Fanconi anemia gene variants in therapy-related myeloid neoplasms

Voso, Maria Teresa; Fabiani, Emiliano; Zang, Zhi Jiang; Fianchi, Luana; Falconi, Giulia; Padella, Antonella; Martini, Maurizio; Zhang, S Li; Santangelo, Rosaria; Larocca, Luigi Maria; Criscuolo, Marianna; Brocca, Antonella La; Cutcutache, Ioana; Rozen, Steve; Simonetti, Giorgia; Manfrini, Marco; Martinelli, Giovanni; Hohaus, Stefan; Leone, Giuseppe; Tan, Puay Hoon; Tenen, Daniel G.

doi:10.1038/bcj.2015.44

Cited by 34 publications

(22 citation statements)

References 14 publications

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“…1). The presence of a germline mutation in genes involved in DNA repair and/ or DNA damage-sensing pathways, such as BRCA1, BRCA2, CHEK2, TP53, and Fanconi anemia genes, has been identified in some patients with t-MN, and may lead to ineffective DNA repair following cytotoxic therapy and the acquisition of somatic mutations (43,(47)(48)(49). Individuals who have CHIP, or small preexisting, age-related resilient clones, may be at increased risk of developing t-MN following cytotoxic therapy (9-13).…”

Section: Discussionmentioning

confidence: 99%

“…Somatic mutations in IDH1 and ATM, and germline mutations in Fanconi anemia genes have been observed in patients with t- MN (refs. 29,43; Supplementary Table S6). In AML samples from patients, curated by the Catalogue Of Somatic Mutations In Cancer (COSMIC) database, there are codon-altering mutations in IDH1, ATM, FANCA, MRE11, RECQL5, USP3, and USP47; FANCD2, PPP5C, TOP3A are mutated only in lymphoid neoplasms (Supplementary Table S6).…”

Section: Research Articlementioning

confidence: 99%

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Cytotoxic Therapy–Induced Effects on Both Hematopoietic and Marrow Stromal Cells Promotes Therapy-Related Myeloid Neoplasms

Stoddart

Wang

Fernald

et al. 2020

Blood Cancer Discovery

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Therapy-related myeloid neoplasms (t-MN) comprise therapy-related acute myeloid leukemia (t-AML) and myelodysplastic syndrome (t-MDS), and are a late complication of cytotoxic therapy, chemotherapy and/or radiotherapy, used in the treatment of both malignant and nonmalignant diseases (1, 2). The genetic profile of t-MN is markedly skewed toward high-risk cytogenetic and molecular abnormalities, and complex karyotypes with deletions of the long arm of chromosome 5, del(5q), and TP53 mutation/loss are profoundly over-represented in t-MNs as compared with de novo counterparts (3, 4). A proximal minimally deleted region (MDR) in 5q31.2 (containing EGR1) was previously identified in t-MN, de novo AML and high-risk MDS, and a distal MDR in 5q33.1(containing mir145, RPS14, and CSNK1A1) was identified in MDS with an isolated del(5q), previously referred to as the 5q-syndrome (1, 5). However, the deletion of 5q in all but rare patients encompasses both MDRs, spanning 5q14-5q33, resulting in loss of one allele for hundreds of genes. Although challenging to identify involved genes, we previously chose to examine two well-characterized del(5q)

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Section: Discussionmentioning

confidence: 99%

Section: Research Articlementioning

confidence: 99%

Cytotoxic Therapy–Induced Effects on Both Hematopoietic and Marrow Stromal Cells Promotes Therapy-Related Myeloid Neoplasms

Stoddart

Wang

Fernald

et al. 2020

Blood Cancer Discovery

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“…However, these are low risk alleles. In the search for higher penetrance inherited variants, researchers have studied cancer survivors who developed t-MN and found that 16-21% of them have a germline mutation associated with inherited cancer susceptibility genes 21–23 . Churpek and colleagues examined the frequency of germline mutations in 42 breast and ovarian cancer susceptibility genes in forty-seven breast cancer survivors who developed a t-MN or t-ALL (therapy-related acute lymphoblastic leukemia) 21 .…”

Section: Inherited Risk Factorsmentioning

confidence: 99%

Therapy-related myeloid neoplasms: when genetics and environment collide

2017

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Therapy-related myeloid neoplasms (t-MN) arise as a late-effect of chemotherapy and/or radiation administered for a primary condition, typically a malignant disease, solid organ transplant, or autoimmune disease. Survival is measured in months, not years, making t-MN one of the most aggressive and lethal cancers. In this review, we discuss recent developments that reframe our understanding of the genetic and environmental etiology of t-MN. Emerging data illuminate who is at highest risk for developing t-MN, why t-MN is chemoresistant, and how we may use this information to treat and ultimately prevent this dreaded disease.

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“…Some data suggest that harboring heterozygous gene mutation in a FANC gene, which is implicated in DNA repair, could determine a predisposition for developing a t-MN, after exposition to either environmental or iatrogenic factor that can activate DNA repair enzymes. 10 …”

Section: Pathogenesismentioning

confidence: 99%

“… 41 In t-MN, FLT3 , NPM1 , and epigenetic and spliceosome mutations have been shown to occur in a minority of patients indicating that in these diseases karyotype has a dominant role. 8 , 10 …”

Section: Epidemiology and Prognosismentioning

confidence: 99%

Therapy-related myeloid neoplasms: clinical perspectives

Fianchi

Criscuolo

Fabiani

et al. 2018

OTT

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Therapy-related myeloid neoplasms (t-MNs) are a complication of cytotoxic treatment for primary tumors and autoimmune diseases. t-MNs result from a complex interaction between individual predisposition and exposition to toxic agents. Some different biological and clinical characteristics can be recognized according to the type of anticancer drug. Compared to de novo myeloid neoplasms, prognosis of t-MN is dismal. Age and karyotype are the most important prognostic factors for t-MN, which should be treated with frontline chemotherapy treatments that are appropriate for patients with myelodysplastic syndrome (MDS) and de novo acute myeloid leukemia (AML) with similar disease characteristics. Allogeneic stem cell transplantation should be considered particularly for unfavorable karyotypes and younger patients with aggressive disease.

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Fanconi anemia gene variants in therapy-related myeloid neoplasms

Cited by 34 publications

References 14 publications

Cytotoxic Therapy–Induced Effects on Both Hematopoietic and Marrow Stromal Cells Promotes Therapy-Related Myeloid Neoplasms

Cytotoxic Therapy–Induced Effects on Both Hematopoietic and Marrow Stromal Cells Promotes Therapy-Related Myeloid Neoplasms

Therapy-related myeloid neoplasms: when genetics and environment collide

Therapy-related myeloid neoplasms: clinical perspectives

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