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
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
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DOI：
10.1097/sla.0000000000004842
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发表时间：
2023-02-01
影响因子：
9
通讯作者：
Furukawa, Toru
中科院分区：
文献类型：
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作者：
Omori, Yuko;Ono, Yusuke;Furukawa, Toru
目的：我们旨在阐明丝氨酸/苏氨酸激酶11（STK11）在胰腺导管内乳头状粘液性肿瘤（IPMN）中的临床病理生物学意义。背景：STK11是一种肿瘤抑制因子，参与某些IPMNs；然而，其意义并不为人所知。方法：在184例不伴有Peutz-Jeghers综合征的IPMN中，采用免疫组化方法分析所有病例中STK11和磷酸化-AMPKa的表达情况，以及140例中p16、p53、SMAD4和β-catenin的表达情况。我们通过靶向测序分析了64例患者的37个基因的突变，包括STK11、CDKN2A、TP53和SMAD4的全编码外显子以及KRAS、BRAF和GNAS的热点。使用数字 PCR 对 86 个 STK11 正常 IPMN 中的 KRAS 和 GNAS 进行了额外分析。结果：184 个 IPMN 中有 26 个 (14%) 观察到 STK11 表达持续丢失或减少。这些 STK11 异常 IPMN 为 45 个胰胆亚型中的 17 个 (38%)、27 个嗜酸细胞亚型中的 8 个 (30%)、54 个胃亚型中的 1 个 (2%)、58 个肠道亚型中的 0 个 (P = 8.5E-11)、66 个侵袭性 IPMN 中的 20 个 (30%)、74 个高级 IPMN 中的 6 个 (8%)、和 0 个，共 44 个 (0%) 低等级 （P = 3.9E-06）。在 15/26 STK11 异常 IPMN 中检测到 16 个体细胞 STK11 突变（5 个移码、6 个无义、1 个剪接和 4 个错义）（P = 4.1E-06）。所有 STK11 异常 IPMN 均为 GNAS 野生型，其中 96% 为 KRAS 或 BRAF 突变型。形态上，STK11 异常 IPMN 呈现“蕨类”树枝状乳头，具有薄的纤维血管核心。 STK11 异常 IPMN 中磷酸化 AMPKa 下调（92%，P = 6.8E-11）。 STK11 异常 IPMN 患者的生存率低于 STK11 正常 IPMN 患者（总体 P = 3.6E-04；无病 P = 6.1E-04）。结论：STK11可能在IPMNs患者的恶性进展和不良生存中发挥典型作用。 STK11 驱动的异常磷酸化 AMPK 下调可能为 mTOR 抑制剂/AMPK 激活剂提供治疗机会。
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 beta-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.