Analysis of genetic status of pivotal driver genes in pancreatic ductal adenocarcinoma and their correlation with clinicopathologic features
Received date: 2020-07-07
Online published: 2023-01-29
目的：探讨胰腺导管腺癌（pancreatic ductal adenocarcinoma, PDAC）重要驱动基因突变特点与临床病理特征间的关系。方法：采用靶向测序技术检测269例PDAC患者中相关基因的突变情况，并分析其中重要驱动基因（KRAS、TP53、SMAD4及CDKN2A）突变状态与包括年龄、肿瘤分化程度、预后等在内的各项临床病理特征之间的关系。结果：在269例PDAC患者中，KRAS、TP53、SMAD4、CDKN2A的突变率分别为82.53%（222/269）、55.02%（148/269）、15.24%（41/269）、11.15%（30/269）。KRAS突变均为错义突变，其中94.59%发生于2号外显子的12位密码子，5.41%则发生于3号外显子的61位密码子。KRAS突变与年龄相关，小于70岁患者中KRAS突变率为80.09%，大于70岁患者中为93.75%（P<0.05）；TP53突变与肿瘤分化程度相关，中、高分化患者中TP53突变率为52.52%，低分化患者中为74.19%（P<0.05）；SMAD4、CDKN2A突变与患者的各项临床病理特征均无关。单因素及多因素生存分析结果显示，TP53突变是影响PDAC患者术后生存的独立危险因素（突变患者的死亡风险为非突变患者的4.3倍）。结论：4种重要驱动基因突变状态中，KRAS、TP53基因突变状态分别与患者年龄、肿瘤分化程度相关，且TP53突变状态可作为预测PDAC术后患者预后的参考指标。
谢吻, 梁怀予, 董磊, 袁菲, 王朝夫, 郭滟 . 胰腺导管腺癌重要驱动基因突变与临床病理特征、预后间相关性的分析[J]. 诊断学理论与实践, 2022 , 21(05) : 581 -587 . DOI: 10.16150/j.1671-2870.2022.05.006
Objective: To investigate the relationship between genetic characteristics of pivotal driver genes and clinicopathological features in pancreatic ductal adenocarcinoma(PDAC). Methods: Mutations in related genes in 269 PDAC patients were detected with targeted sequencing, and the relationship between the genetic status of pivotal driver genes (KRAS、TP53、SMAD4 and CDKN2A) and clinicopathological features (including age, tumor differentiation, and prognosis, etc) were analyzed. Results: Among 269 patients, KRAS, TP53, SMAD4 and CDKN2A mutations were identified in 222 cases (82.53%), 148 cases (55.02%), 41 cases (15.24%) and 30 cases (11.15%) respectively. KRAS mutations were missense mutations, of which 94.59% occurred in codon 12 of exon 2 and 5.41% in codon 61 in exon 3. KRAS mutation might be correlated with age, with a mutation rate of 80.09% in patients younger than 70 years old and 93.75% in patients older than 70 years old (P<0.05); TP53 mutation was correlated with the tumor differentiation, with a mutation rate of 52.52% in well/moderately differentiated patients and 74.19% in poorly differentiated patients (P<0.05); SMAD4 or CDKN2A mutations were not significantly associated with the clinicopathological features. Univariate and multivariate analysis showed that TP53 mutation was an independent risk factor for prognosis of PDAC patients. Conclusions: The genetic status of KRAS and TP53 genes are accociated with the age and tumor differentiation respectively, and TP53 mutation can be used as a reference index to predict the prognosis of PDAC patients.
