Kazuhiro Toriyama, Katsuhiro Masago, Noriko Shibata, Masataka Haneda, Takamichi Kuwahara, Seiji Natsume, Shota Kobayashi, Yasuko Fujita, Eiichi Sasaki, Kenji Yamao, Hiroki Kawashima, Yasuhiro Shimizu, Kazuo Hara, Yasushi Yatabe, Waki Hosoda
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{"title":"KRAS野生型胰腺导管腺癌的临床病理和分子特征揭示了RAS通路基因的致癌突变和融合的前驱病变。","authors":"Kazuhiro Toriyama, Katsuhiro Masago, Noriko Shibata, Masataka Haneda, Takamichi Kuwahara, Seiji Natsume, Shota Kobayashi, Yasuko Fujita, Eiichi Sasaki, Kenji Yamao, Hiroki Kawashima, Yasuhiro Shimizu, Kazuo Hara, Yasushi Yatabe, Waki Hosoda","doi":"10.1002/path.6432","DOIUrl":null,"url":null,"abstract":"<p>Pancreatic ductal adenocarcinomas (PDACs) with wild-type <i>KRAS</i> constitute a small fraction of PDACs, and these tumors were recently shown to harbor frequent actionable oncogenic mutations and fusions. However, the clinicopathological features of <i>KRAS</i> wild-type PDAC have not been well studied. Additionally, precancerous lesions occurring in patients with <i>KRAS</i> wild-type PDACs have rarely been characterized. Here, we investigated the clinicopathological characteristics and outcomes of 75 patients with <i>KRAS</i> wild-type PDAC. Molecular analyses were performed in 40 patients using targeted DNA and whole-exome sequencing and targeted RNA sequencing. We demonstrated that patients with metastatic PDAC with wild-type <i>KRAS</i> were younger (median 59.5 years) than those with mutated <i>KRAS</i> (median 67 years, <i>p</i> < 0.000055). The wild-type <i>KRAS</i> status was not a significant prognostic factor for metastatic disease. Molecularly, genes in the RAS pathway are frequently mutated or rearranged (46%, 16/35), including mutations in <i>BRAF</i>, <i>NRAS</i>, <i>HRAS</i>, <i>EGFR</i>, <i>MAP2K1</i>, <i>FGFR1</i>, <i>FGFR3</i> and <i>ERBB4</i> and fusions of <i>FGFR2</i> (<i>FGFR2</i>::<i>CCDC147</i>, <i>FGFR2</i>::<i>CAT</i>, <i>FGFR2</i>::<i>TXLNA</i>), <i>ALK</i> (<i>STRN</i>::<i>ALK</i>, <i>EML4</i>::<i>ALK</i>), and <i>BRAF</i> (<i>TRIP11</i>::<i>BRAF</i>). Mismatch repair deficiency was identified in 10% (4/39) of patients. Potentially actionable alterations were identified frequently in <i>KRAS</i> wild-type PDACs (30%, 12/40), in which nontubular-type carcinomas were significantly enriched with actionable alterations compared with tubular adenocarcinomas [67% (6/9) versus 16% (5/31); <i>p</i> = 0.007]. Finally, we investigated the precursors of PDACs in 13 pancreatectomy specimens from patients with <i>KRAS</i> wild-type PDAC. We identified three pancreatic intraepithelial neoplasias (PanINs) and two intraductal papillary mucinous neoplasms (IPMNs) harboring oncogenic fusions of <i>ALK</i> and <i>BRAF</i> and driver mutations in <i>BRAF</i> and <i>AKT1</i>. This study suggests that in the context of unmutated <i>KRAS</i>, PDAC is driven by alternative oncogenic mutations or fusions of RAS pathway genes, which may be introduced during the early phase of tumorigenesis. © 2025 The Author(s). <i>The Journal of Pathology</i> published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"266 3","pages":"337-351"},"PeriodicalIF":5.2000,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6432","citationCount":"0","resultStr":"{\"title\":\"Clinicopathological and molecular characterization of KRAS wild-type pancreatic ductal adenocarcinomas reveals precursor lesions with oncogenic mutations and fusions in