PALB2 upregulation is associated with a poor prognosis in pancreatic ductal adenocarcinoma

Ge,Ouyang; Huang,Anle; Wang,Xin; Chen,Yuling; Ye,Yuanchun; Schomburg,Lutz

doi:10.3892/ol.2021.12485

PALB2 upregulation is associated with a poor prognosis in pancreatic ductal adenocarcinoma

Authors:
- Ouyang Ge
- Anle Huang
- Xin Wang
- Yuling Chen
- Yuanchun Ye
- Lutz Schomburg
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Affiliations: Institute for Experimental Endocrinology, Charité‑Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt‑Universität zu Berlin and Berlin Institute of Health, D‑13353 Berlin, Germany, Department of Gastrointestinal Surgery, Xiamen Cancer Hospital, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361003, P.R. China, Medical Department for Hematology and Oncology, Klinikum rechts der Isar, Technische University Munich, D‑81675 Munich, Germany, Department of Rheumatology and Clinical Immunology, Charité‑Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt‑Universität zu Berlin, and Berlin Institute of Health, D‑10117 Berlin, Germany, Department of Gastroenterology, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, Fujian 362000, P.R. China
Published online on: January 24, 2021 https://doi.org/10.3892/ol.2021.12485
Article Number: 224
Copyright: © Ge et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

During DNA repair, BRCA1 and BRCA2 interact with the tumor suppressor partner and localizer of BRCA2 (PALB2). PALB2 mutations are associated with an increased risk of breast and ovarian carcinoma, and upregulated PALB2 expression is associated with poor clinical outcomes. The present study investigated the role and prognostic value of PALB2 in pancreatic ductal adenocarcinoma (PDAC). PALB2 expression was inhibited using a small interfering RNA in PDAC cell lines, and the subsequent effects on cell proliferation and migration were investigated. Tissue microarrays from 157 patients undergoing a pancreaticoduodenectomy for PDAC were analyzed via immunohistochemistry, and PALB2 expression was compared with patient outcomes using Kaplan‑Meier curves and the multivariate Cox regression model. PALB2‑knockdown in PDAC cells had little effect on cell proliferation, but significantly decreased cell migration. Relatively high PALB2 expression was observed in PDAC tissues compared with in peritumoral tissues. Overall survival (OS) was negatively associated with PALB2 expression. TNM stage and PALB2 expression were identified as independent prognostic factors associated with OS via multivariate analysis. Overall, the present study demonstrated that PDAC cell migration was dependent on PALB2, which was further supported by the finding that elevated PALB2 expression in PDAC tissues was associated with poor survival in patients with PDAC. Therefore, PALB2 may serve as a novel prognostic marker in PDAC, which may aid with the development of therapeutic strategies for the disease.

