Numerical chromosomal changes and risk of development of myelodysplastic syndrome–acute myeloid leukemia in patients with Fanconi anemia

Mehta, Parinda A.; Harris, Richard E.; Davies, Stella M.; Kim, Miok; Mueller, Robin; Lampkin, Beatrice C.; Mo, Jun Qin; Myers, Kasiani C.; Smolarek, Teresa A.

doi:10.1016/j.cancergencyto.2010.07.127

Cited by 56 publications

(37 citation statements)

References 22 publications

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“…Common chromosomal rearrangements associated with leukemia (1q gain, 3q gain, and/or chromosome 7 monosomy) were detected by SNP array in blood DNA of 8 of the FA cases with hematologic malignancies. [21][22][23][24] We compared findings by conventional cytogenetic testing in bone marrow aspirates in 5 patients with our findings detected by SNP arrays in peripheral blood DNA, and, generally, we observed that the SNP array of blood DNA detected all CMEs present in the bone marrow along with extra findings (Table 1). Other types of cancer were also diagnosed in FA patients with CMEs, either before sampling (mouth or vulvar SCC and breast cancer) or during follow-up (mouth, anal, or esophagus SCC).…”

Section: Mapping Of Chromosomal Breakpoints and Recurrent Rearrangementsmentioning

confidence: 70%

Detectable clonal mosaicism in blood as a biomarker of cancer risk in Fanconi anemia

et al. 2017

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Key Points• Fanconi anemia patients have exacerbated cytogenetic clonal mosaicism as detected by molecular karyotyping of blood DNA with SNP assays.• Bone marrow clonal abnormalities can be detected in blood DNA and used as biomarkers of cancer risk and poor prognosis.Detectable clonal mosaicism for large chromosomal events has been associated with aging and an increased risk of hematological and some solid cancers. We hypothesized that genetic cancer predisposition disorders, such as Fanconi anemia (FA), could manifest a high rate of chromosomal mosaic events (CMEs) in peripheral blood, which could be used as early biomarkers of cancer risk. We studied the prevalence of CMEs by single-nucleotide polymorphism ( ). Therefore, our data suggest that molecular karyotyping with SNP arrays in easy-to-obtain blood samples could be used for better monitoring of bone marrow clonal events, cancer risk, and overall survival of FA patients.

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Section: Mapping Of Chromosomal Breakpoints and Recurrent Rearrangementsmentioning

confidence: 70%

Detectable clonal mosaicism in blood as a biomarker of cancer risk in Fanconi anemia

et al. 2017

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“…However, the potential role of the FA pathway in the SAC has not been systematically analyzed. Our recent work in a genetically engineered murine model of FA that recapitulates the malignant hematopoietic manifestations of human FA (24) highlighted the correlation among gross aneuploidy, myelodysplasia, and leukemia in FA (14). Interestingly, we observed dysregulation of SAC proteins MAD2 and BUBR1 in this mouse model (D.W. Clapp, unpublished observations).…”

Section: Introductionmentioning

confidence: 59%

“…Mutations in the FA network are etiologically implicated in a significant proportion of inherited breast, pancreatic, and ovarian cancers (6)(7)(8)(9)(10)(11)(12). The high risk of malignant transformation in FA-deficient cells is due to genomic instability characterized by impaired DNA repair, chromosome breakage, and gross aneuploidy (13)(14)(15). Although the role of FA signaling in interphase DNA cross-link repair is well established (5,16), the origins of gross aneuploidy in FA-deficient cells are incompletely understood.…”

Section: Introductionmentioning

confidence: 99%

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Fanconi anemia signaling network regulates the spindle assembly checkpoint

Nalepa¹,

Enzor²,

Sun³

et al. 2013

J. Clin. Invest.

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Fanconi anemia (FA) is a heterogenous genetic disease with a high risk of cancer. The FA proteins are essential for interphase DNA damage repair; however, it is incompletely understood why FA-deficient cells also develop gross aneuploidy, leading to cancer. Here, we systematically evaluated the role of the FA proteins in chromosome segregation through functional RNAi screens and analysis of primary cells from patients with FA. We found that FA signaling is essential for the spindle assembly checkpoint and is therefore required for high-fidelity chromosome segregation and prevention of aneuploidy. Furthermore, we discovered that FA proteins differentially localize to key structures of the mitotic apparatus in a cell cycle-dependent manner. The essential role of the FA pathway in mitosis offers a mechanistic explanation for the aneuploidy and malignant transformation known to occur after disruption of FA signaling. Collectively, our findings provide insight into the genetically unstable cancers resulting from inactivation of the FA/BRCA pathway.

