{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T13:44:03Z","timestamp":1790948643309,"version":"4.1.0"},"reference-count":43,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2019,4,1]],"date-time":"2019-04-01T00:00:00Z","timestamp":1554076800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP18K08612"],"award-info":[{"award-number":["JP18K08612"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Histopathology"],"published-print":{"date-parts":[[2019,5]]},"abstract":"Aims<\/jats:title>SMAD<\/jats:styled-content>4 acts as a tumour suppressor, and the loss of SMAD<\/jats:styled-content>4 is associated with poor prognosis in colorectal cancer (CRC<\/jats:styled-content>) patients. Although next\u2010generation sequencing (NGS<\/jats:styled-content>) enabled us to detect numerous genetic alterations in a single assay, the clinical significance of SMAD<\/jats:styled-content>4<\/jats:italic> alteration detected with NGS<\/jats:styled-content> has not been fully investigated. The aim of this study was to evaluate the clinicopathological characteristics and clinical significance of SMAD<\/jats:styled-content>4<\/jats:italic> alteration detected with NGS<\/jats:styled-content> in CRC<\/jats:styled-content>.<\/jats:p><\/jats:sec>Methods and results<\/jats:title>We retrospectively investigated 201 patients with stage I\u2013IV CRC<\/jats:styled-content>, by using a 415\u2010gene panel. To analyse the relationship between SMAD<\/jats:styled-content>4<\/jats:italic> alteration and other clinicopathological characteristics, we evaluated clinicopathological variables, including invasive\u2010front pathological markers: tumour budding, poorly differentiated cluster, and Crohn\u2010like lymphoid reaction. Fifty\u2010six patients (28%) had SMAD<\/jats:styled-content>4<\/jats:italic> alteration: 24 and 32 patients had SMAD<\/jats:styled-content>4<\/jats:italic> mutation and deletion, respectively. SMAD<\/jats:styled-content>4<\/jats:italic> alteration was significantly associated with T category (P<\/jats:italic>\u00a0=\u00a00.027), N category (P<\/jats:italic>\u00a0=\u00a00.037), M category (P<\/jats:italic>\u00a0=\u00a00.028), and invasive\u2010front pathological markers, such as poorly differentiated cluster grade 3 (P<\/jats:italic>\u00a0=\u00a00.020) and absence of Crohn\u2010like lymphoid reaction (P<\/jats:italic>\u00a0=\u00a00.004). Immunohistochemistry revealed that SMAD<\/jats:styled-content>4<\/jats:italic> alteration was significantly associated with loss of SMAD<\/jats:styled-content>4 (P<\/jats:italic>\u00a0=\u00a00.023). In 90 patients with stage I\u2013III<\/jats:styled-content> disease, SMAD<\/jats:styled-content>4<\/jats:italic> alteration was significantly associated with poor prognosis for relapse\u2010free and overall survival (P<\/jats:italic>\u00a0=\u00a00.047; P<\/jats:italic>\u00a0=\u00a00.022, respectively). Conversely, in 111 patients with stage IV<\/jats:styled-content> disease, SMAD<\/jats:styled-content>4<\/jats:italic> alteration was not significantly associated with overall survival.<\/jats:p><\/jats:sec>Conclusion<\/jats:title>SMAD<\/jats:styled-content>4<\/jats:italic> alteration is associated with invasive\u2010front pathological markers and poor prognosis in stage I\u2013III CRC<\/jats:styled-content> patients.<\/jats:p><\/jats:sec>","DOI":"10.1111\/his.13805","type":"journal-article","created":{"date-parts":[[2019,1,12]],"date-time":"2019-01-12T12:59:38Z","timestamp":1547297978000},"page":"873-882","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":45,"title":["SMAD<\/scp>4<\/i> alteration associates with invasive\u2010front pathological markers and poor prognosis in colorectal cancer"],"prefix":"10.1111","volume":"74","author":[{"given":"Hidehito","family":"Oyanagi","sequence":"first","affiliation":[{"name":"Division of 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