of stem cells, and chronic graft-versus-host disease were found to be independently associated with the risk for secondary malignancy. Changes in transplant protocols have significantly improved the outcome of patients with FA, who should be transplanted at a young age, with bone marrow as the source of stem cells.

Related: Haematological Malignancies & Realted Disorders


Aggarwal M, Banerjee T, Sommers JA, Brosh RM
Targeting an Achilles' heel of cancer with a WRN helicase inhibitor.
Cell Cycle. 2013; 12(20):3329-35 [PubMed] Article available free on PMC after 01/02/2015 Related Publications
Our recently published work suggests that DNA helicases such as the Werner syndrome helicase (WRN) represent a novel class of proteins to target for anticancer therapy. Specifically, pharmacological inhibition of WRN helicase activity in human cells defective in the Fanconi anemia (FA) pathway of interstrand cross-link (ICL) repair are sensitized to the DNA cross-linking agent and chemotherapy drug mitomycin C (MMC) by the WRN helicase inhibitor NSC 617145. (1) The mechanistic basis for the synergistic interaction between NSC 617145 and MMC is discussed in this paper and extrapolated to potential implications for genetic or chemically induced synthetic lethality provoked by cellular exposure to the WRN helicase inhibitor under the context of relevant DNA repair deficiencies associated with cancers or induced by small-molecule inhibitors. Experimental data are presented showing that small-molecule inhibition of WRN helicase elevates sensitivity to MMC-induced stress in human cells that are deficient in both FANCD2 and DNA protein kinase catalytic subunit (DNA-PKcs). These findings suggest a model in which drug-mediated inhibition of WRN helicase activity exacerbates the deleterious effects of MMC-induced DNA damage when both the FA and NHEJ pathways are defective. We conclude with a perspective for the FA pathway and synthetic lethality and implications for DNA repair helicase inhibitors that can be developed for anticancer strategies.

Related: Mitomycin Cancer Prevention and Risk Reduction Signal Transduction


Pfäffle HN, Wang M, Gheorghiu L, et al.
EGFR-activating mutations correlate with a Fanconi anemia-like cellular phenotype that includes PARP inhibitor sensitivity.
Cancer Res. 2013; 73(20):6254-63 [PubMed] Article available free on PMC after 01/02/2015 Related Publications
In patients with lung cancer whose tumors harbor activating mutations in the EGF receptor (EGFR), increased responses to platinum-based chemotherapies are seen compared with wild-type cancers. However, the mechanisms underlying this association have remained elusive. Here, we describe a cellular phenotype of cross-linker sensitivity in a subset of EGFR-mutant lung cancer cell lines that is reminiscent of the defects seen in cells impaired in the Fanconi anemia pathway, including a pronounced G2-M cell-cycle arrest and chromosomal radial formation. We identified a defect downstream of FANCD2 at the level of recruitment of FAN1 nuclease and DNA interstrand cross-link (ICL) unhooking. The effect of EGFR mutation was epistatic with FANCD2. Consistent with the known role of FANCD2 in promoting RAD51 foci formation and homologous recombination repair (HRR), EGFR-mutant cells also exhibited an impaired RAD51 foci response to ICLs, but not to DNA double-strand breaks. EGFR kinase inhibition affected RAD51 foci formation neither in EGFR-mutant nor wild-type cells. In contrast, EGFR depletion or overexpression of mutant EGFR in wild-type cells suppressed RAD51 foci, suggesting an EGFR kinase-independent regulation of DNA repair. Interestingly, EGFR-mutant cells treated with the PARP inhibitor olaparib also displayed decreased FAN1 foci induction, coupled with a putative block in a late HRR step. As a result, EGFR-mutant lung cancer cells exhibited olaparib sensitivity in vitro and in vivo. Our findings provide insight into the mechanisms of cisplatin and PARP inhibitor sensitivity of EGFR-mutant cells, yielding potential therapeutic opportunities for further treatment individualization in this genetically defined subset of lung cancer.