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“…Fanconi anemia (FA) is an autosomal recessive and x-linked inherited DNA repair deficiency syndrome associated with a biallelic mutation in one or more of the 16 FA pathway gene products that leads to congenital abnormalities, bone marrow (BM) failure, defective DNA repair and predisposition to cancer (1–9). Some FA patients experience progressive bone marrow failure during childhood, which frequently requires allogeneic hematopoietic stem cell transplantation (3, 5).…”

Section: Introductionmentioning

confidence: 99%

Amelioration of Radiation-Induced Oral Cavity Mucositis and Distant Bone Marrow Suppression in Fanconi Anemia Fancd2–/– (FVB/N) Mice by Intraoral GS-Nitroxide JP4-039

et al. 2014

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The altered DNA damage response pathway in patients with Fanconi anemia (FA) may increase the toxicity of clinical radiotherapy. We quantitated oral cavity mucositis in irradiated Fanconi anemia Fancd2−/− mice, comparing this to Fancd2+/− and Fancd2+/+ mice, and we measured distant bone marrow suppression and quantitated the effect of the intraoral radioprotector GS-nitroxide, JP4-039 in F15 emulsion. We found that FA mice were more susceptible to radiation injury and that protection from radiation injury by JP4-039/F15 was observed at all radiation doses. Adult 10–12-week-old mice, of FVB/N background Fancd2−/−, Fancd2+/− and Fancd2+/+ were head and neck irradiated with 24, 26, 28 or 30 Gy (large fraction sizes typical of stereotactic radiosurgery treatments) and subgroups received intraoral JP4-039 (0.4 mg/mouse in 100 μL F15 liposome emulsion) preirradiation. On day 2 or 5 postirradiation, mice were sacrificed, tongue tissue and femur marrow were excised for quantitation of radiation-induced stress response, inflammatory and antioxidant gene transcripts, histopathology and assay for femur marrow colony-forming hematopoietic progenitor cells. Fancd2−/− mice had a significantly higher percentage of oral mucosal ulceration at day 5 after 26 Gy irradiation (59.4 ± 8.2%) compared to control Fancd2+/+ mice (21.7 ± 2.9%, P = 0.0063). After 24 Gy irradiation, Fancd2−/− mice had a higher oral cavity percentage of tongue ulceration compared to Fancd2+/+ mice irradiated with higher doses of 26 Gy (P = 0.0123). Baseline and postirradiation oral cavity gene transcripts were altered in Fancd2−/− mice compared to Fancd2+/+ controls. Fancd2−/− mice had decreased baseline femur marrow CFU-GM, BFUe and CFU-GEMM, which further decreased after 24 or 26 Gy head and neck irradiation. These changes were not seen in head- and neck-irradiated Fancd2+/+ mice. In radiosensitive Fancd2−/− mice, biomarkers of both local oral cavity and distant marrow radiation toxicity were ameliorated by intraoral JP4-039/F15. We propose that Fancd2−/− mice are a valuable radiosensitive animal model system, which can be used to evaluate potential radioprotective agents.

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Numerical chromosomal changes and risk of development of myelodysplastic syndrome–acute myeloid leukemia in patients with Fanconi anemia

Cited by 56 publications

References 22 publications

Detectable clonal mosaicism in blood as a biomarker of cancer risk in Fanconi anemia

Detectable clonal mosaicism in blood as a biomarker of cancer risk in Fanconi anemia

Fanconi anemia signaling network regulates the spindle assembly checkpoint

Amelioration of Radiation-Induced Oral Cavity Mucositis and Distant Bone Marrow Suppression in Fanconi Anemia Fancd2–/– (FVB/N) Mice by Intraoral GS-Nitroxide JP4-039

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