Approach Toward Germline Predisposition Syndromes in Patients with Hematologic Malignancies

Atluri, Himachandana; Gerstein, Yoheved; DiNardo, Courtney D.

doi:10.1007/s11899-022-00684-2

Cited by 4 publications

(1 citation statement)

References 62 publications

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“…An international expert panel on behalf of the European LeukemiaNet has recently published recommendations regarding diagnosis and management of AML in adults (Döhner et al, 2022). Others described their approach to recognize patients suspected to carry a germline predisposition to HM and, moreover, the evaluation within a hereditary HM clinic (Atluri et al, 2022). Recommendations and guidelines for specific disorders (e.g., Shwachman-Diamond syndrome and Diamond-Blackfan anemia (Dror et al, 2011;Vlachos et al, 2008)), or heterogenic disease groups (e.g., Fanconi anemia (Behrens et al, 2021;Chao et al, 2015;Ebens et al, 2017) J o u r n a l P r e -p r o o f has been drafted by members of ERN PaedCan's Subnetwork Familial Leukemia with the support of the Host Genome Working Group of SIOPE (https://siope.eu/siope-host-genomeworking-group/), the COST action leukemia gene discovery by data sharing, mining and collaboration (LEGEND, https://www.legend-cost.eu/) as well as MyPred, the German network for rare diseases focusing on young individuals with syndromes predisposing to myeloid malignancies (https://www.research4rare.de/en/research_networks/mypred/).…”

Section: Introductionmentioning

confidence: 99%

European standard clinical practice – Key issues for the medical care of individuals with familial leukemia

Förster

Davenport

Duployez

et al. 2023

European Journal of Medical Genetics

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Section: Introductionmentioning

confidence: 99%

European standard clinical practice – Key issues for the medical care of individuals with familial leukemia

Förster

Davenport

Duployez

et al. 2023

European Journal of Medical Genetics

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Identification of Novel Potential Predisposing Variants in Familial Acute Myeloid Leukemia

Ronchini,

Gigli,

Fontanini

et al. 2024

Cancer Reports

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BackgroundMyeloid neoplasms, including acute myeloid leukemia, have been traditionally among the less investigated cancer types concerning germline predisposition. Indeed, myeloid neoplasms with germline predisposition are challenging to identify because often display similar clinical and morphological characteristics of sporadic cases and have similar age at diagnosis. However, a misidentifications of familiarity in myeloid neoplasms have a critical impact on clinical management both for the carriers and their relatives.AimsWe conducted a family segregation study, in order to identify novel cancer predisposing genes in myeloid neoplasms and classify novel identified variants.Methods and ResultsWe performed a thorough genomic analysis using a large custom gene panel (256 genes), the Myelo‐Panel, targeted on cancer predisposing genes. In particular, we assessed both germline and somatic variants in four families, each with two siblings, who developed hematological neoplasms: seven acute myeloid leukemia and one Philadelphia‐positive chronic myeloid leukemia. In each family, we identified at least one novel potentially predisposing variant, affecting also genes not included in the current European LeukemiaNet guidelines for AML management. Moreover, we suggest reclassification of two germline variants as pathogenic: likely pathogenic p.S21Tfs*139 in CEPBA and VUS p.K392Afs*66 in DDX41.ConclusionWe believe that predisposition to hematological neoplasms is still underestimated and particularly difficult to diagnosed. Considering that misidentification of familiarity in myeloid neoplasms have a critical impact on the clinical management both for the carriers and their relatives, our study highlights the importance of revision, in this clinical context, of clinical practices that should include thorough reconstruction of family history and in‐depth genetic testing.

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Insights into the Molecular Mechanisms of Genetic Predisposition to Hematopoietic Malignancies: The Importance of Gene–Environment Interactions

Cobaleda,

Godley,

Nichols

et al. 2024

Cancer Discovery

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Summary: The recognition of host genetic factors underlying susceptibility to hematopoietic malignancies has increased greatly over the last decade. Historically, germline predisposition was thought to primarily affect the young. However, emerging data indicate that hematopoietic malignancies that develop in people of all ages across the human lifespan can derive from germline predisposing conditions and are not exclusively observed in younger individuals. The age at which hematopoietic malignancies manifest appears to correlate with distinct underlying biological pathways. Progression from having a deleterious germline variant to being diagnosed with overt malignancy involves complex, multistep gene–environment interactions with key external triggers, such as infection and inflammatory stimuli, driving clonal progression. Understanding the mechanisms by which predisposed clones transform under specific pressures may reveal strategies to better treat and even prevent hematopoietic malignancies from occurring. Recent unbiased genome-wide sequencing studies of children and adults with hematopoietic malignancies have revealed novel genes in which disease-causing variants are of germline origin. This paradigm shift is spearheaded by findings in myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) as well as acute lymphoblastic leukemia, but it also encompasses other cancer types. Although not without challenges, the field of genetic cancer predisposition is advancing quickly, and a better understanding of the genetic basis of hematopoietic malignancies risk affects therapeutic decisions as well as genetic counseling and testing of at-risk family members.

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Approach Toward Germline Predisposition Syndromes in Patients with Hematologic Malignancies

Cited by 4 publications

References 62 publications

European standard clinical practice – Key issues for the medical care of individuals with familial leukemia

European standard clinical practice – Key issues for the medical care of individuals with familial leukemia

Identification of Novel Potential Predisposing Variants in Familial Acute Myeloid Leukemia

Insights into the Molecular Mechanisms of Genetic Predisposition to Hematopoietic Malignancies: The Importance of Gene–Environment Interactions

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