SMAD4 loss predicts worse overall and distant metastasis-free survival in patients with resected pancreatic adenocarcinoma.
RNA sequencing
biomarker
genomic aberration
mothers against decapentaplegic homolog 4 (SMAD4)
pancreatic cancer
Journal
Cancer
ISSN: 1097-0142
Titre abrégé: Cancer
Pays: United States
ID NLM: 0374236
Informations de publication
Date de publication:
12 Oct 2023
12 Oct 2023
Historique:
revised:
20
07
2023
received:
19
04
2023
accepted:
08
08
2023
medline:
12
10
2023
pubmed:
12
10
2023
entrez:
12
10
2023
Statut:
aheadofprint
Résumé
In select patients, pancreatic adenocarcinoma remains a local disease, yet there are no validated biomarkers to predict this behavior and who may benefit from aggressive local treatments. This study sought to determine if SMAD4 (mothers against decapentaplegic homolog 4) messenger RNA-sequencing (RNA-seq) expression is a robust method for predicting overall survival (OS) and distant metastasis-free survival (DMFS) in patients with resected pancreatic adenocarcinoma. Utilizing The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC), 322 patients with resected stage I-III pancreatic adenocarcinoma were identified. In TCGA, multivariable proportional hazards models were used to determine the association of SMAD4 genomic aberrations and RNA-seq expression with OS and DMFS. In the ICGC, analysis sought to confirm the predictive performance of RNA-seq via multivariable models and receiver operator characteristic curves. In TCGA, the presence of SMAD4 genomic aberrations was associated with worse OS (hazard ratio [HR], 1.55; 95% CI, 1.00-2.40; p = .048) but not DMFS (HR, 1.33; 95% CI, .87-2.03; p = .19). Low SMAD4 RNA-seq expression was associated with worse OS (HR, 1.83; 95% CI, 1.17-2.86; p = .008) and DMFS (HR, 1.70; 95% CI, 1.14-2.54; p = .009). In the ICGC, increased SMAD4 RNA-seq expression correlated with improved OS (area under the curve [AUC], .92; 95% CI, .86-.94) and DMFS (AUC, .84; 95% CI, .82-.87). In patients with resected pancreatic adenocarcinoma, SMAD4 genomic aberrations are associated with worse OS but do not predict for DMFS. Increased SMAD4 RNA-seq expression is associated with improved OS and DMFS in patients with resected pancreatic adenocarcinoma. This reproducible finding suggests SMAD4 RNA-seq expression may be a useful marker to predict metastatic spread.
Sections du résumé
BACKGROUND
BACKGROUND
In select patients, pancreatic adenocarcinoma remains a local disease, yet there are no validated biomarkers to predict this behavior and who may benefit from aggressive local treatments. This study sought to determine if SMAD4 (mothers against decapentaplegic homolog 4) messenger RNA-sequencing (RNA-seq) expression is a robust method for predicting overall survival (OS) and distant metastasis-free survival (DMFS) in patients with resected pancreatic adenocarcinoma.
METHODS
METHODS
Utilizing The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC), 322 patients with resected stage I-III pancreatic adenocarcinoma were identified. In TCGA, multivariable proportional hazards models were used to determine the association of SMAD4 genomic aberrations and RNA-seq expression with OS and DMFS. In the ICGC, analysis sought to confirm the predictive performance of RNA-seq via multivariable models and receiver operator characteristic curves.
RESULTS
RESULTS
In TCGA, the presence of SMAD4 genomic aberrations was associated with worse OS (hazard ratio [HR], 1.55; 95% CI, 1.00-2.40; p = .048) but not DMFS (HR, 1.33; 95% CI, .87-2.03; p = .19). Low SMAD4 RNA-seq expression was associated with worse OS (HR, 1.83; 95% CI, 1.17-2.86; p = .008) and DMFS (HR, 1.70; 95% CI, 1.14-2.54; p = .009). In the ICGC, increased SMAD4 RNA-seq expression correlated with improved OS (area under the curve [AUC], .92; 95% CI, .86-.94) and DMFS (AUC, .84; 95% CI, .82-.87).
CONCLUSIONS
CONCLUSIONS
In patients with resected pancreatic adenocarcinoma, SMAD4 genomic aberrations are associated with worse OS but do not predict for DMFS. Increased SMAD4 RNA-seq expression is associated with improved OS and DMFS in patients with resected pancreatic adenocarcinoma. This reproducible finding suggests SMAD4 RNA-seq expression may be a useful marker to predict metastatic spread.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2023 American Cancer Society.
