Highlights
- •The role of the epidermal growth factor family in PNET is unknown.
- •EGFR +1562 AG genotype is associated with an increased risk of PNET development.
- •Carriers of AA/AG EGF+61/HER2+1963 combination genotype are at risk of developing PNET.
- •EGFR +1562 AA genotype could be associated with the risk of insulinoma development.
- •EGF, EGFR or HER2 SNPs are not associated with the presence of metastasis.
Abstract
Objectives
Pancreatic neuroendocrine tumors (NETs) are rare and account for about 7% of all cancers
occurring in the pancreas. The epidermal growth factor family of receptors and their
ligands play an important role in the growth and progression of tumors but their role
in PNET development remains unknown. We hypothesized that functional single nucleotide
polymorphisms (SNPs) in the EGF, EGFR, and HER2 genes might affect individual susceptibility to PNETs development and invasion like
it was shown for various other tumors.
Methods
We genotyped 68 patients with unresectable PNETs and 300 controls to evaluate the
association between EGF, EGFR, and HER2 polymorphisms and susceptibility to PNETs and presence of metastases.
Results
Genotype analysis of three SNPs EGF +61A/G (rs4444903), EGFR +1562 G/A (rs11543848), and HER2 +1963 A/G (rs1136201) showed that carriers of EGFR +1562 AG genotype and AA/AG EGF +61/HER2 +1963 genotype combination are at risk of developing PNET. Furthermore, EGFR +1562
AA genotype could be associated with the susceptibility to insulinoma development.
Conclusions
Our results suggest involvement of EGFR signaling pathway in etiology of PNET development.
Keywords
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References
- The landscape of molecular alterations in pancreatic and small intestinal neuroendocrine tumours.Ann Endocrinol. 2019; 80 (Paris): 153-158
- Neuroendocrine tumors of the pancreas.Oncologist. 2009; 14: 456-467
- Vienna consensus conference p. ENETS consensus guidelines update for the management of patients with functional pancreatic neuroendocrine tumors and non-functional pancreatic neuroendocrine tumors.Neuroendocrinology. 2016; 103: 153-171
- Comparison of demographics, tumor characteristics, and survival between pancreatic adenocarcinomas and pancreatic neuroendocrine tumors: a population-based study.Am J Clin Oncol. 2018; 41: 485-491
- The diversity and commonalities of gastroenteropancreatic neuroendocrine tumors.Langenbecks Arch Surg. 2011; 396: 273-298
- Pancreatic neuroendocrine tumors.Curr Opin Gastroenterol. 2019; 35: 468-477
- Decoding the molecular and mutational ambiguities of gastroenteropancreatic neuroendocrine neoplasm pathobiology.Cell Mol Gastroenterol Hepatol. 2015; 1: 131-153
- Gastrointestinal hormones stimulate growth of Foregut Neuroendocrine Tumors by transactivating the EGF receptor.Biochim Biophys Acta. 2013; 1833: 573-582
- Common germline variants within the CDKN2A/2B region affect risk of pancreatic neuroendocrine tumors.Sci Rep. 2016; 6: 39565
- Genetic polymorphisms of interleukin 1beta gene and sporadic pancreatic neuroendocrine tumors susceptibility.World J Gastrointest Oncol. 2016; 8: 520-525
- Genetic polymorphisms involved in mitochondrial metabolism and pancreatic cancer risk.Cancer Epidemiol Biomarkers Prev. 2021; 30: 2342-2345
- Common genetic variants associated with pancreatic adenocarcinoma may also modify risk of pancreatic neuroendocrine neoplasms.Carcinogenesis. 2018; 39: 360-367
- Growth factors, cell proliferation and cancer: an overview.Mol Biol Med. 1983; 1: 169-181
- The EGF receptor family as targets for cancer therapy.Oncogene. 2000; 19: 6550-6565
- Rethink of EGFR in cancer with its kinase independent function on board.Front Oncol. 2019; 9: 800
- Molecular mechanisms of epidermal growth factor receptor overexpression in patients with cervical cancer.Mod Pathol. 2011; 24: 720-728
- [EGFR expression in colorectal cancer and role in tumorigenesis].Bull Cancer. 2005; 92: S5-11
- Expression and clinical significance of MAPK and EGFR in triple-negative breast cancer.Oncol Lett. 2020; 19: 1842-1848
- Comprehensive biomarker analyses identifies HER2, EGFR, MET RNA expression and thymidylate synthase 5′UTR SNP as predictors of benefit from S-1 adjuvant chemotherapy in Japanese patients with stage II/III gastric cancer.J Cancer. 2019; 10: 5130-5138
- Epidermal growth factor receptor: mechanisms of activation and signalling.Exp Cell Res. 2003; 284: 31-53
- Molecular markers for novel therapeutic strategies in pancreatic endocrine tumors.Pancreas. 2013; 42: 411-421
