Heritable defects in telomere and mitotic function selectively predispose to sarcomas

Ballinger, Mandy L. and Pattnaik, Swetansu and Mundra, Piyushkumar A. and Zaheed, Milita and Rath, Emma and Priestley, Peter and Baber, Jonathan and Ray-Coquard, Isabelle and Isambert, Nicholas and Causeret, Sylvain and van der Graaf, Winette T. A. and Puri, Ajay and Duffaud, Florence and Le Cesne, Axel and Seddon, Beatrice and Chandrasekar, Coonoor and Schiffman, Joshua D. and Brohl, Andrew S. and James, Paul A. and Kurtz, Jean-Emmanuel and Penel, Nicolas and Myklebost, Ola and Meza-Zepeda, Leonardo A. and Pickett, Hilda and Kansara, Maya and Waddell, Nicola and Kondrashova, Olga and Pearson, John V. and Barbour, Andrew P. and Li, Shuai and Nguyen, Tuong L. and Fatkin, Diane and Graham, Robert M. and Giannoulatou, Eleni and Green, Melissa J. and Kaplan, Warren and Ravishankar, Shyamsundar and Copty, Joseph and Powell, Joseph E. and Cuppen, Edwin and van Eijk, Kristel and Veldink, Jan and Ahn, Jin-Hee and Kim, Jeong Eun and Randall, R. Lor and Tucker, Kathy and Judson, Ian and Sarin, Rajiv and Ludwig, Thomas and Genin, Emmanuelle and Deleuze, Jean-Francois and Haber, Michelle and Marshall, Glenn and Cairns, Murray J. and Blay, Jean-Yves and Thomas, David M. (2023) Heritable defects in telomere and mitotic function selectively predispose to sarcomas. Science, 379 (6629). pp.253-260. ISSN 0036-8075

Available under License Creative Commons Attribution No Derivatives.

Download (1MB) | Preview
Link to published document: http://doi.org/10.1126/science.abj4784


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.

Item Type: Article
Subjects: R Medicine > R Medicine (General)
Depositing User: Repository Administrator
Date Deposited: 06 Mar 2023 04:23
Last Modified: 10 Mar 2023 06:24
URI: http://eprints.victorchang.edu.au/id/eprint/1346

Actions (login required)

View Item View Item