Related: Cisplatin FANCD2 Lung Cancer Signal Transduction


Martínez S, Pérez L, Galmarini CM, et al.
Inhibitory effects of marine-derived DNA-binding anti-tumour tetrahydroisoquinolines on the Fanconi anaemia pathway.
Br J Pharmacol. 2013; 170(4):871-82 [PubMed] Article available free on PMC after 01/02/2015 Related Publications
BACKGROUND AND PURPOSE: We have previously shown that cells with a defective Fanconi anaemia (FA) pathway are hypersensitive to trabectedin, a DNA-binding anti-cancer tetrahydroisoquinoline (DBAT) whose adducts functionally mimic a DNA inter-strand cross link (ICL). Here we expand these observations to new DBATs and investigate whether our findings in primary untransformed cells can be reproduced in human cancer cells.
EXPERIMENTAL APPROACH: Initially, the sensitivity of transformed and untransformed cells, deficient or not in one component of the FA pathway, to mitomycin C (MMC) and three DBATs, trabectedin, Zalypsis and PM01183, was assessed. Then, the functional interaction of these drugs with the FA pathway was comparatively investigated.
KEY RESULTS: While untransformed FA-deficient haematopoietic cells were hypersensitive to both MMC and DBATs, the response of FA-deficient squamous cell carcinoma (SCC) cells to DBATs was similar to that of their respective FA-competent counterparts, even though these FA-deficient SCC cells were hypersensitive to MMC. Furthermore, while MMC always activated the FA pathway, the DBATs inhibited the FA pathway in the cancer cell lines tested and this enhanced their response to MMC.
CONCLUSIONS AND IMPLICATIONS: Our data show that although DBATs functionally interact with DNA as do agents that generate classical ICL, these drugs should be considered as FA pathway inhibitors rather than activators. Moreover, this effect was most significant in a variety of cancer cells. These inhibitory effects of DBATs on the FA pathway could be exploited clinically with the aim of 'fanconizing' cancer cells in order to make them more sensitive to other anti-tumour drugs.

Related: Mitomycin Cancer Prevention and Risk Reduction Signal Transduction Trabectedin


Cappelli E, Ravera S, Vaccaro D, et al.
Mitochondrial respiratory complex I defects in Fanconi anemia.
Trends Mol Med. 2013; 19(9):513-4 [PubMed] Related Publications
Fanconi anemia (FA) is a rare, complex disorder that manifests in childhood. Children with FA suffer bone marrow failure, leukemias, or solid tumors. FA-associated mutations are found in 15 proteins that are involved in DNA repair. Some of these proteins have extranuclear activities involving redox balance, apoptosis, and energy metabolism; and recent data demonstrate respiratory impairment in FA cells, suggesting that altered mitochondrial function is a factor in this disease.

Related: Apoptosis Mitochondrial Mutations in Cancer Cancer Prevention and Risk Reduction Children's Cancer Web: Home Page


Lin J, Kutler DI
Why otolaryngologists need to be aware of Fanconi anemia.
Otolaryngol Clin North Am. 2013; 46(4):567-77 [PubMed] Related Publications
Fanconi anemia (FA) is a rare disorder inherited in an autosomal recessive fashion, with an estimated incidence of 1:360,000 births. Although hematologic complications are the most common manifestation of this disease, cancers, especially of the head and neck, are also prominent. The chromosomal fragility of patients with FA necessitates careful planning of therapy and monitoring, and awareness of this rare disorder is crucial to recognizing it in the clinic.

Related: Head and Neck Cancers Head and Neck Cancers - Molecular Biology


Du W, Erden O, Pang Q
TNF-α signaling in Fanconi anemia.
Blood Cells Mol Dis. 2014; 52(1):2-11 [PubMed] Article available free on PMC after 01/01/2015 Related Publications
Tumor necrosis factor-alpha (TNF-α) is a major pro-inflammatory cytokine involved in systemic inflammation and the acute phase reaction. Dysregulation of TNF production has been implicated in a variety of human diseases including Fanconi anemia (FA). FA is a genomic instability syndrome characterized by progressive bone marrow failure and cancer susceptibility. The patients with FA are often found overproducing TNF-α, which may directly affect hematopoietic stem cell (HSC) function by impairing HSC survival, homing and proliferation, or indirectly change the bone marrow microenvironment critical for HSC homeostasis and function, therefore contributing to disease progression in FA. In this brief review, we discuss the link between TNF-α signaling and FA pathway with emphasis on the implication of inflammation in the pathophysiology and abnormal hematopoiesis in FA.