- Growth factor receptor expression in human gastroenteropancreatic neuroendocrine tumours.Eur J Clin Invest. 1998; 28: 1038-1049
- Expression of the HER-1-4 family of receptor tyrosine kinases in neuroendocrine tumours.Oncol Rep. 2010; 23: 909-915
- Blood-based next-generation sequencing analysis of neuroendocrine neoplasms.Oncotarget. 2020; 11: 1749-1757
- Studies of growth regulation in a neuroendocrine cell line.Acta Oncol. 1993; 32: 125-130
- Epidermal growth factor receptor and activated epidermal growth factor receptor expression in gastrointestinal carcinoids and pancreatic endocrine carcinomas.Mod Pathol. 2005; 18: 1329-1335
- Polymorphisms of the epidermal growth factor receptor (EGFR) and survival in patients with advanced cancer of the head and neck (HNSCC).Anticancer Res. 2012; 32: 421-425
- Association between polymorphisms in EGFR and tumor response during cetuximab and oxaliplatin-based combination therapy in metastatic colorectal cancer: analysis of data from two clinical trials.Oncol Lett. 2019; 18: 4555-4562
- -216G/T (rs712829), a functional variant of the EGFR promoter, is associated with the pleural metastasis of lung adenocarcinoma.Oncol Lett. 2013; 6: 693-698
- Association of the epidermal growth factor gene +61A>G polymorphism with hepatocellular carcinoma in an Iranian population.Gastroenterol Hepatol Bed Bench. 2017; 10: 284-288
- HER1 R497K and HER2 I655V polymorphisms are linked to development of breast cancer.Dis Markers. 2013; 34: 407-417
- EGFR R497K polymorphism is a favorable prognostic factor for advanced lung cancer.J Cancer Res Clin Oncol. 2009; 135: 313-318
- A polymorphism of the interleukin-1 beta gene influences survival in pancreatic cancer.Br J Cancer. 2000; 83: 1443-1447
- Neuroendocrine tumors of the gastro-entero-pancreatic system.World J Gastroenterol. 2008; 14: 5377-5384
- Prognostic value of hMLH1 methylation and microsatellite instability in pancreatic endocrine neoplasms.Surgery. 2003; 134 (discussion 9): 902-908
- Interleukin-1 beta-induced nitric oxide production activates apoptosis in pancreatic RINm5F cells.Exp Cell Res. 1994; 213: 172-177
- Human tumour bank in croatia: a possible model for a small bank as part of the future European tumour bank network.Eur J Cancer. 1994; 30A: 419
- Neuroendocrine neoplasia of the gastrointestinal tract revisited: towards precision medicine.Nat Rev Endocrinol. 2020; 16: 590-607
- Overexpression of epidermal growth factor and hepatocyte growth factor receptors in a proportion of gastrinomas correlates with aggressive growth and lower curability.Clin Cancer Res. 2002; 8: 2273-2285
- Association between the epidermal growth factor +61G/A polymorphism and glioma risk: a meta-analysis.PLoS One. 2014; 9: e95139
- A single nucleotide polymorphism in the 5′ untranslated region of the EGF gene is associated with occurrence and malignant progression of gastric cancer.Pathobiology. 2005; 72: 133-138
- Epidermal-growth-factor receptor status as predictor of early recurrence of and death from breast cancer.Lancet. 1987; 1: 1398-1402
- Staging of head and neck squamous cell carcinoma using the MET oncogene product as marker of tumor cells in lymph node metastases.Int J Cancer. 2000; 89: 286-292
- Overexpression of c-Met protein in human thyroid tumors correlated with lymph node metastasis and clinicopathologic stage.Pathol Res Pract. 1999; 195: 427-433
- Relationship of epidermal growth factor binding capacity to histopathologic features and prognosis in human renal cell carcinoma.Invasion Metastasis. 1997; 17: 94-100
- In pancreatic carcinoma, dual EGFR/HER2 targeting with cetuximab/trastuzumab is more effective than treatment with trastuzumab/erlotinib or lapatinib alone: implication of receptors' down-regulation and dimers' disruption.Neoplasia. 2012; 14: 121-130
- A phase II trial of gefitinib in patients (pts) with progressive metastatic neuroendocrine tumors (NET): a phase II consortium (P2C) study.J. Clin. Oncol. 2006; 24: 4043
- Whole exome sequencing of insulinoma reveals recurrent T372R mutations in YY1.Nat Commun. 2013; 4: 2810
- Mutation and expression of gene YY1 in pancreatic neuroendocrine tumors and its clinical significance.Endocr Pract. 2021; 27: 874-880
- DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors.Science. 2011; 331: 1199-1203
Article info
Publication history
Published online: June 21, 2022
Accepted:
June 14,
2022
Received in revised form:
May 31,
2022
Received:
November 17,
2021
Identification
Copyright
© 2022 Published by Elsevier Inc.
