Heritable defects in telomere and mitotic function selectively predispose to sarcomas

• 成果类型: Article
• 署名作者: Ballinger, Mandy L.; Pattnaik, Swetansu; Mundra, Piyushkumar A.; Zaheed, Milita; Rath, Emma; Priestley, Peter; Baber, Jonathan; Ray-Coquard, Isabelle; Isambert, Nicholas; Causeret, Sylvain; van der Graaf, Winette T. A.; Puri, Ajay; Duffaud, Florence; Le Cesne, Axel; Seddon, Beatrice; Chandrasekar, Coonoor; Schiffman, Joshua D.; Brohl, Andrew S.; James, Paul A.; Kurtz, Jean-Emmanuel; Penel, Nicolas; Myklebost, Ola; Meza-Zepeda, Leonardo A.; Pickett, Hilda; Kansara, Maya; Waddell, Nicola; Kondrashova, Olga; Pearson, John, V; Barbour, Andrew P.; Li, Shuai; Nguyen, Tuong L.; Fatkin, Diane; Graham, Robert M.; Giannoulatou, Eleni; Green, Melissa J.; Kaplan, Warren; Ravishankar, Shyamsundar; Copty, Joseph; Powell, Joseph E.; Cuppen, Edwin; van Eijk, Kristel; Veldink, Jan; Ahn, Jin-Hee; Kim, Jeong Eun; Randall, R. Lor; Tucker, Kathy; Judson, Ian; Sarin, Rajiv; Ludwig, Thomas; Genin, Emmanuelle; Deleuze, Jean-Francois; Haber, Michelle; Marshall, Glenn; Cairns, Murray J.; Blay, Jean-Yves; Thomas, David M.
• 署名单位: Garvan Institute of Medical Research; University of New South Wales Sydney; University of New South Wales Sydney; Prince of Wales Hospital (POWH); UNICANCER; Centre Leon Berard; Universite Claude Bernard Lyon 1; UNICANCER; Universite Bourgogne Europe; Centre Georges-Francois Leclerc; Royal Marsden NHS Foundation Trust; Tata Memorial Centre (TMC); Tata Memorial Hospital; Aix-Marseille Universite; Assistance Publique-Hopitaux de Marseille; UNICANCER; Gustave Roussy; University of London; University College London; Utah System of Higher Education; University of Utah; Huntsman Cancer Institute; H Lee Moffitt Cancer Center & Research Institute; University of Melbourne; Peter Maccallum Cancer Center; Peter Maccallum Cancer Center; Melbourne Health; Royal Melbourne Hospital; CHU Strasbourg; UNICANCER; Centre Oscar Lambret; University of Bergen; Haukeland University Hospital; University of Bergen; University of Oslo; University of Sydney; Children's Medical Research Institute - Australia; QIMR Berghofer Medical Research Institute; University of Queensland; University of Melbourne; University of Cambridge; Monash University; Murdoch Children's Research Institute; Royal Children's Hospital Melbourne; Victor Chang Cardiac Research Institute; NSW Health; St Vincents Hospital Sydney; Victor Chang Cardiac Research Institute; University of New South Wales Sydney; University of New South Wales Sydney; Utrecht University; Utrecht University Medical Center; University of Ulsan; Asan Medical Center; University of California System; University of California Davis; Tata Memorial Centre (TMC); Tata Memorial Hospital; Advance Centre for Treatment, Research & Education in Cancer (ACTREC); Institut National de la Sante et de la Recherche Medicale (Inserm); Universite de Bretagne Occidentale; CHU Brest; Universite Paris Saclay; Children's Cancer Institute; University of New South Wales Sydney; NSW Health; Sydney Childrens Hospitals Network; University of Newcastle; University of Newcastle; Hunter Medical Research Institute
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-13151
• DOI: 10.1126/science.abj4784
• 发表日期: 2023-01-20
• 页码: 253-260
• 关键词: replication stress; cancer; mutations; genome; genes; pot1; maintenance; aneuploidy; shelterin; breast

摘要

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 defects in the shelterin complex link susceptibility to sarcoma, melanoma, and thyroid cancers. These studies indicate a specific role for heritable defects in mitotic and telomere biology in risk of sarcomas.