Related: Apoptosis Signal Transduction TNF


Shah A, John BM, Sondhi V
Acute lymphoblastic leukemia with treatment--naive Fanconi anemia.
Indian Pediatr. 2013; 50(5):508-10 [PubMed] Related Publications
Fanconi anemia is known to have a predisposition to cancer, mostly associated with acute myeloid leukemia. We report an eight year old girl with treatment and naive FA who developed acute lymphoblastic leukemia. She was initiated on chemotherapy but she failed to respond to treatment and died during induction phase of chemotherapy. While this association may be coincidental but possibility of transition of Fanconi anemia to ALL should be considered in view of high predisposition to cancer in this disorder.

Related: Acute Lymphocytic Leukemia (ALL) Childhood Acute lymphoblastic leukaemia (ALL) ALL - Molecular Biology


Kashiyama K, Nakazawa Y, Pilz DT, et al.
Malfunction of nuclease ERCC1-XPF results in diverse clinical manifestations and causes Cockayne syndrome, xeroderma pigmentosum, and Fanconi anemia.
Am J Hum Genet. 2013; 92(5):807-19 [PubMed] Article available free on PMC after 01/01/2015 Related Publications
Cockayne syndrome (CS) is a genetic disorder characterized by developmental abnormalities and photodermatosis resulting from the lack of transcription-coupled nucleotide excision repair, which is responsible for the removal of photodamage from actively transcribed genes. To date, all identified causative mutations for CS have been in the two known CS-associated genes, ERCC8 (CSA) and ERCC6 (CSB). For the rare combined xeroderma pigmentosum (XP) and CS phenotype, all identified mutations are in three of the XP-associated genes, ERCC3 (XPB), ERCC2 (XPD), and ERCC5 (XPG). In a previous report, we identified several CS cases who did not have mutations in any of these genes. In this paper, we describe three CS individuals deficient in ERCC1 or ERCC4 (XPF). Remarkably, one of these individuals with XP complementation group F (XP-F) had clinical features of three different DNA-repair disorders--CS, XP, and Fanconi anemia (FA). Our results, together with those from Bogliolo et al., who describe XPF alterations resulting in FA alone, indicate a multifunctional role for XPF.


Yeo CJ, Gilman AL
Interleukin-2-induced graft-versus-leukemia for the treatment of AML in a BRCA2 Fanconi anemia patient.
J Pediatr Hematol Oncol. 2014; 36(2):e78-80 [PubMed] Related Publications
Biallelic BRCA2 mutations occur in 2% of patients with Fanconi anemia and are associated with a high risk of acute leukemia at an early age and a poor prognosis. For the first time, we report the use of interleukin-2 to stimulate a graft-versus-leukemia effect and induce complete remission in a patient with BRCA2 Fanconi anemia and refractory acute myelogenous leukemia, suggesting the potential of immunotherapy in this setting. Interleukin-2 was associated with significant infusion-related toxicity.

Related: BRCA2 Interleukin 2 (Aldesleukin) Acute Myeloid Leukemia (AML)


Alter BP, Giri N, Savage SA, et al.
Squamous cell carcinomas in patients with Fanconi anemia and dyskeratosis congenita: a search for human papillomavirus.
Int J Cancer. 2013; 133(6):1513-5 [PubMed] Article available free on PMC after 01/01/2015 Related Publications
Patients with Fanconi anemia (FA) and dyskeratosis congenita (DC) are at high risk of head and neck squamous cell carcinomas (HNSCC) and anogenital squamous cell carcinomas (SCC). In the general population, these sites (particularly oropharyngeal SCC) may be associated with infection with human papillomavirus (HPV). In FA and DC, however, the majority of HNSCC occur in the oral cavity. We investigated the HPV status of HNSCC and vulvar SCC from nine patients with FA and four with DC using a very sensitive PCR assay, and found HPV16 DNA in only a single vulvar tumor from one patient with FA, and in none of the HNSCC. These results suggest that HPV may not be the cause of SCC in patients with FA or DC, and that vaccination may not reduce the incidence of HNSCC in these patients.

