Journal article
Heritable defects in telomere and mitotic function selectively predispose to sarcomas
ML Ballinger, S Pattnaik, PA Mundra, M Zaheed, E Rath, P Priestley, J Baber, I Ray-Coquard, N Isambert, S Causeret, WTA van der Graaf, A Puri, F Duffaud, A Le Cesne, B Seddon, C Chandrasekar, JD Schiffman, AS Brohl, PA James, JE Kurtz Show all
Science | Published : 2023
Abstract
Cancer genetics has to date focused on epithelial malignancies, identifying multiple histotype-specific pathways underlying cancer susceptibility. Sarcomas are rare malignancies predominantly derived from embryonic mesoderm. To identify pathways specific to mesenchymal cancers, we performed whole-genome germline sequencing on 1644 sporadic cases and 3205 matched healthy elderly controls. Using an extreme phenotype design, a combined rare-variant burden and ontologic analysis identified two sarcoma-specific pathways involved in mitotic and telomere functions. Variants in centrosome genes are linked to malignant peripheral nerve sheath and gastrointestinal stromal tumors, whereas heritable def..
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Awarded by Victorian Cancer Agency
Funding Acknowledgements
Australian National Health and Medical Research Council APP1004017, APP1081477 (D.M.T., M.L.B.), Bioplatforms Australia (D.M.T.), NSW Office of Health and Medical Research Cancer Moonshot Program (D.M.T.), Cancer Australia Priority-driven Collaborative Cancer Research Scheme APP1067094 (D.M.T., M.L.B.), Australian Genomics Health Alliance (D.M.T.), Rainbows for Kate Foundation (D.M.T., M.L.B.), Liddy Shriver Sarcoma Initiative (D.M.T., M.L.B., J.D.S., I.J., A.P.), Johanna Sewell Research Foundation (D.M.T., M.L.B.), Victorian Cancer Agency BFRes11_03 (M.L.B., D.M.T.), CanTeen (D.M.T., M.L.B.), NSW Office of Health and Medical Research (D.M.T.), Sydney Genomics Collaborative Grants Scheme (D.M.T.), Lions Club Kids Cancer Genome Project (D.M.T.), Sarcoma UK (I.J., B.S.), National Health Service funding to the National Institute for Health Research Biomedical Research Centre, UK (I.J.), Norwegian Cancer Society 144385 (O.M.), Norwegian Radium Hospital Legacy, 170502 (O.M.), Trond Mohn Foundation (O.M.), Norwegian Research Council 218241 and 221580 (O.M.), Bergen Research Foundation BFS2017TMT04 (O.M.), Australian National Health and Medical Research Council Principal Research Fellowship APP1104364 (D.M.T.), Cancer Institute NSW Career Development Fellowship CDF171109 (M.L.B.), Cure Cancer Australia Foundation through Cancer Australia Priority-driven Collaborative Cancer Research Scheme (APP1159399) (T.L.N.), Victorian Cancer Council Post-Doctoral Fellowship (CCV1139144) (T.L.N.), Picchi Foundation (T.L.N.), Victorian Comprehensive Cancer Centre (T.L.N.), Victorian Cancer Agency Early Career Research Fellowship ECRF19020 (S.L.), National Health and Medical Research Council of Australia Senior Research Fellowship APP1139071 (N.W.), NetSARC+ INCA and DGOS (J.-Y.B., I.R.-C., N.P., N.I., F.D., J.-E.K.), EURACAN EC 739521 (J.-Y.B. and I.R.-C.) LYRICAN INCA-DGOSINSERM 12563 (J.-Y.B. and I.R.-C.), LabEx DEvweCAN ANR-10LABX-0061 (J.-Y.B. and I.R.-C.), Institut Convergence PLASCAN 17-CONV-0002 (J.-Y.B. and I.R.-C.), RHU4 DEPGYN (ANR-18RHUS-0009 (J.-Y.B. and I.R.-C.), TMRG (INCA and DGOS) (J.-Y.B. and I.R.-C.), InterSARC (INCA and DGOS) (J.-Y.B. and I.R.-C.), Foundation ARC Ligue Contre Le Cancer (J.-Y.B. and I.R.-C.), Cancer Institute NSW Cancer Genetics Training Grant (M.Z.), Hyundai Hope on Wheels (J.D.S.), Soccer for Hope Foundation (J.D.S.), Li-Fraumeni Syndrome Association (J.D.S.), Kneaders Bakery & Cafe Hope Campaign (J.D.S.), 5 For The Fight (Qualtrics) (J.D.S.), Elephant p53 (EP53) Program funded through Huntsman Cancer Institute by the State of Utah (J.D.S.), Australian National Health and Medical Research Council Senior Research Fellowship APP1121474 (M.J.C.), and University of Newcastle Faculty of Health and Medicine Gladys M Brawn Senior Fellowship (M.J.C.). The FREX consortium was supported by France Genomique National infrastructure, funded as part of "Investissement d'avenir" program managed by Agence Nationale pour la Recherche (contrat ANR-10-INBS-09), https://www.france-genomique.org/.