@article{cb2d5588b87e4f85b376cce6ad5e80d9,
title = "Germline DNMT3A mutation in familial acute myeloid leukaemia",
abstract = "Acute myeloid leukaemia (AML) is a heterogeneous myeloid malignancy characterized by recurrent clonal events, including mutations in epigenetically relevant genes such as DNMT3A, ASXL1, IDH1/2, and TET2. Next-generation sequencing analysis of a mother and son pair who both developed adult-onset diploid AML identified a novel germline missense mutation DNMT3A p.P709S. The p.P709S protein-altering variant resides in the highly conserved catalytic DNMT3A methyltransferase domain. Functional studies demonstrate that the p.P709S variant confers dominant negative effects when interacting with wildtype DNMT3A. LINE-1 pyrosequencing and reduced representation bisulphite sequencing (RBBS) analysis demonstrated global DNA hypomethylation in germline samples, not present in the leukaemic samples. Somatic acquisition of IDH2 p.R172K mutations, in concert with additional acquired clonal DNMT3A events in both patients at the time of AML diagnosis, confirms the important pathogenic interaction of epigenetically active genes, and implies a strong selection and regulation of methylation in leukaemogenesis. Improved characterization of germline mutations may enable us to better predict malignant clonal evolution, improving our ability to provide customized treatment or future preventative strategies.",
keywords = "AML, DNMT3A, germline, hereditary, predisposition",
author = "DiNardo, {Courtney D.} and Beird, {Hannah C.} and Marcos Estecio and Swanand Hardikar and Koichi Takahashi and Bannon, {Sarah A.} and Gautam Borthakur and Elias Jabbour and Curtis Gumbs and Khoury, {Joseph D.} and Mark Routbort and Ting Gong and Kimie Kondo and Hagop Kantarjian and Guillermo Garcia-Manero and Taiping Chen and Futreal, {P. Andrew}",
note = "Funding Information: This work was supported in part by the MD Anderson Cancer Center Support Grant P30 CA016672 and by generous philanthropic contributions to MD Anderson{\textquoteright}s MDS/AML Moon Shot Program. CDD is also supported by the Jeanne F. Shelby Scholarship Fund which has supported her R. Lee Clark Fellow award. Cancer Prevention Research Institute (R120501) and Welch Foundation{\textquoteright}s Robert A. Welch Distinguished University Chair Awards (G-0040) were given to PAF. An NIH R01 grant (1R01AI121403-01A1) was awarded to TC. AML samples were a gift from Hui Yang and Carlos Bueso-Ramos; CMML samples were given by K.P. Patel). These sponsors were public and nonprofit organizations who did not take part in collecting, processing, or interpreting the data. The results in the discussion on IDH2 frequencies are in part based upon data generated by the TCGA Research Network: https://www.cancer.gov/tcga . Funding Information: This work was supported by the Cancer Prevention and Research Institute of Texas [R120501]; National Institutes of Health [1R01AI121403-01A1]; University of Texas MD Anderson Cancer Center [MDS/AML Moon Shot Program]; University of Texas MD Anderson Cancer Center [P30 CA016672]; University of Texas MD Anderson Cancer Center [R. Lee Clark Fellow award]; Welch Foundation [G-0040]. This work was supported in part by the MD Anderson Cancer Center Support Grant P30 CA016672 and by generous philanthropic contributions to MD Anderson?s MDS/AML Moon Shot Program. CDD is also supported by the Jeanne F. Shelby Scholarship Fund which has supported her R. Lee Clark Fellow award. Cancer Prevention Research Institute (R120501) and Welch Foundation?s Robert A. Welch Distinguished University Chair Awards (G-0040) were given to PAF. An NIH R01 grant (1R01AI121403-01A1) was awarded to TC. AML samples were a gift from Hui Yang and Carlos Bueso-Ramos; CMML samples were given by K.P. Patel). These sponsors were public and nonprofit organizations who did not take part in collecting, processing, or interpreting the data. The results in the discussion on IDH2 frequencies are in part based upon data generated by the TCGA Research Network: https://www.cancer.gov/tcga. Publisher Copyright: {\textcopyright} 2020 Informa UK Limited, trading as Taylor & Francis Group.",
year = "2021",
doi = "10.1080/15592294.2020.1809871",
language = "English (US)",
volume = "16",
pages = "567--576",
journal = "Epigenetics",
issn = "1559-2294",
publisher = "Landes Bioscience",
number = "5",
}