Related: Head and Neck Cancers Head and Neck Cancers - Molecular Biology


Ayas M, Saber W, Davies SM, et al.
Allogeneic hematopoietic cell transplantation for fanconi anemia in patients with pretransplantation cytogenetic abnormalities, myelodysplastic syndrome, or acute leukemia.
J Clin Oncol. 2013; 31(13):1669-76 [PubMed] Article available free on PMC after 01/01/2015 Related Publications
PURPOSE: Allogeneic hematopoietic cell transplantation (HCT) can cure bone marrow failure in patients with Fanconi anemia (FA). Data on outcomes in patients with pretransplantation cytogenetic abnormalities, myelodysplastic syndrome (MDS), or acute leukemia have not been separately analyzed.
PATIENTS AND METHODS: We analyzed data on 113 patients with FA with cytogenetic abnormalities (n = 54), MDS (n = 45), or acute leukemia (n = 14) who were reported to the Center for International Blood and Marrow Transplant Research from 1985 to 2007.
RESULTS: Neutrophil recovery occurred in 78% and 85% of patients at days 28 and 100, respectively. Day 100 cumulative incidences of acute graft-versus-host disease grades B to D and C to D were 26% (95% CI, 19% to 35%) and 12% (95% CI, 7% to 19%), respectively. Survival probabilities at 1, 3, and 5 years were 64% (95% CI, 55% to 73%), 58% (95% CI, 48% to 67%), and 55% (95% CI, 45% to 64%), respectively. In univariate analysis, younger age was associated with superior 5-year survival (≤ v > 14 years: 69% [95% CI, 57% to 80%] v 39% [95% CI, 26% to 53%], respectively; P = .001). In transplantations from HLA-matched related donors (n = 82), younger patients (≤ v > 14 years: 78% [95% CI, 64% to 90%] v 34% [95% CI, 20% to 50%], respectively; P < .001) and patients with cytogenetic abnormalities only versus MDS/acute leukemia (67% [95% CI, 52% to 81%] v 43% [95% CI, 27% to 59%], respectively; P = .03) had superior 5-year survival.
CONCLUSION: Our analysis indicates that long-term survival for patients with FA with cytogenetic abnormalities, MDS, or acute leukemia is achievable. Younger patients and recipients of HLA-matched related donor transplantations who have cytogenetic abnormalities only have the best survival.

Related: Acute Lymphocytic Leukemia (ALL) Childhood Acute lymphoblastic leukaemia (ALL) ALL - Molecular Biology


Yao CJ, Du W, Zhang Q, et al.
Fanconi anemia pathway--the way of DNA interstrand cross-link repair.
Pharmazie. 2013; 68(1):5-11 [PubMed] Related Publications
The study of rare genetic diseases usually inspires the research of cancer biology. Fanconi anemia (FA), is a rare cancer susceptibility syndrome with an incidence of only 1 per 350,000 births. FA is an autosomal recessive disease with three main features: chromosome instability, hypersensitivity to DNA cross-linking agents such as mitomycin C (MMC), cisplatin and so on, and susceptible to a number of cancer types, mainly leukemia and squamous cell carcinomas of the head and neck or gynecologic system. DNA crosslinking agents may led to DNA cross-linking lesion, and Fanconi anemia pathway plays a key role in repairing its cross-linking. However, FA pathway is closely linked with carcinogenesis and tumor drug resistance. This paper mainly focuses on the FA pathway and its progress in cancer research.

