丝氨酸/苏氨酸激酶11在KRAS突变型和GNAS野生型胰腺导管内乳头状黏液性肿瘤的恶性进展中发挥典型作用。
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.
作者信息
Omori Yuko, Ono Yusuke, Morikawa Takanori, Motoi Fuyuhiko, Higuchi Ryota, Yamamoto Masakazu, Hayakawa Yuko, Karasaki Hidenori, Mizukami Yusuke, Unno Michiaki, Furukawa Toru
机构信息
Department of Investigative Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan.
Institute of Biomedical Research, Sapporo Higashi Tokushukai Hospital, Sapporo, Japan.
出版信息
Ann Surg. 2023 Feb 1;277(2):e384-e395. doi: 10.1097/SLA.0000000000004842. Epub 2023 Jan 10.
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.
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黏液性肿瘤（IPMNs）中的临床病理生物学意义。
背景
STK11是一种参与某些IPMNs的肿瘤抑制因子；然而，其意义尚不清楚。
方法
在184例无黑斑息肉综合征的IPMNs中，我们通过免疫组织化学分析了所有病例中STK11和磷酸化-AMPKa的表达，以及140例病例中p16、p53、SMAD4和β-连环蛋白的表达；并通过靶向测序分析了64例病例中37个基因的突变，包括STK11、CDKN2A、TP53和SMAD4的整个编码外显子，以及KRAS、BRAF和GNAS的热点突变。另外，使用数字PCR对86例STK11正常的IPMNs中的KRAS和GNAS进行了分析。
结果
在184例（14%）IPMNs中的26例中观察到STK11表达持续缺失或降低。这些STK11异常的IPMNs在45例（38%）胰胆管型、27例（30%）嗜酸性细胞型、54例（2%）胃型和58例（0%）肠型亚型中分别有17例、8例、1例和0例（P = 8.5E-11），在66例（30%）浸润性、74例（8%）高级别和44例（0%）低级别中分别有20例、6例和0例（P = 3.9E-06）。在15/26例STK11异常的IPMNs中检测到16个体细胞STK11突变（5个移码突变、6个无义突变、1个剪接突变和4个错义突变）（P = 4.1E-06）。所有STK11异常的IPMNs均为GNAS野生型，其中96%为KRAS或BRAF突变型。形态学上，STK11异常的IPMNs表现为具有细纤维血管轴心的“蕨类样”分支乳头。磷酸化-AMPKa在STK11异常的IPMNs中下调（92%，P = 6.8E-11）。STK11异常的IPMNs患者的生存率低于STK11正常的IPMNs患者（总体P = 3.6E-04；无病生存率P = 6.1E-04）。
结论
STK11可能在IPMNs患者的恶性进展和不良生存中起典型作用。异常的STK11驱动的磷酸化AMPK下调可能为mTOR抑制剂/AMPK激活剂提供治疗机会。
Zotero 插件