{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T08:40:21Z","timestamp":1790930421574,"version":"4.1.0"},"reference-count":33,"publisher":"National Academy of Sciences","issue":"17","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2001,8,14]]},"abstract":"<jats:p>\n                    Loss of chromosome 18q21 is well documented in colorectal cancer,\n and it has been suggested that this loss targets the\n                    <jats:italic>DCC<\/jats:italic>\n                    ,\n                    <jats:italic>DPC4<\/jats:italic>\n                    \/\n                    <jats:italic>SMAD4<\/jats:italic>\n                    , and\n                    <jats:italic>SMAD2<\/jats:italic>\n                    genes. Recently, the importance of\n                    <jats:italic>SMAD4<\/jats:italic>\n                    , a downstream regulator in the TGF-\u03b2 signaling\n pathway, in colorectal cancer has been highlighted, although the\n frequency of\n                    <jats:italic>SMAD4<\/jats:italic>\n                    mutations appears much lower than\n that of 18q21 loss. We set out to investigate allele loss, mutations,\n protein expression, and cytogenetics of chromosome 18 copy number in a\n collection of 44 colorectal cancer cell lines of known status with\n respect to microsatellite instability (MSI). Fourteen of thirty-two\n MSI\n                    <jats:sup>\u2212<\/jats:sup>\n                    lines showed loss of SMAD4 protein expression;\n usually, one allele was lost and the other was mutated in one of a\n number of ways, including deletions of various sizes, splice site\n changes, and missense and nonsense point mutations (although no\n frameshifts). Of the 18 MSI\n                    <jats:sup>\u2212<\/jats:sup>\n                    cancers with retained SMAD4\n expression, four harbored missense mutations in the 3\u2032 part of the gene\n and showed allele loss. The remaining 14 MSI\n                    <jats:sup>\u2212<\/jats:sup>\n                    lines had no\n detectable\n                    <jats:italic>SMAD4<\/jats:italic>\n                    mutation, but all showed allele loss at\n                    <jats:italic>SMAD4<\/jats:italic>\n                    and\/or\n                    <jats:italic>DCC<\/jats:italic>\n                    .\n                    <jats:italic>SMAD4<\/jats:italic>\n                    mutations can therefore account for about 50\u201360% of the 18q21 allele\n loss in colorectal cancer. No MSI\n                    <jats:sup>+<\/jats:sup>\n                    cancer showed loss of\n SMAD4 protein or\n                    <jats:italic>SMAD4<\/jats:italic>\n                    mutation, and very few had\n allelic loss at\n                    <jats:italic>SMAD4<\/jats:italic>\n                    or\n                    <jats:italic>DCC<\/jats:italic>\n                    , although\n many of these MSI\n                    <jats:sup>+<\/jats:sup>\n                    lines did carry\n                    <jats:italic>TGFBIIR<\/jats:italic>\n                    changes. Although\n                    <jats:italic>SMAD4<\/jats:italic>\n                    mutations have been associated\n with late-stage or metastatic disease, our combined molecular and\n cytogenetic data best fit a model in which\n                    <jats:italic>SMAD4<\/jats:italic>\n                    mutations occur before colorectal cancers become aneuploid\/polyploid,\n but after the MSI\n                    <jats:sup>+<\/jats:sup>\n                    and MSI\n                    <jats:sup>\u2212<\/jats:sup>\n                    pathways diverge.\n Thus, MSI\n                    <jats:sup>+<\/jats:sup>\n                    cancers may diverge first, followed by\n CIN\n                    <jats:sup>+<\/jats:sup>\n                    (chromosomal instability) cancers, leaving other\n cancers to follow a CIN\n                    <jats:sup>\u2212<\/jats:sup>\n                    MSI\n                    <jats:sup>\u2212<\/jats:sup>\n                    pathway.\n                  <\/jats:p>","DOI":"10.1073\/pnas.171321498","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T10:34:10Z","timestamp":1027679650000},"page":"9719-9723","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":156,"title":["SMAD4 mutations in colorectal cancer probably occur before chromosomal instability, but after divergence of the microsatellite instability pathway"],"prefix":"10.1073","volume":"98","author":[{"given":"K. L.","family":"Woodford-Richens","sequence":"first","affiliation":[{"name":"Molecular and Population Genetics Laboratory, Imperial Cancer\r Research Fund, London WC2A 3PX, United Kingdom; Cancer\r and Immunogenetics Laboratory, Imperial Cancer Research Fund, Institute\r of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DZ, United\r Kingdom; and Department of Oncology, Hammersmith\r Hospital, Du Cane Road, London W12 0HS, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. J.","family":"Rowan","sequence":"additional","affiliation":[{"name":"Molecular and Population Genetics Laboratory, Imperial Cancer\r Research Fund, London WC2A 3PX, United Kingdom; Cancer\r and Immunogenetics Laboratory, Imperial Cancer Research Fund, Institute\r of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DZ, United\r Kingdom; and Department of Oncology, Hammersmith\r Hospital, Du Cane Road, London W12 