Références
Heestand GM, Kurzrock R. Molecular landscape of pancreatic cancer: implications for current clinical trials. Oncotarget. 2015;6(7):4553-4561. doi:10.18632/oncotarget.2972
Jones S, Zhang X, Parsons DW, et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science. 2008;321(5897):1801-1806. doi:10.1126/science.1164368
Waddell N, Pajic M, Patch A-M, et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature. 2015;518(7540):495-501. doi:10.1038/nature14169
Notta F, Chan-Seng-Yue M, Lemire M, et al. A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns. Nature. 2016;538(7625):378-382. doi:10.1038/nature19823
Dey P, Baddour J, Muller F, et al. Genomic deletion of malic enzyme 2 confers collateral lethality in pancreatic cancer. Nature. 2017;542(7639):119-123. doi:10.1038/nature21052
Izeradjene K, Combs C, Best M, et al. Kras(G12D) and Smad4/Dpc4 haploinsufficiency cooperate to induce mucinous cystic neoplasms and invasive adenocarcinoma of the pancreas. Cancer Cell. 2007;11(3):229-243. doi:10.1016/j.ccr.2007.01.017
Iacobuzio-Donahue CA, Fu B, Yachida S, et al. DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer. J Clin Oncol. 2009;27(11):1806-1813. doi:10.1200/jco.2008.17.7188
Shugang X, Hongfa Y, Jianpeng L, et al. Prognostic value of SMAD4 in pancreatic cancer: a meta-analysis. Transl Oncol. 2016;9(1):1-7. doi:10.1016/j.tranon.2015.11.007
Hua Z, Zhang Y-C, Hu X-M, et al. Loss of DPC4 expression and its correlation with clinicopathological parameters in pancreatic carcinoma. World J Gastroenterol. 2003;9(12):2764-2767. doi:10.3748/wjg.v9.i12.2764
Jiang H, He C, Geng S, et al. RhoT1 and Smad4 are correlated with lymph node metastasis and overall survival in pancreatic cancer. PLoS One. 2012;7:e42234. doi:10.1371/journal.pone.0042234
Oshima M, Okano K, Muraki S, et al. Immunohistochemically detected expression of 3 major genes (CDKN2A/p16, TP53, and SMAD4/DPC4) strongly predicts survival in patients with resectable pancreatic cancer. Ann Surg. 2013;258(2):336-346. doi:10.1097/sla.0b013e3182827a65
Ottenhof NA, Morsink FHM, Ten Kate F, van Noorden CJF, Offerhaus GJA. Multivariate analysis of immunohistochemical evaluation of protein expression in pancreatic ductal adenocarcinoma reveals prognostic significance for persistent Smad4 expression only. Cell Oncol (Dordr). 2012;35(2):119-126. doi:10.1007/s13402-012-0072-x
Wang J-D, Jin K, Chen X-Y, Lv JQ, Ji KW. Clinicopathological significance of SMAD4 loss in pancreatic ductal adenocarcinomas: a systematic review and meta-analysis. Oncotarget. 2017;8(10):16704-16711. doi:10.18632/oncotarget.14335
Qian ZR, Rubinson DA, Nowak JA, et al. Association of alterations in main driver genes with outcomes of patients with resected pancreatic ductal adenocarcinoma. JAMA Oncol. 2018;4(3):e173420. doi:10.1001/jamaoncol.2017.3420
Blackford A, Serrano OK, Wolfgang CL, et al. SMAD4 gene mutations are associated with poor prognosis in pancreatic cancer. Clin Cancer Res. 2009;15(14):4674-4679. doi:10.1158/1078-0432.ccr-09-0227
Cox DR. Regression models and life tables. J R Stat Soc Series B Methodol. 1972;34(2):187-220. doi:10.1111/j.2517-6161.1972.tb00899.x
Bender R, Augustin T, Blettner M. Generating survival times to simulate Cox proportional hazards models. Stat Med. 2005;24(11):1713-1723. doi:10.1002/sim.2059
Akaike H. Likelihood of a model and information criteria. J Econom. 1981;16(1):3-14. doi:10.1016/0304-4076(81)90071-3
Burnham K, Anderson D. Multimodel inference: understanding AIC and BIC in model selection. Sociol Methods Res. 2004;33(2):261-304. doi:10.1177/0049124104268644
Cao Y, Lin H, Wu TZ, Yu Y. Penalized spline estimation for functional coefficient regression models. Comput Stat Data Anal. 2010;54(4):891-905. doi:10.1016/j.csda.2009.09.036
Roshani D, Ghaderi E. Comparing smoothing techniques for fitting the nonlinear effect of covariate in Cox models. Acta Inform Med. 2016;24(1):38-41. doi:10.5455/aim.2016.24.38-41
Christopoulos AMH. Fitting Models to Biological Data Using Linear and Nonlinear Regression. Oxford University Press; 2004.
