{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T12:20:39Z","timestamp":1773922839298,"version":"3.50.1"},"reference-count":52,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2004,1,9]],"date-time":"2004-01-09T00:00:00Z","timestamp":1073606400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Intl Journal of Cancer"],"published-print":{"date-parts":[[2004,4,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Ras signaling is important for the intracellular transduction of mitogenic stimuli from activated growth factor receptors. We have investigated 37 sporadic malignant melanomas (15 primary cutaneous melanomas and 22 melanoma metastases) and 6 melanoma cell lines for mutations in the 3 Ras genes <jats:italic>NRAS<\/jats:italic>, <jats:italic>KRAS<\/jats:italic> and <jats:italic>HRAS<\/jats:italic>. All tumors and cell lines were additionally analyzed for mutation and expression of <jats:italic>BRAF<\/jats:italic>, which encodes a Ras\u2010regulated serine\/threonine kinase with oncogenic properties, as well as for expression of <jats:italic>RASSF1A<\/jats:italic>, which encodes a Ras\u2010binding protein with tumor suppressor properties. Mutational analyses identified somatic <jats:italic>NRAS<\/jats:italic> mutations in 2 primary melanomas, 4 melanoma metastases and 2 cell lines. One melanoma metastasis showed a somatic <jats:italic>KRAS<\/jats:italic> mutation whereas <jats:italic>HRAS<\/jats:italic> mutations were not detected. Eight primary melanomas, 6 melanoma metastases and 4 melanoma cell lines carried <jats:italic>BRAF<\/jats:italic> mutations affecting the known hot\u2010spot codon 599. None of the tumors or cell lines with <jats:italic>BRAF<\/jats:italic> mutation demonstrated <jats:italic>NRAS<\/jats:italic> or <jats:italic>KRAS<\/jats:italic> mutations. Real\u2010time reverse transcription\u2010PCR showed that 8 melanomas (3 primary tumors, 5 melanoma metastases) had reduced <jats:italic>RASSF1A<\/jats:italic> transcript levels of \u226450% relative to benign melanocytic nevi and normal skin. Three melanoma cell lines lacked detectable <jats:italic>RASSF1A<\/jats:italic> transcripts. The <jats:italic>RASSF1A<\/jats:italic> gene promoter was hypermethylated in these 3 cell lines as well as in 6 of 8 melanomas with reduced <jats:italic>RASSF1A<\/jats:italic> mRNA levels. Treatment of the cell lines with 5\u2010aza\u20102\u2032\u2010deoxycytidine and trichostatin A resulted in demethylation of the <jats:italic>RASSF1A<\/jats:italic> promoter and re\u2010expression of <jats:italic>RASSF1A<\/jats:italic> transcripts. Most tumors and all cell lines with <jats:italic>RASSF1A<\/jats:italic> promoter methylation additionally carried <jats:italic>BRAF<\/jats:italic> or <jats:italic>NRAS<\/jats:italic> mutations, suggesting a synergistic effect of these aberrations on melanoma growth. Taken together, 57% of the investigated melanomas and 100% of the melanoma cell lines carried mutations in either <jats:italic>NRAS<\/jats:italic>, <jats:italic>KRAS<\/jats:italic> or <jats:italic>BRAF<\/jats:italic>. In addition, 22% of the melanomas and 50% of the cell lines showed reduced <jats:italic>RASSF1A<\/jats:italic> transcript levels. Thus, alterations of Ras pathway genes are of paramount importance in the pathogenesis of sporadic melanomas. \u00a9 2004 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/ijc.11722","type":"journal-article","created":{"date-parts":[[2004,2,9]],"date-time":"2004-02-09T18:27:44Z","timestamp":1076351264000},"page":"377-384","source":"Crossref","is-referenced-by-count":109,"title":["Frequent alterations of Ras signaling pathway genes in sporadic malignant melanomas"],"prefix":"10.1002","volume":"109","author":[{"given":"Julia","family":"Reifenberger","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christiane B.","family":"Knobbe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Astrid A.","family":"Sterzinger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Britta","family":"Blaschke","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Klaus W.","family":"Schulte","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Ruzicka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guido","family":"Reifenberger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2004,1,9]]},"reference":[{"key":"e_1_2_5_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0190-9622(96)90041-9"},{"key":"e_1_2_5_3_2","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/93.9.678"},{"key":"e_1_2_5_4_2","volume-title":"SEER Cancer Statistics Review, 1973\u20131999.","author":"Ries LAG","year":"2002"},{"key":"e_1_2_5_5_2","first-page":"667","article-title":"The genetics of cutaneous melanoma","volume":"20","author":"Pollock PM","year":"2000","journal-title":"Clin Lab Med"},{"key":"e_1_2_5_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0923-1811(01)00085-8"},{"key":"e_1_2_5_7_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1523-1747.2002.00217.x"},{"key":"e_1_2_5_8_2","doi-asserted-by":"publisher","DOI":"10.1111\/1523-1747.ep12371783"},{"key":"e_1_2_5_9_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.0022-202x.2001.01601.x"},{"key":"e_1_2_5_10_2","first-page":"3468","article-title":"Screening of N\u2010ras codon 61 mutations in paired primary and metastatic cutaneous melanomas: mutations occur early and persist throughout tumor progression","volume":"8","author":"Omholt K","year":"2002","journal-title":"Clin Cancer Res"},{"key":"e_1_2_5_11_2","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/95.11.790"},{"key":"e_1_2_5_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature00766"},{"key":"e_1_2_5_13_2","first-page":"6997","article-title":"BRAF and RAS mutations in human lung cancer and melanoma","volume":"62","author":"Brose MS","year":"2002","journal-title":"Cancer Res"},{"key":"e_1_2_5_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1054"},{"key":"e_1_2_5_15_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.10109"},{"key":"e_1_2_5_16_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1020602"},{"key":"e_1_2_5_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1097"},{"key":"e_1_2_5_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/77083"},{"key":"e_1_2_5_19_2","first-page":"6116","article-title":"The 630\u2010kb lung cancer homozygous deletion region on human chromosome 3p21.3: identification and evaluation of the resident candidate tumor suppressor genes. 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