Germline ETV6 Mutations Confer Susceptibility to Acute Lymphoblastic Leukemia and Thrombocytopenia

Topka, Sabine; Vijai, Joseph; Walsh, Michael F.; Jacobs, Lauren; Maria, Ann; Villano, Danylo J.; Gaddam, Pragna; Wu, Gang; McGee, Rose B.; Quinn, Emily A.; Inaba, Hiroto; Hartford, Christine; Pui, Ching Hon; Pappo, Alberto S.; Edmonson, Michael N.; Zhang, Michael Y.; Stepensky, Polina; Steinherz, Peter G.; Schrader, Kasmintan A.; Lincoln, Anne; Bussel, James B.; Lipkin, Steve M.; Goldgur, Yehuda; Harit, M.; Stadler, Zsofia K.; Mullighan, Charles G.; Weintraub, Michael; Shimamura, Akiko; Zhang, Jinghui; Downing, James R.; Nichols, Kim E.; Offit, Kenneth

doi:10.1371/journal.pgen.1005262

Cited by 132 publications

(127 citation statements)

References 51 publications

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“…5,6 Moreover, Zhang et al previously reported one ETV6-RT pedigree carrying a different germline missense variant affecting the same residue (p.R369Q). Similarly to our patients with the p.R369W, the subjects with p.R369Q had mild thrombocytopenia and normal platelet morphology.…”

Section: Discussionmentioning

confidence: 99%

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Clinical and pathogenic features of ETV6 -related thrombocytopenia with predisposition to acute lymphoblastic leukemia

et al. 2016

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Section: Discussionmentioning

confidence: 99%

“…[3][4][5][6] However, only a few families have been reported so far and the clinical and laboratory features of ETV6-RT remain poorly defined.…”

Section: Introductionmentioning

confidence: 99%

Clinical and pathogenic features of ETV6 -related thrombocytopenia with predisposition to acute lymphoblastic leukemia

et al. 2016

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“…Familial clustering of myeloid malignancies with autosomal dominant (AD) inheritance has been recognized phenotypically for over 100 years (reviewed in [4]), with the first molecular basis discovered through the identification of germline RUNX1 mutations associated with familial platelet disorder with predisposition to myeloid malignancy in 1999 (FPD-MM, OMIM #601399) [5]. Since that time, and recently accelerated by the advent of next-generation sequencing, a growing number of genes have been associated with AD germline predisposition to myeloid malignancies, including mutations in GATA2 [6] as described by us and others [7], as well as ANKRD26 [8], ETV6 [9], CEBPA [10], RBBP6 [11], TERT, TERC [12], DDX41 [13] and most recently mutations in SAMD9 [14] and SAMD9L [15,16]. This growing recognition and molecular identification of the germline predisposition to a subset of myeloid malignancies has been formalized in the most recent revision to the World Health Organisation guidelines [1].…”

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confidence: 99%

Myeloid neoplasms with germline DDX41 mutation

et al. 2017

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to DDX41 mutation and highlights how each of these suggest potential therapeutic opportunities through the use of pathway-specific inhibitors.Keywords DDX41 · Myeloid malignancy · Myelodysplastic syndrome · Acute myeloid leukemia · Germline mutation · Predisposition Familial predisposition to myeloid neoplasmsMyeloid neoplasms are a heterogeneous group of diseases encompassing myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), all of which are characterized by abnormal growth and development of cells of the myeloid blood lineage. These disease groups can be further sub-categorized by a number of different morphological and molecular approaches which may correlate with responses to specific treatments [1]. AML and MDS Abstract Recently, DDX41 mutations have been identified both as germline and acquired somatic mutations in families with multiple cases of late-onset myelodysplastic syndrome (MDS) and/or acute myeloid leukemia. The majority of germline mutations are frameshift mutations suggesting loss of function with DDX41 acting as a tumor suppressor, and there is a common somatic missense mutation found in a majority of germline mutated tumors. Clinically, DDX41 mutations lead to development of high-risk MDS at an age similar to that observed in sporadic cohorts, presenting a unique challenge to hematologists in recognizing the familial context. Functionally, DDX41 has been shown to contribute to multiple pathways and processes including mRNA splicing, innate immunity and rRNA processing. Mutations in DDX41 result in aberrations to each of these in ways that could potentially impact on tumorigenesis-initiation, maintenance or progression. This review discusses the various molecular, clinical and biological aspects of myeloid malignancy predisposition due

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“…44,45 Individuals carrying germline ETV6 mutations have increased risks for hematologic malignancies, including AML, MDS, B-lymphoblastic leukemia, chronic myelomonocytic leukemia, and plasma cell myeloma. [44][45][46][47][48] Given the increasing awareness of germline mutations with predisposition to hematologic malignancies, it is recommended that patients with autosomal dominant familial thrombocytopenia and normal platelet size be tested for mutations in ETV6, RUNX1, and ANKRD26. …”

Section: Myeloid Neoplasms With Germline Etv6 Mutationmentioning

confidence: 99%

Myeloid Neoplasm With Germline Predisposition: A 2016 Update for Pathologists

Gao

Gong

Chen

2018

Archives of Pathology &Amp; Laboratory Medicine

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Context.— Myeloid neoplasms with familial occurrence have been rarely reported in the past. With the advance of molecular technology and better understanding of the molecular pathogenesis of myeloid neoplasms, investigating the genetic causes of familial acute myeloid leukemia or myelodysplastic syndrome has become feasible in the clinical setting. Recent studies have identified a rapidly expanding list of germline mutations associated with increased risks of developing myeloid neoplasm in the affected families. It is important to recognize these entities, as such a diagnosis may dictate a unique approach in clinical management and surveillance for the patients and carriers. Objective.— To raise the awareness of myeloid neoplasms arising in the setting of familial inheritance among practicing pathologists. Data Sources.— Based on recent literature and the 2016 revision of the World Health Organization classification of hematopoietic neoplasms, we provide an up-to-date review of myeloid neoplasm with germline predisposition. Conclusions.— This short review focuses on the clinical, pathologic, and molecular characterization of myeloid neoplasm with germline predisposition. We emphasize the important features that will help practicing pathologists to recognize these newly described entities.

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Germline ETV6 Mutations Confer Susceptibility to Acute Lymphoblastic Leukemia and Thrombocytopenia

Cited by 132 publications

References 51 publications

Clinical and pathogenic features of ETV6 -related thrombocytopenia with predisposition to acute lymphoblastic leukemia

Clinical and pathogenic features of ETV6 -related thrombocytopenia with predisposition to acute lymphoblastic leukemia

Myeloid neoplasms with germline DDX41 mutation

Myeloid Neoplasm With Germline Predisposition: A 2016 Update for Pathologists

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