0HS, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P.","family":"Gorman","sequence":"additional","affiliation":[{"name":"Molecular and Population Genetics Laboratory, Imperial Cancer\r Research Fund, London WC2A 3PX, United Kingdom; Cancer\r and Immunogenetics Laboratory, Imperial Cancer Research Fund, Institute\r of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DZ, United\r Kingdom; and Department of Oncology, Hammersmith\r Hospital, Du Cane Road, London W12 0HS, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.","family":"Halford","sequence":"additional","affiliation":[{"name":"Molecular and Population Genetics Laboratory, Imperial Cancer\r Research Fund, London WC2A 3PX, United Kingdom; Cancer\r and Immunogenetics Laboratory, Imperial Cancer Research Fund, Institute\r of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DZ, United\r Kingdom; and Department of Oncology, Hammersmith\r Hospital, Du Cane Road, London W12 0HS, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. C.","family":"Bicknell","sequence":"additional","affiliation":[{"name":"Molecular and Population Genetics Laboratory, Imperial Cancer\r Research Fund, London WC2A 3PX, United Kingdom; Cancer\r and Immunogenetics Laboratory, Imperial Cancer Research Fund, Institute\r of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DZ, United\r Kingdom; and Department of Oncology, Hammersmith\r Hospital, Du Cane Road, London W12 0HS, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H. S.","family":"Wasan","sequence":"additional","affiliation":[{"name":"Molecular and Population Genetics Laboratory, Imperial Cancer\r Research Fund, London WC2A 3PX, United Kingdom; Cancer\r and Immunogenetics Laboratory, Imperial Cancer Research Fund, Institute\r of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DZ, United\r Kingdom; and Department of Oncology, Hammersmith\r Hospital, Du Cane Road, London W12 0HS, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. R.","family":"Roylance","sequence":"additional","affiliation":[{"name":"Molecular and Population Genetics Laboratory, Imperial Cancer\r Research Fund, London WC2A 3PX, United Kingdom; Cancer\r and Immunogenetics Laboratory, Imperial Cancer Research Fund, Institute\r of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DZ, United\r Kingdom; and Department of Oncology, Hammersmith\r Hospital, Du Cane Road, London W12 0HS, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W. F.","family":"Bodmer","sequence":"additional","affiliation":[{"name":"Molecular and Population Genetics Laboratory, Imperial Cancer\r Research Fund, London WC2A 3PX, United Kingdom; Cancer\r and Immunogenetics Laboratory, Imperial Cancer Research Fund, Institute\r of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DZ, United\r Kingdom; and Department of Oncology, Hammersmith\r Hospital, Du Cane Road, London W12 0HS, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I. P. M.","family":"Tomlinson","sequence":"additional","affiliation":[{"name":"Molecular and Population Genetics Laboratory, Imperial Cancer\r Research Fund, London WC2A 3PX, United Kingdom; Cancer\r and Immunogenetics Laboratory, Imperial Cancer Research Fund, Institute\r of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DZ, United\r Kingdom; and Department of Oncology, Hammersmith\r Hospital, Du Cane Road, London W12 0HS, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2001,7,31]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng0796-343"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(90)90186-I"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1002\/1097-0142(19920901)70:3 <1216::AID-CNCR2820701505>3.0.CO;2-F"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng0796-347"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1053\/gast.1996.v111.pm8898652"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1202642"},{"key":"e_1_3_3_7_2","first-page":"490","volume":"56","author":"Hahn S A","year":"1996","unstructured":"S A Hahn, A T Hoque, C A Moskaluk, L T da Costa, M Schutte, E Rozenblum, A B Seymour, C L Weinstein, C J Yeo, R H Hruban, S E Kern Cancer Res 56, 490\u2013494 (1996).","journal-title":"Cancer Res"},{"key":"e_1_3_3_8_2","first-page":"71","volume":"406","author":"Koyama M","year":"1999","unstructured":"M Koyama, M Ito, H Nagai, M Emi, Y Moriyama Mutat Res 406, 71\u201377 (1999).","journal-title":"Mutat Res"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)64625-1"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.280.5366.1086"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/7.12.1907"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/19.19.5178"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M002815200"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.275.15.11320"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/92.17.1388"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1203798"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.97.7.3352"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)64703-7"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1359641"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1136\/mp.52.5.243"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.041603298"},{"key":"e_1_3_3_22_2","first-page":"2477","volume":"60","author":"Woodford-Richens K","year":"2000","unstructured":"K Woodford-Richens, J Williamson, S Bevan, J Young, B Leggett, I Frayling, Y Thway, S Hodgson, J C Kim, T Iwama, et al. 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