为了确定间充质癌的特异性途径，研究人员对1644例散发病例和3205例匹配的健康老年人对照组进行了全基因组生殖系测序。利用极端表型设计，并结合罕见变异负荷和本体学分析确定了两种涉及有丝分裂和端粒功能的肉瘤特异性通路。中心体基因的变异与恶性周围神经鞘和胃肠道间质肿瘤有关，而端粒蛋白复合体的遗传缺陷与肉瘤、黑色素瘤和甲状腺癌的敏感性有关。这些研究表明有丝分裂和端粒生物学的遗传缺陷在肉瘤的风险中具有特定的作用。
据介绍，迄今为止，癌症遗传学一直以上皮性恶性肿瘤为主题，并确定了多种组织类型特异性的癌症敏感性途径。肉瘤是一种罕见的恶性肿瘤，主要来源于胚胎中胚层。
附：英文原文
Title: Heritable defects in telomere and mitotic function selectively predispose to sarcomas
Author: Mandy L. Ballinger, Swetansu Pattnaik, Piyushkumar A. Mundra, Milita Zaheed, Emma Rath, Peter Priestley, Jonathan Baber, Isabelle Ray-Coquard, Nicholas Isambert, Sylvain Causeret, Winette T. A. van der Graaf, Ajay Puri, Florence Duffaud, Axel Le Cesne, Beatrice Seddon, Coonoor Chandrasekar, Joshua D. Schiffman, Andrew S. Brohl, Paul A. James, Jean-Emmanuel Kurtz, Nicolas Penel, Ola Myklebost, Leonardo A. Meza-Zepeda, Hilda Pickett, Maya Kansara, Nicola Waddell, Olga Kondrashova, John V. Pearson, Andrew P. Barbour, Shuai Li, Tuong L. Nguyen, Diane Fatkin, Robert M. Graham, Eleni Giannoulatou, Melissa J. Green, Warren Kaplan, Shyamsundar Ravishankar, Joseph Copty, Joseph E. Powell, Edwin Cuppen, Kristel van Eijk, Jan Veldink, Jin-Hee Ahn, Jeong Eun Kim, R. Lor Randall, Kathy Tucker, Ian Judson, Rajiv Sarin, Thomas Ludwig, Emmanuelle Genin, Jean-Francois Deleuze, the French Exome Project Consortium, Michelle Haber, Glenn Marshall, Murray J. Cairns, Jean-Yves Blay, the International Sarcoma Kindred Study, David M. Thomas, Martin Tattersall, Susan Neuhaus, Craig Lewis, Kathy Tucker, Richard Carey-Smith, David Wood, Sandro Porceddu, Ian Dickinson, Heather Thorne, Paul James, Isabelle Ray-Coquard, Jean-Yves Blay, Philippe Cassier, Axel Le Cesne, Florence Duffaud, Nicolas Penel, Nicolas Isambert, Jean-Emmanuel Kurtz, Ajay Puri, Rajiv Sarin, Jin-Hee Ahn, Jeong Eun Kim, Iain Ward, Ian Judson, Winette van der Graaf, Beatrice Seddon, Coonoor Chandrasekar, Rory Rickar, Ivo Hennig, Joshua Schiffman, R. Lor Randall, Audrey Silvestri, Anaiis Zaratzian, Michael Tayao, Kelly Walwyn, Eveline Niedermayr, Denia Mang, Richard Clark, Tina Thorpe, Jessica MacDonald, Kim Riddell, Jasmine Mar, Vicki Fennelly, Allison Wicht, Belinda Zielony, Emma Galligan, Genna Glavich, Johanna Stoeckert, Lynda Williams, Lana Djandjgava, Iwona Buettner, Carla Osinki, Sonya Stephens, Muriel Rogasik, Laure Bouclier, Magali Girodet, Amandine Charreton, Yohan Fayet, Saniya Crasto, Bhanupriya Sandupatla, Yeon Yoon, Noda Je, Liz Thompson, Trent Fowler, Bella Johnson, Galina Petrikova, Thomas Hambridge, Angela Hutchins, Diego Bottero, Deborah Scanlon, Jo Stokes-Denson, Emmanuelle Génin, Dominique Campion, Jean-Franois Dartigues, Jean-Franois Deleuze, Jean-Charles Lambert, Richard Redon, Thomas Ludwig, Benjamin Grenier-Boley, Sébastien Letort, Pierre Lindenbaum, Vincent Meyer, Olivier Quenez, Christian Dina, Céline Bellenguez, Camille Charbonnier -Le Clézio, Joanna Giemza, Stéphanie Chatel, Claude Férec, Hervé Le Marec, Luc Letenneur, Gal Nicolas
Issue&Volume: 2023-01-20
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 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.
DOI: abj4784
Source: https://www.science.org/doi/10.1126/science.abj4784