Browsing by Author "Patel, Keyur P."

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    Somatic mutational landscape of hereditary hematopoietic malignancies caused by germline variants in RUNX1, GATA2, and DDX41
    (American Society of Hematology, 2023) Homan, Claire C.; Drazer, Michael W.; Yu, Kai; Lawrence, David M.; Feng, Jinghua; Arriola-Martinez, Luis; Pozsgai, Matthew J.; McNeely, Kelsey E.; Ha, Thuong; Venugopal, Parvathy; Arts, Peer; King-Smith, Sarah L.; Cheah, Jesse; Armstrong, Mark; Wang, Paul; Bödör, Csaba; Cantor, Alan B.; Cazzola, Mario; Degelman, Erin; DiNardo, Courtney D.; Duployez, Nicolas; Favier, Remi; Fröhling, Stefan; Rio-Machin, Ana; Klco, Jeffery M.; Krämer, Alwin; Kurokawa, Mineo; Lee, Joanne; Malcovati, Luca; Morgan, Neil V.; Natsoulis, Georges; Owen, Carolyn; Patel, Keyur P.; Preudhomme, Claude; Raslova, Hana; Rienhoff, Hugh; Ripperger, Tim; Schulte, Rachael; Tawana, Kiran; Velloso, Elvira; Yan, Benedict; Kim, Erika; Sood, Raman; Hsu, Amy P.; Holland, Steven M.; Phillips, Kerry; Poplawski, Nicola K.; Babic, Milena; Wei, Andrew H.; Forsyth, Cecily; Fan, Helen Mar; Lewis, Ian D.; Cooney, Julian; Susman, Rachel; Fox, Lucy C.; Blombery, Piers; Singhal, Deepak; Hiwase, Devendra; Phipson, Belinda; Schreiber, Andreas W.; Hahn, Christopher N.; Scott, Hamish S.; Liu, Paul; Godley, Lucy A.; Brown, Anna L.; NISC Comparative Sequencing Program; Pediatrics, School of Medicine
    Individuals with germ line variants associated with hereditary hematopoietic malignancies (HHMs) have a highly variable risk for leukemogenesis. Gaps in our understanding of premalignant states in HHMs have hampered efforts to design effective clinical surveillance programs, provide personalized preemptive treatments, and inform appropriate counseling 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 germ line variants for the acquisition of somatic variants in BCOR, PHF6, and TET2 and second hits in RUNX1 are warranted.
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    The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms
    (Springer, 2022) Khoury, Joseph D.; Solary, Eric; Abla, Oussama; Akkari, Yassmine; Alaggio, Rita; Apperley, Jane F.; Bejar, Rafael; Berti, Emilio; Busque, Lambert; Chan, John K. C.; Chen, Weina; Chen, Xueyan; Chng, Wee-Joo; Choi, John K.; Colmenero, Isabel; Coupland, Sarah E.; Cross, Nicholas C. P.; De Jong, Daphne; Elghetany, M. Tarek; Takahashi, Emiko; Emile, Jean-Francois; Ferry, Judith; Fogelstrand, Linda; Fontenay, Michaela; Germing, Ulrich; Gujral, Sumeet; Haferlach, Torsten; Harrison, Claire; Hodge, Jennelle C.; Hu, Shimin; Jansen, Joop H.; Kanagal-Shamanna, Rashmi; Kantarjian, Hagop M.; Kratz, Christian P.; Li, Xiao-Qiu; Lim, Megan S.; Loeb, Keith; Loghavi, Sanam; Marcogliese, Andrea; Meshinchi, Soheil; Michaels, Phillip; Naresh, Kikkeri N.; Natkunam, Yasodha; Nejati, Reza; Ott, German; Padron, Eric; Patel, Keyur P.; Patkar, Nikhil; Picarsic, Jennifer; Platzbecker, Uwe; Roberts, Irene; Schuh, Anna; Sewell, William; Siebert, Reiner; Tembhare, Prashant; Tyner, Jeffrey; Verstovsek, Srdan; Wang, Wei; Wood, Brent; Xiao, Wenbin; Yeung, Cecilia; Hochhaus, Andreas; Medical and Molecular Genetics, School of Medicine
    The upcoming 5th edition of the World Health Organization (WHO) Classification of Haematolymphoid Tumours is part of an effort to hierarchically catalogue human cancers arising in various organ systems within a single relational database. This paper summarizes the new WHO classification scheme for myeloid and histiocytic/dendritic neoplasms and provides an overview of the principles and rationale underpinning changes from the prior edition. The definition and diagnosis of disease types continues to be based on multiple clinicopathologic parameters, but with refinement of diagnostic criteria and emphasis on therapeutically and/or prognostically actionable biomarkers. While a genetic basis for defining diseases is sought where possible, the classification strives to keep practical worldwide applicability in perspective. The result is an enhanced, contemporary, evidence-based classification of myeloid and histiocytic/dendritic neoplasms, rooted in molecular biology and an organizational structure that permits future scalability as new discoveries continue to inexorably inform future editions.