Journal of Diagnostics Concepts & Practice >

2022 , Vol. 21 >Issue 05: 581 - 587

DOI: https://doi.org/10.16150/j.1671-2870.2022.05.006

Original articles

Analysis of genetic status of pivotal driver genes in pancreatic ductal adenocarcinoma and their correlation with clinicopathologic features

Expand
  • Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China

Received date: 2020-07-07

  Online published: 2023-01-29

Fold

Abstract

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.

Key words： Pancreatic ductal adenocarcinoma; Driver gene; Clinicopathological feature; Prognosis

Cite this article

XIE Wen, LIANG Huaiyu, DONG Lei, YUAN Fei, WANG Chaofu, GUO Yan . Analysis of genetic status of pivotal driver genes in pancreatic ductal adenocarcinoma and their correlation with clinicopathologic features[J]. Journal of Diagnostics Concepts & Practice, 2022 , 21(05) : 581 -587 . DOI: 10.16150/j.1671-2870.2022.05.006

References

[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.
Options
Outlines

/

〈 〉