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1	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2020. CA Cancer J Clin. 70:7–30. 2020. View Article : Google Scholar : PubMed/NCBI
2	Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM and Matrisian LM: Projecting cancer incidence and deaths to 2030: The unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 74:2913–2921. 2014. View Article : Google Scholar : PubMed/NCBI
3	Kamisawa T, Wood LD, Itoi T and Takaori K: Pancreatic cancer. Lancet. 388:73–85. 2016. View Article : Google Scholar : PubMed/NCBI
4	Zhang X, Shi S, Zhang B, Ni Q, Yu X and Xu J: Circulating biomarkers for early diagnosis of pancreatic cancer: Facts and hopes. Am J Cancer Res. 8:332–353. 2018.PubMed/NCBI
5	Venkitaraman AR: Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell. 108:171–182. 2002. View Article : Google Scholar : PubMed/NCBI
6	Huang L, Wu C, Yu D, Wang C, Che X, Miao X, Zhai K, Chang J, Jiang G, Yang X, et al: Identification of common variants in BRCA2 and MAP2K4 for susceptibility to sporadic pancreatic cancer. Carcinogenesis. 34:1001–1015. 2013. View Article : Google Scholar : PubMed/NCBI
7	Sikdar N, Saha G, Dutta A, Ghosh S, Shrikhande SV and Banerjee S: Genetic alterations of periampullary and pancreatic ductal adenocarcinoma: An overview. Curr Genomics. 19:444–463. 2018. View Article : Google Scholar : PubMed/NCBI
8	Zhang F, Ma J, Wu J, Ye L, Cai H, Xia B and Yu X: PALB2 links BRCA1 and BRCA2 in the DNA-damage response. Curr Biol. 19:524–529. 2009. View Article : Google Scholar : PubMed/NCBI
9	Reid S, Schindler D, Hanenberg H, Barker K, Hanks S, Kalb R, Neveling K, Kelly P, Seal S, Freund M, et al: Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer. Nat Genet. 39:162–164. 2007. View Article : Google Scholar : PubMed/NCBI
10	Xia B, Dorsman JC, Ameziane N, de Vries Y, Rooimans MA, Sheng Q, Pals G, Errami A, Gluckman E, Llera J, et al: Fanconi anemia is associated with a defect in the BRCA2 partner PALB2. Nat Genet. 39:159–161. 2007. View Article : Google Scholar : PubMed/NCBI
11	Chen P, Liang J, Wang Z, Zhou X, Chen L, Li M, Xie D, Hu Z, Shen H and Wang H: Association of common PALB2 polymorphisms with breast cancer risk: A case-control study. Clin Cancer Res. 14:5931–5937. 2008. View Article : Google Scholar : PubMed/NCBI
12	Southey MC, Teo ZL and Winship I: PALB2 and breast cancer: Ready for clinical translation! Appl Clin Genet. 6:43–52. 2013. View Article : Google Scholar : PubMed/NCBI
13	Borecka M, Zemankova P, Vocka M, Soucek P, Soukupova J, Kleiblova P, Sevcik J, Kleibl Z and Janatova M: Mutation analysis of the PALB2 gene in unselected pancreatic cancer patients in the Czech Republic. Cancer Genet. 209:199–204. 2016. View Article : Google Scholar : PubMed/NCBI
14	Blanco A, de la Hoya M, Osorio A, Diez O, Miramar MD, Infante M, Martinez-Bouzas C, Torres A, Lasa A, Llort G, et al: Analysis of PALB2 gene in BRCA1/BRCA2 negative Spanish hereditary breast/ovarian cancer families with pancreatic cancer cases. PLoS One. 8:e675382013. View Article : Google Scholar : PubMed/NCBI
15	Harinck F, Kluijt I, van Mil SE, Waisfisz Q, van Os TA, Aalfs CM, Wagner A, Olderode-Berends M, Sijmons RH, Kuipers EJ, et al: Routine testing for PALB2 mutations in familial pancreatic cancer families and breast cancer families with pancreatic cancer is not indicated. Eur J Hum Genet. 20:577–579. 2012. View Article : Google Scholar : PubMed/NCBI
16	Hofstatter EW, Domchek SM, Miron A, Garber J, Wang M, Componeschi K, Boghossian L, Miron PL, Nathanson KL and Tung N: PALB2 mutations in familial breast and pancreatic cancer. Fam Cancer. 10:225–231. 2011. View Article : Google Scholar : PubMed/NCBI
17	Takeuchi S, Doi M, Ikari N, Yamamoto M and Furukawa T: Mutations in BRCA1, BRCA2, and PALB2, and a panel of 50 cancer-associated genes in pancreatic ductal adenocarcinoma. Sci Rep. 8:81052018. View Article : Google Scholar : PubMed/NCBI
18	Waddell N, Pajic M, Patch AM, Chang DK, Kassahn KS, Bailey P, Johns AL, Miller D, Nones K, Quek K, et al: Whole genomes redefine the mutational landscape of pancreatic cancer. Nature. 518:495–501. 2015. View Article : Google Scholar : PubMed/NCBI
19	Golan T, Kanji ZS, Epelbaum R, Devaud N, Dagan E, Holter S, Aderka D, Paluch-Shimon S, Kaufman B, Gershoni-Baruch R, et al: Overall survival and clinical characteristics of pancreatic cancer in BRCA mutation carriers. Br J Cancer. 111:1132–1138. 2014. View Article : Google Scholar : PubMed/NCBI
20	Wattenberg MM, Asch D, Yu S, O'Dwyer PJ, Domchek SM, Nathanson KL, Rosen MA, Beatty GL, Siegelman ES and Reiss KA: Platinum response characteristics of patients with pancreatic ductal adenocarcinoma and a germline BRCA1, BRCA2 or PALB2 mutation. Br J Cancer. 122:333–339. 2020. View Article : Google Scholar : PubMed/NCBI