Related: Cancer Prevention and Risk Reduction Signal Transduction


Böhringer M, Obermeier K, Griner N, et al.
siRNA screening identifies differences in the Fanconi anemia pathway in BALB/c-Trp53+/- with susceptibility versus C57BL/6-Trp53+/- mice with resistance to mammary tumors.
Oncogene. 2013; 32(48):5458-70 [PubMed] Article available free on PMC after 01/01/2015 Related Publications
BALB/c mice heterozygous for Trp53 develop a high proportion of spontaneous mammary tumors, a phenotype distinct from other mouse strains. BALB/c-Trp53+/- female mice, thus, resemble the hereditary Li-Fraumeni syndrome (LFS) characterized by early-onset of breast cancer, even though LFS involves TP53 mutations, which may involve not only loss- but also gain-of-function. Previous analysis of tumors in BALB/c-Trp53+/- females showed frequent loss of heterozygosity involving the wild-type allele of Trp53 and displayed characteristics indicative of mitotic recombination. Critical involvement of DNA double-strand break (DSB) repair dysfunction, particularly of homologous recombination (HR), was also noticed in the etiology of human breast cancer. To better define functional alterations in BALB/c-Trp53+/- mice, we applied a fluorescence-based DSB repair assay on mouse embryonic fibroblasts (MEFs) from BALB/c-Trp53+/- versus C57BL/6J-Trp53+/- mice. This approach revealed deregulation of HR but not non-homologous end-joining (NHEJ) in BALB/c-Trp53+/-, which was further confirmed for mammary epithelial cells. Screening of a small interfering RNA-library targeting DSB repair, recombination, replication and signaling genes, identified 25 genes causing differences between homologous DSB repair in the two strains upon silencing. Interactome analysis of the hits revealed clustering of replication-related and fanconi anemia (FA)/breast cancer susceptibility (BRCA) genes. Further dissection of the functional change in BALB/c-Trp53+/- by immunofluorescence microscopy of nuclear 53BP1, Replication protein A (RPA) and Rad51 foci uncovered differences in crosslink and replication-associated repair. Chromosome breakage, G2 arrest and biochemical analyses indicated a FA pathway defect downstream of FancD2 associated with reduced levels of BRCA2. Consistent with polygenic models for BRCA, mammary carcinogenesis in BALB/c-Trp53+/- mice may, therefore, be promoted by a BRCA modifier allele in the FA pathway in the context of partial p53 loss-of-function.

Related: Signal Transduction TP53


Romick-Rosendale LE, Lui VW, Grandis JR, Wells SI
The Fanconi anemia pathway: repairing the link between DNA damage and squamous cell carcinoma.
Mutat Res. 2013 Mar-Apr; 743-744:78-88 [PubMed] Article available free on PMC after 01/01/2015 Related Publications
Fanconi anemia (FA) is a rare inherited recessive disease caused by mutations in one of fifteen genes known to encode FA pathway components. In response to DNA damage, nuclear FA proteins associate into high molecular weight complexes through a cascade of post-translational modifications and physical interactions, followed by the repair of damaged DNA. Hematopoietic cells are particularly sensitive to the loss of these interactions, and bone marrow failure occurs almost universally in FA patients. FA as a disease is further characterized by cancer susceptibility, which highlights the importance of the FA pathway in tumor suppression, and will be the focus of this review. Acute myeloid leukemia is the most common cancer type, often subsequent to bone marrow failure. However, FA patients are also at an extreme risk of squamous cell carcinoma (SCC) of the head and neck and gynecological tract, with an even greater incidence in those individuals who have received a bone marrow transplant and recovered from hematopoietic disease. FA tumor suppression in hematopoietic versus epithelial compartments could be mechanistically similar or distinct. Definition of compartment specific FA activities is now critical to assess the effects of today's bone marrow failure treatments on tomorrow's solid tumor development. It is our hope that current therapies can then be optimized to decrease the risk of malignant transformation in both hematopoietic and epithelial cells. Here we review our current understanding of the mechanisms of action of the Fanconi anemia pathway as it contributes to stress responses, DNA repair and squamous cell carcinoma susceptibility.


Kottemann MC, Smogorzewska A
Fanconi anaemia and the repair of Watson and Crick DNA crosslinks.
Nature. 2013; 493(7432):356-63 [PubMed] Article available free on PMC after 01/01/2015 Related Publications
The function of Fanconi anaemia proteins is to maintain genomic stability. Their main role is in the repair of DNA interstrand crosslinks, which, by covalently binding the Watson and the Crick strands of DNA, impede replication and transcription. Inappropriate repair of interstrand crosslinks causes genomic instability, leading to cancer; conversely, the toxicity of crosslinking agents makes them a powerful chemotherapeutic. Fanconi anaemia proteins can promote stem-cell function, prevent tumorigenesis, stabilize replication forks and inhibit inaccurate repair. Recent advances have identified endogenous aldehydes as possible culprits of DNA damage that may induce the phenotypes seen in patients with Fanconi anaemia.