RAS pathway genes\",\"authors\":\"Kazuhiro Toriyama, Katsuhiro Masago, Noriko Shibata, Masataka Haneda, Takamichi Kuwahara, Seiji Natsume, Shota Kobayashi, Yasuko Fujita, Eiichi Sasaki, Kenji Yamao, Hiroki Kawashima, Yasuhiro Shimizu, Kazuo Hara, Yasushi Yatabe, Waki Hosoda\",\"doi\":\"10.1002/path.6432\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>Pancreatic ductal adenocarcinomas (PDACs) with wild-type <i>KRAS</i> constitute a small fraction of PDACs, and these tumors were recently shown to harbor frequent actionable oncogenic mutations and fusions. However, the clinicopathological features of <i>KRAS</i> wild-type PDAC have not been well studied. Additionally, precancerous lesions occurring in patients with <i>KRAS</i> wild-type PDACs have rarely been characterized. Here, we investigated the clinicopathological characteristics and outcomes of 75 patients with <i>KRAS</i> wild-type PDAC. Molecular analyses were performed in 40 patients using targeted DNA and whole-exome sequencing and targeted RNA sequencing. We demonstrated that patients with metastatic PDAC with wild-type <i>KRAS</i> were younger (median 59.5 years) than those with mutated <i>KRAS</i> (median 67 years, <i>p</i> < 0.000055). The wild-type <i>KRAS</i> status was not a significant prognostic factor for metastatic disease. Molecularly, genes in the RAS pathway are frequently mutated or rearranged (46%, 16/35), including mutations in <i>BRAF</i>, <i>NRAS</i>, <i>HRAS</i>, <i>EGFR</i>, <i>MAP2K1</i>, <i>FGFR1</i>, <i>FGFR3</i> and <i>ERBB4</i> and fusions of <i>FGFR2</i> (<i>FGFR2</i>::<i>CCDC147</i>, <i>FGFR2</i>::<i>CAT</i>, <i>FGFR2</i>::<i>TXLNA</i>), <i>ALK</i> (<i>STRN</i>::<i>ALK</i>, <i>EML4</i>::<i>ALK</i>), and <i>BRAF</i> (<i>TRIP11</i>::<i>BRAF</i>). Mismatch repair deficiency was identified in 10% (4/39) of patients. Potentially actionable alterations were identified frequently in <i>KRAS</i> wild-type PDACs (30%, 12/40), in which nontubular-type carcinomas were significantly enriched with actionable alterations compared with tubular adenocarcinomas [67% (6/9) versus 16% (5/31); <i>p</i> = 0.007]. Finally, we investigated the precursors of PDACs in 13 pancreatectomy specimens from patients with <i>KRAS</i> wild-type PDAC. We identified three pancreatic intraepithelial neoplasias (PanINs) and two intraductal papillary mucinous neoplasms (IPMNs) harboring oncogenic fusions of <i>ALK</i> and <i>BRAF</i> and driver mutations in <i>BRAF</i> and <i>AKT1</i>. This study suggests that in the context of unmutated <i>KRAS</i>, PDAC is driven by alternative oncogenic mutations or fusions of RAS pathway genes, which may be introduced during the early phase of tumorigenesis. © 2025 The Author(s). <i>The Journal of Pathology</i> published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>\",\"PeriodicalId\":232,\"journal\":{\"name\":\"The Journal of Pathology\",\"volume\":\"266 3\",\"pages\":\"337-351\"},\"PeriodicalIF\":5.2000,\"publicationDate\":\"2025-05-02\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6432\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"The Journal of Pathology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1002/path.6432\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"The Journal of Pathology","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/path.6432","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
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