21	Dell'Aquila E, Fulgenzi CAM, Minelli A, Citarella F, Stellato M, Pantano F, Russano M, Cursano MC, Napolitano A, Zeppola T, et al: Prognostic and predictive factors in pancreatic cancer. Oncotarget. 11:924–941. 2020. View Article : Google Scholar : PubMed/NCBI
22	Edge S, Byrd DR, Compton CC, Fritz AG, Greene FL and Trotti A: AJCC Cancer Staging Manual. 7th edition. Springer-Verlag; New York, NY: 2009
23	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
24	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2019. CA Cancer J Clin. 69:7–34. 2019. View Article : Google Scholar : PubMed/NCBI
25	Ducy M, Sesma-Sanz L, Guitton-Sert L, Lashgari A, Gao Y, Brahiti N, Rodrigue A, Margaillan G, Caron MC, Côté J, et al: The tumor suppressor PALB2: Inside out. Trends Biochem Sci. 44:226–240. 2019. View Article : Google Scholar : PubMed/NCBI
26	Sy SM, Huen MS and Chen J: PALB2 is an integral component of the BRCA complex required for homologous recombination repair. Proc Natl Acad Sci USA. 106:7155–7160. 2009. View Article : Google Scholar : PubMed/NCBI
27	Yang G, Mercado-Uribe I, Multani AS, Sen S, Shih Ie M, Wong KK, Gershenson DM and Liu J: RAS promotes tumorigenesis through genomic instability induced by imbalanced expression of Aurora-A and BRCA2 in midbody during cytokinesis. Int J Cancer. 133:275–285. 2013. View Article : Google Scholar : PubMed/NCBI
28	Egawa C, Miyoshi Y, Taguchi T, Tamaki Y and Noguchi S: High BRCA2 mRNA expression predicts poor prognosis in breast cancer patients. Int J Cancer. 98:879–882. 2002. View Article : Google Scholar : PubMed/NCBI
29	Li J, Li M, Chen P and Ba Q: High expression of PALB2 predicts poor prognosis in patients with advanced breast cancer. FEBS Open Bio. 8:56–63. 2017. View Article : Google Scholar : PubMed/NCBI
30	Poumpouridou N, Acha-Sagredo A, Goutas N, Vlachodimitropoulos D, Chatziioannidou I, Lianidou E, Liloglou T and Kroupis C: Development and validation of molecular methodologies to assess PALB2 expression in sporadic breast cancer. Clin Biochem. 49:253–259. 2016. View Article : Google Scholar : PubMed/NCBI
31	Bleuyard JY, Butler RM and Esashi F: Perturbation of PALB2 function by the T413S mutation found in small cell lung cancer. Wellcome Open Res. 2:1102017. View Article : Google Scholar : PubMed/NCBI
32	Nakagomi H, Sakamoto I, Hirotsu Y, Amemiya K, Mochiduki H and Omata M: Analysis of PALB2 mutations in 155 Japanese patients with breast and/or ovarian cancer. Int J Clin Oncol. 21:270–275. 2016. View Article : Google Scholar : PubMed/NCBI
33	Rahman N, Seal S, Thompson D, Kelly P, Renwick A, Elliott A, Reid S, Spanova K, Barfoot R, Chagtai T, et al: PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat Genet. 39:165–167. 2007. View Article : Google Scholar : PubMed/NCBI
34	Casadei S, Norquist BM, Walsh T, Stray S, Mandell JB, Lee MK, Stamatoyannopoulos JA and King MC: Contribution of inherited mutations in the BRCA2-interacting protein PALB2 to familial breast cancer. Cancer Res. 71:2222–2229. 2011. View Article : Google Scholar : PubMed/NCBI
35	Zhu Y, Zhai K, Ke J, Li J, Gong Y, Yang Y, Tian J, Zhang Y, Zou D, Peng X, et al: BRCA1 missense polymorphisms are associated with poor prognosis of pancreatic cancer patients in a Chinese population. Oncotarget. 8:36033–36039. 2017. View Article : Google Scholar : PubMed/NCBI
36	Jones S, Hruban RH, Kamiyama M, Borges M, Zhang X, Parsons DW, Lin JC, Palmisano E, Brune K, Jaffee EM, et al: Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Science. 324:2172009. View Article : Google Scholar : PubMed/NCBI
37	Slater EP, Langer P, Niemczyk E, Strauch K, Butler J, Habbe N, Neoptolemos JP, Greenhalf W and Bartsch DK: PALB2 mutations in European familial pancreatic cancer families. Clin Genet. 78:490–494. 2010. View Article : Google Scholar : PubMed/NCBI
38	Giovannetti E, van der Borden CL, Frampton AE, Ali A, Firuzi O and Peters GJ: Never let it go: Stopping key mechanisms underlying metastasis to fight pancreatic cancer. Semin Cancer Biol. 44:43–59. 2017. View Article : Google Scholar : PubMed/NCBI
39	Garces-Descovich A, Beker K, Jaramillo-Cardoso A, James Moser A and Mortele KJ: Applicability of current NCCN Guidelines for pancreatic adenocarcinoma resectability: Analysis and pitfalls. Abdom Radiol (NY). 43:314–322. 2018. View Article : Google Scholar : PubMed/NCBI
40	Lefebvre C, Bachelot T, Filleron T, Pedrero M, Campone M, Soria JC, Massard C, Lévy C, Arnedos M, Lacroix-Triki M, et al: Mutational profile of metastatic breast cancers: A retrospective analysis. PLoS Med. 13:e10022012016. View Article : Google Scholar : PubMed/NCBI
41	Pritchard CC, Mateo J, Walsh MF, De Sarkar N, Abida W, Beltran H, Garofalo A, Gulati R, Carreira S, Eeles R, et al: Inherited DNA-Repair gene mutations in men with metastatic prostate cancer. New Engl J Med. 375:443–453. 2016. View Article : Google Scholar : PubMed/NCBI