Gravells P, Hoh L, Solovieva S, et al.
Reduced FANCD2 influences spontaneous SCE and RAD51 foci formation in uveal melanoma and Fanconi anaemia.
Oncogene. 2013; 32(46):5338-46 [PubMed] Article available free on PMC after 01/01/2015 Related Publications
Uveal melanoma (UM) is unique among cancers in displaying reduced endogenous levels of sister chromatid exchange (SCE). Here we demonstrate that FANCD2 expression is reduced in UM and that ectopic expression of FANCD2 increased SCE. Similarly, FANCD2-deficient fibroblasts (PD20) derived from Fanconi anaemia patients displayed reduced spontaneous SCE formation relative to their FANCD2-complemented counterparts, suggesting that this observation is not specific to UM. In addition, spontaneous RAD51 foci were reduced in UM and PD20 cells compared with FANCD2-proficient cells. This is consistent with a model where spontaneous SCEs are the end product of endogenous recombination events and implicates FANCD2 in the promotion of recombination-mediated repair of endogenous DNA damage and in SCE formation during normal DNA replication. In both UM and PD20 cells, low SCE was reversed by inhibiting DNA-PKcs (DNA-dependent protein kinase, catalytic subunit). Finally, we demonstrate that both PD20 and UM are sensitive to acetaldehyde, supporting a role for FANCD2 in repair of lesions induced by such endogenous metabolites. Together, these data suggest FANCD2 may promote spontaneous SCE by influencing which double-strand break repair pathway predominates during normal S-phase progression.

Related: FANCD2 Melanoma Ocular Melanoma IntraOcular Melanoma


Bakker ST, de Winter JP, te Riele H
Learning from a paradox: recent insights into Fanconi anaemia through studying mouse models.
Dis Model Mech. 2013; 6(1):40-7 [PubMed] Article available free on PMC after 01/01/2015 Related Publications
Fanconi anaemia (FA) is a rare autosomal recessive or X-linked inherited disease characterised by an increased incidence of bone marrow failure (BMF), haematological malignancies and solid tumours. Cells from individuals with FA show a pronounced sensitivity to DNA interstrand crosslink (ICL)-inducing agents, which manifests as G2-M arrest, chromosomal aberrations and reduced cellular survival. To date, mutations in at least 15 different genes have been identified that cause FA; the products of all of these genes are thought to function together in the FA pathway, which is essential for ICL repair. Rapidly following the discovery of FA genes, mutant mice were generated to study the disease and the affected pathway. These mutant mice all show the characteristic cellular ICL-inducing agent sensitivity, but only partially recapitulate the developmental abnormalities, anaemia and cancer predisposition seen in individuals with FA. Therefore, the usefulness of modelling FA in mice has been questioned. In this Review, we argue that such scepticism is unjustified. We outline that haematopoietic defects and cancer predisposition are manifestations of FA gene defects in mice, albeit only in certain genetic backgrounds and under certain conditions. Most importantly, recent work has shown that developmental defects in FA mice also arise with concomitant inactivation of acetaldehyde metabolism, giving a strong clue about the nature of the endogenous lesion that must be repaired by the functional FA pathway. This body of work provides an excellent example of a paradox in FA research: that the dissimilarity, rather than the similarity, between mice and humans can provide insight into human disease. We expect that further study of mouse models of FA will help to uncover the mechanistic background of FA, ultimately leading to better treatment options for the disease.

Related: Cancer Prevention and Risk Reduction


O'Driscoll M
Diseases associated with defective responses to DNA damage.
Cold Spring Harb Perspect Biol. 2012; 4(12) [PubMed] Related Publications
Within the last decade, multiple novel congenital human disorders have been described with genetic defects in known and/or novel components of several well-known DNA repair and damage response pathways. Examples include disorders of impaired nucleotide excision repair, DNA double-strand and single-strand break repair, as well as compromised DNA damage-induced signal transduction including phosphorylation and ubiquitination. These conditions further reinforce the importance of multiple genome stability pathways for health and development in humans. Furthermore, these conditions inform our knowledge of the biology of the mechanics of genome stability and in some cases provide potential routes to help exploit these pathways therapeutically. Here, I will review a selection of these exciting findings from the perspective of the disorders themselves, describing how they were identified, how genotype informs phenotype, and how these defects contribute to our growing understanding of genome stability pathways.

