bims-lifras 2023-07-09 papers

Issue of 2023‒07‒09
five papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet

Leukemia. 2023 Jul 01.

Needle in a haystack or elephant in the room? Identifying germline predisposition syndromes in the setting of a new myeloid malignancy diagnosis.

Erica F Reinig, Jeremy D Rubinstein, Apoorva T Patil, Amanda L Schussman, Vanessa L Horner, Rashmi Kanagal-Shamanna, Jane E Churpek, Daniel R Matson.

Myeloid malignancies associated with germline predisposition syndromes account for up to 10% of myeloid neoplasms. They are classified into three categories by the proposed 5th Edition of the World Health Organization Classification of Hematolymphoid Tumors: (1) neoplasms with germline predisposition without a pre-existing platelet disorder or organ dysfunction, (2) neoplasms with germline predisposition and pre-existing platelet disorder, or (3) neoplasms with germline predisposition and potential organ dysfunction. Recognizing these entities is critical because patients and affected family members benefit from interfacing with hematologists who specialize in these disorders and can facilitate tailored treatment strategies. However, identification of these syndromes in routine pathology practice is often challenging, as characteristic findings associated with these diagnoses at baseline are frequently absent, nonspecific, or impossible to evaluate in the setting of a myeloid malignancy. Here we review the formally classified germline predisposition syndromes associated with myeloid malignancies and summarize practical recommendations for pathologists evaluating a new myeloid malignancy diagnosis. Our intent is to empower clinicians to better screen for germline disorders in this common clinical setting. Recognizing when to suspect a germline predisposition syndrome, pursue additional ancillary testing, and ultimately recommend referral to a cancer predisposition clinic or hematology specialist, will ensure optimal patient care and expedite research to improve outcomes for these individuals.

DOI: https://doi.org/10.1038/s41375-023-01955-4

Lancet Oncol. 2023 Jul;pii: S1470-2045(23)00295-4. [Epub ahead of print]24(7): 709

Meeting the need for germline testing.

The Lancet Oncology.

DOI: https://doi.org/10.1016/S1470-2045(23)00295-4

Blood Adv. 2023 Jul 05. pii: bloodadvances.2023010045. [Epub ahead of print]

Somatic mutational landscape of hereditary hematopoietic malignancies caused by germ line RUNX1, GATA2, and DDX41 variants.

Claire C Homan, Michael W Drazer, Kai Yu, David Michael Lawrence, Jinghua Feng, Luis Alberto Arriola-Martinez, Matthew J Pozsgai, Kelsey E McNeely, Thuong Thi Ha, Parvathy Venugopal, Peer Arts, Sarah King-Smith, Jesse Jc Cheah, Mark Armstrong, Paul Wang, Csaba Bödör, Alan B Cantor, Mario Cazzola, Erin S Degelman, Courtney D DiNardo, Nicolas Duployez, Rémi Favier, Stefan Fröhling, Ana Rio-Machin, Jeffery M Klco, Alwin Krämer, Mineo Kurokawa, Joanne Lee, Luca Malcovati, Neil V Morgan, Natsoulis Georges, Carolyn Owen, Keyur P Patel, Claude Preudhomme, Hana Raslova, Hugh Young Rienhoff, Tim Ripperger, Rachael R Schulte, Kiran Tawana, Elvira Velloso, Yan Benedict, Erika Mijin Kwon Kim, Raman Sood, Amy P Hsu, Steven M Holland, Kerry Phillips, Nicola Poplawski, Milena Babic, Andrew H Wei, Cecily J Forsyth, Helen Mar Fan, Ian Lewis, Julian P Cooney, Rachel Susman, Lucy C Fox, Piers Blombery, Deepak Singhal, Devendra K Hiwase, Belinda Phipson, Andreas W Schreiber, Christopher N Hahn, Hamish S Scott, Paul P Liu, Lucy A Godley, Anna L Brown.