| [1] | Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015[J]. CA Cancer J Clin, 2016, 66(2):115-132. |
| [2] | Rahib L, Smith BD, Aizenberg R, et al. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States[J]. Cancer Res, 2014, 74(11):2913-2921. |
| [3] | Kamisawa T, Wood LD, Itoi T, et al. Pancreatic cancer[J]. Lancet, 2016, 388(10039):73-85. |
| [4] | Chantrill LA, Nagrial AM, Watson C, et al. Precision medicine for advanced pancreas cancer: The Individuali-zed Molecular Pancreatic Cancer Therapy (IMPaCT) Trial[J]. Clin Cancer Res, 2015, 21(9):2029-2037. |
| [5] | Cancer Genome Atlas Research Network. Integrated genomic characterization of pancreatic ductal adenocarcinoma[J]. Cancer Cell, 2017, 32(2):185-203,e13. |
| [6] | Waddell N, Pajic M, Patch AM, et al. Whole genomes redefine the mutational landscape of pancreatic cancer[J]. Nature, 2015, 518(7540):495-501. |
| [7] | Bailey P, Chang DK, Nones K, et al. Genomic analyses identify molecular subtypes of pancreatic cancer[J]. Nature, 2016, 531(7592):47-52. |
| [8] | Morton JP, Timpson P, Karim SA, et al. Mutant p53 drives metastasis and overcomes growth arrest/senescence in pancreatic cancer[J]. Proc Natl Acad Sci U S A, 2010, 107(1):246-251. |
| [9] | Oshima M, Okano K, Muraki S, et al. Immunohistoche-mically detected expression of 3 major genes (CDKN2A/p16, TP53, and SMAD4/DPC4) strongly predicts survival in patients with resectable pancreatic cancer[J]. Ann Surg, 2013, 258(2):336-346. |
| [10] | Qian ZR, Rubinson DA, Nowak JA, et al. Association of alterations in main driver genes with outcomes of patients with resected pancreatic ductal adenocarcinoma[J]. JAMA Oncol, 2018, 4(3):e173420. |
| [11] | 沈璟, 高绥之, 王欢, 等. 四种驱动基因突变状态对根治性切除胰腺癌患者预后的评估价值[J]. 中华外科杂志, 2019, 57(11):840-847. |
| [11] | Shen J, Gao SZ, Wang H, et al. Prognostic value of important driver gene mutations in patients with radical resection of pancreatic cancer[J]. Chin J Surg, 2019, 57(11):840-847. |
| [12] | Yachida S, White CM, Naito Y, et al. Clinical significance of the genetic landscape of pancreatic cancer and implications for identification of potential long-term survivors[J]. Clin Cancer Res, 2012, 18(22):6339-6347. |
| [13] | Wen C, Deng X, Ren D, et al. Tumor copy number instability is a significant predictor for late recurrence after radical surgery of pancreatic ductal adenocarcinoma[J]. Cancer Med, 2020, 9(20):7626-7636. |
| [14] | Jones S, Zhang X, Parsons DW, et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses[J]. Science, 2008, 321(5897):1801-1806. |
| [15] | Lewis R, Drebin JA, Callery MP, et al. A contemporary analysis of survival for resected pancreatic ductal adenocarcinoma[J]. HPB (Oxford), 2013, 15(1):49-60. |
| [16] | Goldstein JB, Zhao L, Wang X, et al. Germline DNA sequencing reveals novel mutations predictive of overall survival in a cohort of patients with pancreatic cancer[J]. Clin Cancer Res, 2020, 26(6):1385-1394. |
| [17] | Tsai FD, Lopes MS, Zhou M, et al. K-Ras4A splice var-iant is widely expressed in cancer and uses a hybrid membrane-targeting motif[J]. Proc Natl Acad Sci U S A, 2015, 112(3):779-784. |
| [18] | Hashimoto D, Arima K, Yokoyama N, et al. Heteroge-neity of KRAS Mutations in Pancreatic Ductal Adenocarci-noma[J]. Pancreas, 2016, 45(8):1111-1114. |
| [19] | Brychta N, Krahn T, von Ahsen O. Detection of KRAS Mutations in Circulating Tumor DNA by Digital PCR in Early Stages of Pancreatic Cancer[J]. Clin Chem, 2016, 62(11):1482-1491. |
| [20] | Kamerkar S, LeBleu VS, Sugimoto H, et al. Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer[J]. Nature, 2017, 546(7659):498-503. |
| [21] | Leroy B, Anderson M, Soussi T. TP53 mutations in human cancer: database reassessment and prospects for the next decade[J]. Hum Mutat, 2014, 35(6):672-688. |
| [22] | Molina-Vila MA, Bertran-Alamillo J, Gascó A, et al. Nondisruptive p53 mutations are associated with shorter survival in patients with advanced non-small cell lung cancer[J]. Clin Cancer Res, 2014, 20(17):4647-4659. |
| [23] | Masetti M, Acquaviva G, Visani M, et al. Long-term survivors of pancreatic adenocarcinoma show low rates of genetic alterations in KRAS, TP53 and SMAD4[J]. Cancer Biomark, 2018, 21(2):323-334. |
| [24] | Schwarte-Waldhoff I, Volpert OV, Bouck NP, et al. Smad4/DPC4-mediated tumor suppression through suppression of angiogenesis[J]. Proc Natl Acad Sci U S A, 2000, 97(17):9624-9629. |
| [25] | Wood LD, Hruban RH. Pathology and molecular genetics of pancreatic neoplasms[J]. Cancer J, 2012, 18(6):492-501. |
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