Related: Breast Cancer Ovarian Cancer


Wong WM, Parvathaneni U, Jewell PD, et al.
Squamous cell carcinoma of the oral tongue in a patient with Fanconi anemia treated with radiotherapy and concurrent cetuximab: a case report and review of the literature.
Head Neck. 2013; 35(10):E292-8 [PubMed] Related Publications
BACKGROUND: Fanconi anemia (FA) is a rare autosomal recessive genetic disorder characterized by bone marrow failure and increased risk of cancers including acute myelogenous leukemia and various solid tumors, especially head and neck cancer. Management of head and neck cancer in the setting of FA is complicated by pancytopenia, poor tolerance of chemotherapy, and potentially increased radiosensitivity. There are limited reports on tolerance of radiotherapy (RT) in patients with FA.
METHODS: We report a case of a patient with FA who presented with a small oral tongue cancer that was excised. He rapidly developed extensive locoregional recurrence and underwent surgical resection followed by postoperative RT with concurrent cetuximab.
RESULTS: Both RT and cetuximab were well tolerated with manageable toxicities. Unfortunately, the patient died of early locoregional disease progression.
CONCLUSIONS: RT with concurrent cetuximab was well tolerated and may be an appropriate option in patients with FA. However, many patients have a poor prognosis due to aggressive disease.

Related: Cetuximab (Erbitux)


Yuan C, Xu N, Liao J
Switch of FANCL, a key FA-BRCA component, between tumor suppressor and promoter by alternative splicing.
Cell Cycle. 2012; 11(18):3356 [PubMed] Article available free on PMC after 01/01/2015 Related Publications
Comment on: Panneerselvam J, et al. Cell Cycle 2012; 11:2947-55.

Related: FANCL gene Bladder Cancer Bladder Cancer - Molecular Biology


Panneerselvam J, Park HK, Zhang J, et al.
FAVL impairment of the Fanconi anemia pathway promotes the development of human bladder cancer.
Cell Cycle. 2012; 11(15):2947-55 [PubMed] Article available free on PMC after 01/01/2015 Related Publications
Effectiveness of DNA cross-linking drugs in the treatment of bladder cancer suggests that bladder cancer cells may have harbored an insufficient cellular response to DNA cross-link damage, which will sensitize cells to DNA cross-linking agents. Cell sensitivity benefits from deficient DNA damage responses, which, on the other hand, can cause cancer. Many changed cellular signaling pathways are known to be involved in bladder tumorigenesis; however, DNA cross-link damage response pathway [Fanconi anemia (FA) pathway], whose alterations appear to be a plausible cause of the development of bladder cancer, remains an under-investigated area in bladder cancer research. In this study, we found FAVL (variant of FA protein L--FANCL) was elevated substantially in bladder cancer tissues examined. Ectopic expression of FAVL in bladder cancer cells as well as normal human cells confer an impaired FA pathway and hypersensitivity to Mitomycin C, similar to those found in FA cells, indicating that FAVL elevation may possess the same tumor promotion potential as an impaired FA pathway harbored in FA cells. Indeed, a higher level of FAVL expression can promote the growth of bladder cancer cells in vitro and in vivo, which, at least partly, results from FAVL perturbation of FANCL expression, an essential factor for the activation of the FA pathway. Moreover, a higher level of FAVL expression was found to be associated with chromosomal instability and the invasiveness of bladder cancer cells. Collectively, FAVL elevation can increase the tumorigenic potential of bladder cancer cells, including the invasive potential that confers the development of advanced bladder cancer. These results enhance our understanding the pathogenesis of human bladder cancer, holding a promise to develop additional effective tools to fight human bladder cancer.

Related: FANCL gene Mitomycin Signal Transduction Bladder Cancer Bladder Cancer - Molecular Biology


Dumitriu B, Young NS
Damage control and its costs: BM failure in Fanconi anemia stems from overactive p53/p21.
Cell Stem Cell. 2012; 11(1):7-8 [PubMed] Article available free on PMC after 01/01/2015 Related Publications
Despite having well-characterized disease-associated mutations, the mechanisms underlying the progressive bone marrow failure and cancer susceptibility of Fanconi anemia have been unclear. In this issue of Cell Stem Cell, Ceccaldi et al. identify an overactive p53/p21 stress response and cell cycle arrest as an underlying cause that starts during fetal development.

