Heritable defects in telomere and mitotic function selectively predispose to sarcomas

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dc.contributor.authorBallinger, M.L.
dc.contributor.authorPattnaik, S.
dc.contributor.authorMundra, P.A.
dc.contributor.authorZaheed, M.
dc.contributor.authorRath, E.
dc.contributor.authorPriestley, P.
dc.contributor.authorBaber, J.
dc.contributor.authorRay-Coquard, I.
dc.contributor.authorIsambert, N.
dc.contributor.authorCauseret, S.
dc.contributor.authorvan der Graaf, W.T.A.
dc.contributor.authorPuri, A.
dc.contributor.authorDuffaud, F.
dc.contributor.authorLe Cesne, A.
dc.contributor.authorSeddon, B.
dc.contributor.authorChandrasekar, C.
dc.contributor.authorSchiffman, J.D.
dc.contributor.authorBrohl, A.S.
dc.contributor.authorJames, P.A.
dc.contributor.authorKurtz, J.-E.
dc.contributor.authoret al.
dc.date.issued2023
dc.description.abstractCancer 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.
dc.description.statementofresponsibilityMandy L. Ballinger ... Shyamsundar Ravishankar ... the International Sarcoma Kindred Study ... et al.
dc.identifier.citationScience, 2023; 379(6629):253-260
dc.identifier.doi10.1126/science.abj4784
dc.identifier.issn0036-8075
dc.identifier.issn1095-9203
dc.identifier.orcidRavishankar, S. [0000-0003-3006-6134]
dc.identifier.urihttps://hdl.handle.net/2440/138044
dc.language.isoen
dc.publisherAmerican Association for the Advancement of Science (AAAS)
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1004017
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1081477
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1104364
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1139071
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1121474
dc.rights© 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works
dc.source.urihttps://doi.org/10.1126/science.abj4784
dc.subjectFrench Exome Project Consortium
dc.subjectInternational Sarcoma Kindred Study
dc.subjectGerm Cells
dc.subjectTelomere
dc.subjectHumans
dc.subjectSarcoma
dc.subjectMelanoma
dc.subjectGenetic Predisposition to Disease
dc.subjectMitosis
dc.subjectGerm-Line Mutation
dc.subjectGenetic Variation
dc.subjectShelterin Complex
dc.subject.meshGerm Cells
dc.subject.meshTelomere
dc.subject.meshHumans
dc.subject.meshSarcoma
dc.subject.meshMelanoma
dc.subject.meshGenetic Predisposition to Disease
dc.subject.meshMitosis
dc.subject.meshGerm-Line Mutation
dc.subject.meshGenetic Variation
dc.subject.meshShelterin Complex
dc.titleHeritable defects in telomere and mitotic function selectively predispose to sarcomas
dc.typeJournal article
pubs.publication-statusPublished

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