Individuals with germline variants associated with hereditary hematopoietic malignancies (HHMs) have a highly variable risk for leukemogenesis. Gaps in our understanding of pre-malignant states in HHMs have hampered efforts to design effective clinical surveillance programs, provide personalized pre-emptive treatments and inform appropriate counselling for patients. We used the largest known comparative international cohort of germline RUNX1, GATA2, or DDX41 variant carriers without and with hematopoietic malignancies (HMs) to identify patterns of genetic drivers that are unique to each HHM syndrome before and after leukemogenesis. These patterns included striking heterogeneity in rates of early-onset clonal hematopoiesis (CH), with a high prevalence of CH in RUNX1 and GATA2 variant carriers who did not have malignancies ("carriers-without HM"). We observed a paucity of CH in DDX41 carriers-without HM. In RUNX1 carriers-without HM with CH, we detected variants in TET2, PHF6, and, most frequently, BCOR. These genes were recurrently mutated in RUNX1-driven malignancies, suggesting CH is a direct precursor to malignancy in RUNX1-driven HHMs. Leukemogenesis in RUNX1 and DDX41 carriers was often driven by second-hits in RUNX1 and DDX41, respectively. This study may inform the development of HHM-specific clinical trials and gene-specific approaches to clinical monitoring. For example, trials investigating the potential benefits of monitoring DDX41 carriers-without HM for low-frequency second hits in DDX41 may now be beneficial. Similarly, trials monitoring carriers-without HM with RUNX1 germline variants for the acquisition of somatic variants in BCOR, PHF6, TET2, and second hits in RUNX1 are warranted.

DOI: https://doi.org/10.1182/bloodadvances.2023010045

Front Oncol. 2023 ;13 1207695

Identifying childhood leukemia with an excess of hematological malignancies in first-degree relatives in Brazil.

Daniela P Mendes-de-Almeida, Francianne G Andrade, Maria do Perpétuo Socorro Sampaio Carvalho, José Carlos Córdoba, Marcelo Dos Santos Souza, Paulo Chagas Neto, Logan G Spector, Maria S Pombo-de-Oliveira.

Background: Familial aggregation in childhood leukemia is associated with epidemiological and genomic factors. Albeit epidemiological studies on the familial history of hematological malignancies (FHHMs) are scarce, genome-wide studies have identified inherited gene variants associated with leukemia risk. We revisited a dataset of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) patients to explore the familial aggregation of malignancies among their relatives.Methods: A series of 5,878 childhood leukemia (≤21 years of age) from the EMiLI study (2000-2019) were assessed. Lack of well-documented familial history of cancer (FHC) and 670 cases associated with genetic phenotypic syndromes were excluded. Leukemia subtypes were established according to World Health Organization recommendations. Logistic regression-derived odds ratios (ORs) and 95% confidence intervals (CIs) were performed and adjusted by age as a continuous variable, where ALL was the reference group for AML and conversely. The pedigree of 18 families with excess hematological malignancy was constructed.
Results: FHC was identified in 472 of 3,618 eligible cases (13%). Ninety-six of the 472 patients (20.3%) had an occurrence of FHHMs among relatives. Overall, FHC was significantly associated with AML (OR, 1.36; 95% CI, 1.01-1.82; p = 0.040). Regarding the first-degree relatives, the OR, 2.92 95% CI,1.57-5.42 and the adjOR, 1.16 (1.03-1.30; p0.001) were found for FHC and FHHM, respectively.
Conclusion: Our findings confirmed that AML subtypes presented a significant association with hematological malignancies in first-degree relatives. Genomic studies are needed to identify germline mutations that significantly increase the risk of developing myeloid malignancies in Brazil.

Keywords: Brazil; childhood leukemia; familial history of hematological disorders; lymphoblastic acute leukemia; myeloid leukemia

DOI: https://doi.org/10.3389/fonc.2023.1207695