{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T00:29:28Z","timestamp":1791160168623,"version":"4.1.0"},"reference-count":26,"publisher":"National Academy of Sciences","issue":"22","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2001,10,23]]},"abstract":"<jats:p>\n                    Although mechanisms for chromosomal instability in tumors have been described in animal and\n                    <jats:italic>in vitro<\/jats:italic>\n                    models, little is known about these processes in man. To explore cytogenetic evolution in human tumors, chromosomal breakpoint profiles were constructed for 102 pancreatic carcinomas and 140 osteosarcomas, two tumor types characterized by extensive genomic instability. Cases with few chromosomal alterations showed a preferential clustering of breakpoints to the terminal bands, whereas tumors with many changes showed primarily interstitial and centromeric breakpoints. The terminal breakpoint frequency was negatively correlated to telomeric TTAGGG repeat length, and fluorescence\n                    <jats:italic>in situ<\/jats:italic>\n                    hybridization with telomeric TTAGGG probes consistently indicated shortened telomeres and &gt;10% of chromosome ends lacking telomeric signals. Because telomeric dysfunction may lead to formation of unstable ring and dicentric chromosomes, mitotic figures were also evaluated. Anaphase bridges were found in all cases, and fluorescence\n                    <jats:italic>in situ<\/jats:italic>\n                    hybridization demonstrated extensive structural rearrangements of chromosomes, with terminal transferase detection showing fragmented DNA in 5\u201320% of interphase cells. Less than 2% of cells showed evidence of necrosis or apoptosis, and telomerase was expressed in the majority of cases. Telomeric dysfunction may thus trigger chromosomal fragmentation through persistent bridge-breakage events in pancreatic carcinomas and osteosarcomas, leading to a continuous reorganization of the tumor genome. Telomerase expression is not sufficient for completely stabilizing the chromosome complement but may be crucial for preventing complete genomic deterioration and maintaining cellular survival.\n                  <\/jats:p>","DOI":"10.1073\/pnas.211357798","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T10:34:10Z","timestamp":1027679650000},"page":"12683-12688","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":333,"title":["Telomere dysfunction triggers extensive DNA fragmentation and evolution of complex chromosome abnormalities in human malignant tumors"],"prefix":"10.1073","volume":"98","author":[{"given":"David","family":"Gisselsson","sequence":"first","affiliation":[{"name":"Department of Clinical Genetics, University Hospital, SE-221 85 Lund, Sweden; Section of Neuronal Survival, Department of Neurobiology, Lund University, SE-22362 Lund, Sweden; and Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tord","family":"Jonson","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, University Hospital, SE-221 85 Lund, Sweden; Section of Neuronal Survival, Department of Neurobiology, Lund University, SE-22362 Lund, Sweden; and Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u212bsa","family":"Peters\u00e9n","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, University Hospital, SE-221 85 Lund, Sweden; Section of Neuronal Survival, Department of Neurobiology, Lund University, SE-22362 Lund, Sweden; and Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bodil","family":"Str\u00f6mbeck","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, University Hospital, SE-221 85 Lund, Sweden; Section of Neuronal Survival, Department of Neurobiology, Lund University, SE-22362 Lund, Sweden; and Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Dal Cin","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, University Hospital, SE-221 85 Lund, Sweden; Section of Neuronal Survival, Department of Neurobiology, Lund University, SE-22362 Lund, Sweden; and Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mattias","family":"H\u00f6glund","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, University Hospital, SE-221 85 Lund, Sweden; Section of Neuronal Survival, Department of Neurobiology, Lund University, SE-22362 Lund, Sweden; and Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix","family":"Mitelman","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, University Hospital, SE-221 85 Lund, Sweden; Section of Neuronal Survival, Department of Neurobiology, Lund University, SE-22362 Lund, Sweden; and Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fredrik","family":"Mertens","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, University Hospital, SE-221 85 Lund, Sweden; 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