Journal ArticleDOI
Inactivation of the Type II TGF-β Receptor in Colon Cancer Cells with Microsatellite Instability
Sanford D. Markowitz,Jing Wang,Lois Myeroff,Ramon Parsons,Lu Zhe Sun,James Lutterbaugh,Robert S. Fan,Elizabeth Zborowska,Kenneth W. Kinzler,Bert Vogelstein,Bert Vogelstein,Michael G. Brattain,James K V Willson +12 more
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TLDR
Human colon cancer cell lines with high rates of microsatellite instability were found to harbor mutations in the type II TGF-beta receptor (RII) gene, which links DNA repair defects with a specific pathway of tumor progression.Abstract:
Transforming growth factor-beta (TGF-beta) is a potent inhibitor of epithelial cell growth. Human colon cancer cell lines with high rates of microsatellite instability were found to harbor mutations in the type II TGF-beta receptor (RII) gene. Eight such examples, due to three different mutations, were identified. The mutations were clustered within small repeated sequences in the RII gene, were accompanied by the absence of cell surface RII receptors, and were usually associated with small amounts of RII transcript. RII mutation, by inducing the escape of cells from TGF-beta-mediated growth control, links DNA repair defects with a specific pathway of tumor progression.read more
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The hallmarks of cancer.
TL;DR: This work has been supported by the Department of the Army and the National Institutes of Health, and the author acknowledges the support and encouragement of the National Cancer Institute.
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TGF-beta signal transduction.
TL;DR: The transforming growth factor beta (TGF-beta) family of growth factors control the development and homeostasis of most tissues in metazoan organisms and mutations in these pathways are the cause of various forms of human cancer and developmental disorders.
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PD-1 Blockade in Tumors with Mismatch-Repair Deficiency
Dung T. Le,Jennifer N. Uram,Hao Wang,Bjarne Bartlett,Holly Kemberling,Aleksandra Eyring,Andrew D. Skora,Brandon Luber,Nilofer S. Azad,Daniel A. Laheru,Barbara A. Biedrzycki,Ross C. Donehower,Atif Zaheer,George A. Fisher,Todd S. Crocenzi,James J. Lee,Steven M. Duffy,Richard M. Goldberg,Richard M. Goldberg,Albert de la Chapelle,Albert de la Chapelle,Minori Koshiji,Feriyl Bhaijee,Thomas Huebner,Ralph H. Hruban,Laura D. Wood,Nathan Cuka,Drew M. Pardoll,Nickolas Papadopoulos,Kenneth W. Kinzler,Shibin Zhou,Toby C. Cornish,Janis M. Taube,Robert A. Anders,James R. Eshleman,Bert Vogelstein,Luis A. Diaz +36 more
TL;DR: This study showed that mismatch-repair status predicted clinical benefit of immune checkpoint blockade with pembrolizumab, and high somatic mutation loads were associated with prolonged progression-free survival.
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Lessons from Hereditary Colorectal Cancer
TL;DR: The authors are grateful to the members of their laboratories for their contributions to the reviewed studies and to F. Giardiello and S. Hamilton for photographs of colorectal lesions.
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Genetic instabilities in human cancers
TL;DR: There is now evidence that most cancers may indeed be genetically unstable, but that the instability exists at two distinct levels, and recognition and comparison of these instabilities are leading to new insights into tumour pathogenesis.
References
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Journal ArticleDOI
Microsatellite instability in cancer of the proximal colon
TL;DR: Colorectal tumor DNA was examined for somatic instability at (CA)n repeats on human chromosomes 5q, 15q, 17p, and 18q, and this instability was significantly correlated with the tumor's location in the proximal colon and with increased patient survival and loss of heterozygosity.
Journal ArticleDOI
The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer.
Richard Fishel,Mary Kay Lescoe,M.R.S. Rao,Neal G. Copeland,Nancy A. Jenkins,Judy Garber,Michael F. Kane,Richard D. Kolodner +7 more
TL;DR: Data and reports indicating that S. cerevisiae msh2 mutations cause an instability of dinucleotide repeats like those associated with H NPCC suggest that hMSH2 is the HNPCC gene.
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Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis
TL;DR: It is shown that 12 per cent of colorectal carcinomas carry somatic deletions in poly(dA . dT) sequences and other simple repeats, and it is concluded that these mutations reflect a previously undescribed form of carcinogenesis in the colon mediated by a mutation in a DNA replication factor resulting in reduced fidelity for replication or repair (a 'mutator mutation').
Journal ArticleDOI
Clues to the pathogenesis of familial colorectal cancer
Lauri A. Aaltonen,Päivi Peltomäki,Fredrick S. Leach,Pertti Sistonen,Lea Pylkkänen,Jukka-Pekka Mecklin,Heikki Järvinen,Steven M. Powell,Jin Jen,Stanley R. Hamilton,Gloria M. Petersen,Kenneth W. Kinzler,Bert Vogelstein,Albert de la Chapelle +13 more
TL;DR: Molecular features of "familial" cancers were compared with those of sporadic colon cancers, and a mechanism for familial tumorigenesis different from that mediated by classic tumor suppressor genes is suggested.