{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T22:13:48Z","timestamp":1773699228225,"version":"3.50.1"},"reference-count":60,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2005,9,29]],"date-time":"2005-09-29T00:00:00Z","timestamp":1127952000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancer"],"published-print":{"date-parts":[[2005,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>BACKGROUND<\/jats:title><jats:p>Evidence of genetic heterogeneity within urothelial carcinomas of the bladder has raised questions about the clonal origin of urothelial carcinoma and its metastases. High\u2010grade urothelial carcinoma of the bladder frequently metastasizes to multiple regional lymph nodes in the pelvis. Whether or not these multiple lymph node metastases originate from the same tumor clone is uncertain. Molecular analysis of microsatellite alterations and X\u2010chromosome inactivation status of distinct tumor cell populations from the same patient may further our understanding of the genetic basis of carcinoma progression and metastasis.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p>The authors examined 24 patients who underwent radical cystectomy for urothelial carcinoma. All patients had multiple (from two to four) lymph node metastases. Genomic DNA samples were prepared from formalin fixed, paraffin embedded tissue sections using laser\u2010assisted microdissection. Loss of heterozygosity (LOH) assays for 3 microsatellite polymorphic markers on chromosome 9p21 (D9S171, region of putative tumor suppressor gene <jats:italic>p16<\/jats:italic>), 9q32 (D9S177, putative tumor suppressor gene involved in urothelial carcinoma tumorigenesis), and 17p13 (TP53, the <jats:italic>p53<\/jats:italic> locus) were performed. In addition, X\u2010chromosome inactivation analysis was performed in primary tumors and metastases from 10 female patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>In total, 79 tumors were analyzed. The overall frequency of allelic loss was 67% (16 of 24 tumors) in the primary urothelial carcinomas and 79% (19 of 24 tumors) in the metastatic carcinomas. The primary urothelial carcinoma showed LOH at the D9S171, D9S177, and TP53 loci in 39% (9 of 23 tumors), 30% (6 of 20 tumors), and 30% (7 of 23 tumors) of informative samples, respectively. LOH in \u2265 1 lymph node metastases was seen at the D9S171, D9S177, and TP53 loci in 35% (8 of 23 tumors), 45% (9 of 20 tumors), and 48% (11 of 23 tumors) of informative samples, respectively. Eleven tumors demonstrated identical allelic loss patterns at all DNA loci both in the primary carcinoma and in all corresponding lymph node metastases. Three tumors showed allelic loss in the metastatic carcinoma but not in its matched primary carcinoma. Six tumors demonstrated a different LOH pattern in each of its lymph node metastases. Clonality analysis showed the same pattern of nonrandom X\u2010chromosome inactivation both in the primary urothelial carcinoma and in all of the lymph node metastases in five of nine informative tumors studied. Four tumors showed a random pattern of X\u2010chromosome inactivation in both the primary carcinoma and in the metastases.<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSIONS<\/jats:title><jats:p>LOH and X\u2010chromosome inactivation assays showed that multiple lymph node metastases and matched primary urothelial carcinomas of the bladder had the same clonal origin, suggesting that the capability for metastasis often arises in only a single clonal population in the primary tumor. The variable LOH patterns observed in some of the tumors likely reflect genetic divergence during the clonal evolution of urothelial carcinoma. Cancer 2005. \u00a9 2005 American Cancer Society.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cncr.21466","type":"journal-article","created":{"date-parts":[[2005,9,29]],"date-time":"2005-09-29T18:48:55Z","timestamp":1128019735000},"page":"1901-1910","source":"Crossref","is-referenced-by-count":44,"title":["Clonal origin of lymph node metastases in bladder carcinoma"],"prefix":"10.1002","volume":"104","author":[{"given":"Timothy D.","family":"Jones","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew D.","family":"Carr","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John N.","family":"Eble","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mingsheng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonio","family":"Lopez\u2010Beltran","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liang","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2005,9,29]]},"reference":[{"key":"e_1_2_5_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1098"},{"key":"e_1_2_5_3_2","doi-asserted-by":"publisher","DOI":"10.3322\/canjclin.55.1.10"},{"key":"e_1_2_5_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-5347(17)51695-X"},{"key":"e_1_2_5_5_2","doi-asserted-by":"publisher","DOI":"10.1097\/00000478-200110000-00002"},{"key":"e_1_2_5_6_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0142(20000401)88:7<1663::AID-CNCR21>3.0.CO;2-8"},{"key":"e_1_2_5_7_2","volume-title":"World Health Organization classification of tumours: pathology and genetics of tumours of the urinary system and male genital organs","author":"Eble JN","year":"2004"},{"key":"e_1_2_5_8_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4757-3656-4"},{"key":"e_1_2_5_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)63602-4"},{"key":"e_1_2_5_10_2","first-page":"6063","article-title":"Stroma adjacent to metastatic mature teratoma after chemotherapy for testicular germ cell tumors is derived from the same progenitor cells as the teratoma","volume":"63","author":"Brandli DW","year":"2003","journal-title":"Cancer Res."},{"key":"e_1_2_5_11_2","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.20343"},{"key":"e_1_2_5_12_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199203123261104"},{"key":"e_1_2_5_13_2","doi-asserted-by":"publisher","DOI":"10.1002\/1097-0215(20000815)87:4<522::AID-IJC10>3.0.CO;2-X"},{"key":"e_1_2_5_14_2","first-page":"177","article-title":"Pathways of development and progression in bladder cancer: new correlations between clinical observations and molecular mechanisms","volume":"11","author":"Jones PA","year":"1993","journal-title":"Semin Urol."},{"key":"e_1_2_5_15_2","first-page":"784","article-title":"Two molecular pathways to transitional cell carcinoma of the bladder","volume":"54","author":"Spruck CH","year":"1994","journal-title":"Cancer Res."},{"key":"e_1_2_5_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/351453a0"},{"key":"e_1_2_5_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)63397-4"},{"key":"e_1_2_5_18_2","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/90.3.233"},{"key":"e_1_2_5_19_2","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/93.15.1147"},{"key":"e_1_2_5_20_2","article-title":"Molecular genetic evidence for the independent origin of multifocal papillary tumors in patients with papillary renal cell carcinoma","author":"Jones TD","journal-title":"Clin Cancer Res."},{"key":"e_1_2_5_21_2","first-page":"6130","article-title":"Criticial factors in the biology of human cancer metastasis: twenty\u2010eighth G.H.A. 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