Bland JM, Altman DG. Multiple significance tests: the Bonferroni method. BMJ. 1995;310(6973):170. doi:10.1136/bmj.310.6973.170
Cancer Genome Atlas Research Network. Integrated genomic characterization of pancreatic ductal adenocarcinoma. Cancer Cell. 2017;32(2):185-203.e13. doi:10.1016/j.ccell.2017.07.007
Hayashi H, Kohno T, Ueno H, et al. Utility of assessing the number of mutated KRAS, CDKN2A, TP53, and SMAD4 genes using a targeted deep sequencing assay as a prognostic biomarker for pancreatic cancer. Pancreas. 2017;46(3):335-340. doi:10.1097/mpa.0000000000000760
Barrett MT, Deiotte R, Lenkiewicz E, et al. Clinical study of genomic drivers in pancreatic ductal adenocarcinoma. Br J Cancer. 2017;117(4):572-582. doi:10.1038/bjc.2017.209
Sims D, Sudbery I, Ilott NE, Heger A, Ponting CP. Sequencing depth and coverage: key considerations in genomic analyses. Nat Rev Genet. 2014;15(2):121-132. doi:10.1038/nrg3642
Ben-Aharon I, Elkabets M, Pelossof R, et al. Genomic landscape of pancreatic adenocarcinoma in younger versus older patients: does age matter? Clin Cancer Res. 2019;25(7):2185-2193. doi:10.1158/1078-0432.ccr-18-3042
Wang F, Xia X, Yang C, et al. SMAD4 gene mutation renders pancreatic cancer resistance to radiotherapy through promotion of autophagy. Clin Cancer Res. 2018;24(13):3176-3185. doi:10.1158/1078-0432.ccr-17-3435
Neoptolemos JP, Stocken DD, Friess H, et al. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004;350(12):1200-1210. doi:10.1056/nejmoa032295
Oettle H, Neuhaus P, Hochhaus A, et al. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA. 2013;310(14):1473-1481. doi:10.1001/jama.2013.279201
Neoptolemos JP, Palmer DH, Ghaneh P, et al. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet. 2017;389(10073):1011-1024. doi:10.1016/s0140-6736(16)32409-6
Conroy T, Hammel P, Hebbar M, et al. FOLFIRINOX or gemcitabine as adjuvant therapy for pancreatic cancer. N Engl J Med. 2018;379(25):2395-2406. doi:10.1056/nejmoa1809775
Blackford A, Parmigiani G, Kensler TW, et al. Genetic mutations associated with cigarette smoking in pancreatic cancer. Cancer Res. 2009;69(8):3681-3688. doi:10.1158/0008-5472.can-09-0015
Yuan C, Morales-Oyarvide V, Babic A, et al. Cigarette smoking and pancreatic cancer survival. J Clin Oncol. 2017;35(16):1822-1828. doi:10.1200/jco.2016.71.2026
LoConte NK, Brewster AM, Kaur JS, Merrill JK, Alberg AJ. Alcohol and cancer: a statement of the American Society of Clinical Oncology. J Clin Oncol. 2018;36(1):83-93. doi:10.1200/jco.2017.76.1155
Kirkegård J, Mortensen FV, Cronin-Fenton D. Chronic pancreatitis and pancreatic cancer risk: a systematic review and meta-analysis. Am J Gastroenterol. 2017;112(9):1366-1372. doi:10.1038/ajg.2017.218
Yuan C, Rubinson DA, Qian ZR, et al. Survival among patients with pancreatic cancer and long-standing or recent-onset diabetes mellitus. J Clin Oncol. 2015;33(1):29-35. doi:10.1200/jco.2014.57.5688
Abe T, Blackford AL, Tamura K, et al. Deleterious germline mutations are a risk factor for neoplastic progression among high-risk individuals undergoing pancreatic surveillance. J Clin Oncol. 2019;37(13):1070-1080.
Yuan C, Bao Y, Wu C, et al. Prediagnostic body mass index and pancreatic cancer survival. J Clin Oncol. 2013;31(33):4229-4234. doi:10.1200/jco.2013.51.7532
Islami F, Goding Sauer A, Gapstur SM, Jemal A. Proportion of cancer cases attributable to excess body weight by US state, 2011-2015. JAMA Oncol. 2018;5(3):384. doi:10.1001/jamaoncol.2018.5639
Berger AC, Garcia M, Hoffman JP, et al. Postresection CA 19-9 predicts overall survival in patients with pancreatic cancer treated with adjuvant chemoradiation: a prospective validation by RTOG 9704. J Clin Oncol. 2008;26(36):5918-5922. doi:10.1200/jco.2008.18.6288
Mega JL, Sabatine MS, Antman EM. Population and personalized medicine in the modern era. JAMA. 2014;312(19):1969-1970. doi:10.1001/jama.2014.15224
Collins FS, Varmus H. A new initiative on precision medicine. N Engl J Med. 2015;372(9):793-795. doi:10.1056/nejmp1500523
Falls KC, Sharma RA, Lawrence YR, et al. Radiation-drug combinations to improve clinical outcomes and reduce normal tissue toxicities: current challenges and new approaches: report of the symposium held at the 63rd Annual Meeting of the Radiation Research Society, 15-18 October 2017; Cancun, Mexico. Radiat Res. 2018;190(4):350-360. doi:10.1667/rr15121.1
Rahib L, Fleshman JM, Matrisian LM, Berlin JD. Evaluation of pancreatic cancer clinical trials and benchmarks for clinically meaningful future trials: a systematic review. JAMA Oncol. 2016;2(9):1209-1216. doi:10.1001/jamaoncol.2016.0585