Related: CDKN1A Leukemia TP53


Mushtaq N, Wali R, Fadoo Z, Saleem AF
Acute lymphoblastic leukemia in a child with Fanconi's anaemia.
J Coll Physicians Surg Pak. 2012; 22(7):458-60 [PubMed] Related Publications
Fanconi anaemia (FA) is an autosomal recessive inherited disorder with progressive bone marrow failure, associated congenital malformation and solid and haematological malignancies. Acute myeloid leukemia is the commonest haematological malignancy followed by myelodysplastic syndrome in children with FA. FA transformed into acute lymphoblastic leukemia (ALL) is a rare phenomenon and one of the rarest haematological malignancies associated with this disorder. We are reporting a 13 years old girl with FA and positive chromosomal breakage. She required regular blood product transfusion. She was planned for haematopoietic stem cell transplantation (HSCT) but the sibling-matched donor was found to have chromosomal breaks as well. Later on, her peripheral smear showed blast cell. Bone marrow showed pre-B ALL. She was started on chemotherapy but died shortly due to complications of the treatment. For this rare condition conservative management is indeed essential, however, safe and appropriate chemotherapy regimen is needed.


Stecklein SR, Jensen RA
Identifying and exploiting defects in the Fanconi anemia/BRCA pathway in oncology.
Transl Res. 2012; 160(3):178-97 [PubMed] Related Publications
Defects in components of DNA repair pathways are responsible for numerous hereditary cancer syndromes and are also common in many sporadic malignancies. Inherited mutations in the breast cancer susceptibility genes BRCA1 and BRCA2 or components of the Fanconi anemia (FA) complex incite genomic instability and predispose to malignancy. The products of the BRCA and FA genes participate in a conserved DNA damage repair pathway that is responsible for repairing interstrand crosslinks and double-strand DNA breaks by homologous recombination. While the genetic instability resulting from FA/BRCA dysfunction contributes to cancer pathogenesis, deficiency of these genes also lends to therapeutic exploitation. Crosslinking agents and ionizing radiation induce damage in cancer cells that requires the FA/BRCA pathway to be resolved; thus cancers that are deficient in BRCA1, BRCA2, or any other component of the FA/BRCA pathway are hypersensitive to these agents. Moreover, emerging synthetic lethal strategies offer opportunities to selectively target cancer cells with defects in homologous recombination. Conversely, enhanced activity of the FA/BRCA pathway is responsible for acquired resistance to specific therapeutic agents, suggesting that both dysfunction and hyperfunction of the FA/BRCA repair machinery are rational targets for cancer therapy. Selection of specific cytotoxic agents based on repair capacity may improve responses and enable personalized cytotoxic chemotherapy. This article reviews the FA/BRCA pathway and current approaches to identify deficiencies within it, discusses synthetic lethality and enhanced repair capacity as causes of therapeutic hypersensitivity and resistance, respectively, and highlights recent studies that have linked FA/BRCA pathway function with therapeutic efficacy.

Related: BRCA1 BRCA2 Cancer Prevention and Risk Reduction


Rochowski A, Olson SB, Alonzo TA, et al.
Patients with Fanconi anemia and AML have different cytogenetic clones than de novo cases of AML.
Pediatr Blood Cancer. 2012; 59(5):922-4 [PubMed] Article available free on PMC after 01/01/2015 Related Publications
Specific cytogenetic clones might distinguish patients with unrecognized Fanconi anemia (FA) who present with acute myeloid leukemia (AML) from those with sporadic AML. Cytogenetic reports in literature cases of FA and AML were compared with de novo cases enrolled on CCG-2961. Gain of 1q, gain of 3q, monosomy 7, deleted 7q, gain of 13q, and deleted 20q were more frequent in FA AML; t(8;21), trisomy 8, t(9;11), t(6;9), and inversion 16 were exclusive to de novo AML cases. Observation of the FA AML cytogenetic clonal patterns should raise suspicion of an underlying leukemia predisposition syndrome and influence management.

Related: Acute Myeloid Leukemia (AML) Childhood Acute Myeloid Leukaemia AML - Molecular Biology


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