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ヒグチ リヨウタ
HIGUCHI Ryota
樋口 亮太 所属 医学部 医学科（附属八千代医療センター） 職種 講師 |
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| 論文種別 | 原著 |
| 言語種別 | 英語 |
| 査読の有無 | 査読なし |
| 表題 | Serine/Threonine Kinase 11 Plays a Canonical Role in Malignant Progression of KRAS -Mutant and GNAS -Wild-Type Intraductal Papillary Mucinous Neoplasms of the Pancreas. |
| 掲載誌名 | 正式名：Annals of surgery 略 称：Ann Surg ISSNコード：15281140/00034932 |
| 掲載区分 | 国外 |
| 巻・号・頁 | 277(2),pp.e384-e395 |
| 著者・共著者 | OMORI Yuko, ONO Yusuke, MORIKAWA Takanori, MOTOI Fuyuhiko, HIGUCHI Ryota, YAMAMOTO Masakazu, HAYAKAWA Yuko, KARASAKI Hidenori, MIZUKAMI Yusuke, UNNO Michiaki, FURUKAWA Toru |
| 発行年月 | 2023/02 |
| 概要 | OBJECTIVE:We aimed to elucidate the clinicopathobiological significance of Serine/Threonine Kinase 11 (STK11) in pancreatic intraductal papillary mucinous neoplasms (IPMNs).BACKGROUND:STK11 is a tumor suppressor involved in certain IPMNs; however, its significance is not well known.METHODS:In 184 IPMNs without Peutz-Jeghers syndrome, we analyzed expression of STK11 and phosphorylated-AMPKa in all cases, and p16, p53, SMAD4, and β-catenin in 140 cases by immunohistochemistry; and we analyzed mutations in 37 genes, including whole coding exons of STK11, CDKN2A, TP53, and SMAD4, and hotspots of KRAS, BRAF, and GNAS in 64 cases by targeted sequencing. KRAS and GNAS were additionally analyzed in 86 STK11-normal IPMNs using digital-PCR.RESULTS:Consistent loss or reduction of STK11 expression was observed in 26 of 184 (14%) IPMNs. These STK11-aberrant IPMNs were 17 of 45 (38%) pancreatobiliary, 8 of 27 (30%) oncocytic, 1 of 54 (2%) gastric, and 0 of 58 (0%) intestinal subtypes ( P = 8.5E-11), and 20 of 66 (30%) invasive, 6 of 74 (8%) high-grade, and 0 of 44 (0%) low-grade ( P = 3.9E-06). Sixteen somatic STK11 mutations (5 frameshift, 6 nonsense, 1 splicing, and 4 missense) were detected in 15/26 STK11-aberrant IPMNs ( P = 4.1E-06). All STK11-aberrantIPMNs were GNAS -wild-type and 96% of them were KRAS or BRAF -mutant.Morphologically, STK11-aberrant IPMNs presented "fern-like" arborizing papillae with thin fibrovascular core. Phosphorylated-AMPKa was down-regulated in STK11-aberrant IPMNs (92%, P = 6.8E-11). Patients with STK11-aberrant IPMNs showed poorer survival than patients with STK11-normal IPMNs ( P = 3.6E-04 overall; P = 6.1E-04 disease-free).CONCLUSION:STK11 may play a canonical role in malignant progression and poor survival of patients with IPMNs. Aberrant STK11-driven phosphorylated AMPK downregulation may provide therapeutic opportunities with mTOR inhibitors/AMPK activators. |
| DOI | 10.1097/SLA.0000000000004842 |
| PMID | 33914475 |