PATHOLOGICAL SIGNIFICANCE OF CDH1/E-CADHERIN GERMLINE SEQUENCE VARIANTS IN BREAST CANCER PATIENTS
DOI:
https://doi.org/10.15407/exp-oncology.2023.02.170Keywords:
breast cancer, CDH1, E-cadherin, SSCP, sequencing, variant analysis.Abstract
Background. Germline alterations of the CDH1 (E-cadherin) tumor suppressor gene have been reported in several epithelial malignancies like hereditary diffuse gastric cancer and lobular breast cancer. E-cadherin plays a central role in proliferation, maintenance of cell-to-cell adhesion, polarity, and epithelial-mesenchymal transition of tissue cells. It is necessary to analyze the impact of the CDH1 germline sequence variants on protein and predict its clinical significance in breast cancer (BC) progression. The aim of the current study was to evaluate the impact and association of CDH1 gene potentially pathogenic variants/likely pathogenic variants (PVs/LPVs) with the initiation and progression of BC. Materials and Methods. In this study, the clinical data of 200 BC patients have been analyzed based on the type of BC, age, grade, stage, hormonal status, and risk factors. Blood samples from 50 healthy donors were used as a control. Furthermore, CDH1 gene molecular analysis, along with in silico analysis, was provided to assess the invasiveness and progression of BC caused by the E-cadherin protein. Results. Four variants were identified by genetic screening within the CDH1 gene that included variations in exons 7, 8, 10, 11, and 13. Exon 10 had splice site mutation at position c.1337C>A, affecting the protein structure. In exon 11, there was an insertion of T base at position 1669, resulting in truncated protein compared to a normal one that can lead to the disease-causing non- sense-mediated decay and exon 13 variant c.2076T>C has already known polymorphism. In silico analysis of CDH1 showed the presence of the different variants that indicated the overall disruption of protein structure and function. Conclusions. The further functional analysis of these variants and their association with BC can be ensured by increasing the sample size and in vivo studies using mouse models.
References
Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209-249. doi: 10.3322/caac.21660
Bilal M, Bilal M, Tabassum S, et al. Optical screening of female breast cancer from whole blood using Raman spectroscopy. Appl Spectrosc. 2017;71:1004-1013. doi: 10.1177/0003702816667516
Begum N. Breast cancer in Pakistan: A looming epidemic. J Coll Physicians Surg Pakistan. 2018;28:87-88. doi:10.29271/jcpsp.2018.02.87
Dossus L, Benusiglio PR. Lobular breast cancer: incidence and genetic and non-genetic risk factors. Breast Can cer Res. 2015;17:37. doi:10.1186/s13058-015-0546-7
Incorvaia L, Fanale D, Badalamenti G, et al. Hereditary breast and ovarian cancer in families from Southern Italy (Sicily) — prevalence and geographic distribution of pathogenic variants in BRCA1/2 genes. Cancers. 2020;12(5):1158. doi: 10.3390/cancers12051158
El Ansari FZ, Jouali F, Marchoudi N, et al. Screening of BRCA1/2 genes mutations and copy number variations in patients with high risk for hereditary breast and ovarian cancer syndrome (HBOC). BMC Cancer. 2020;20:747. doi: 10.1186/s12885-020-07250-0
Russo A, Calò V, Bruno L, et al. Is BRCA1-5083del19, identified in breast cancer patients of Sicilian origin, a Calabrian founder mutation? Breast Cancer Res Treat. 2009;113(1):67-70.doi: 10.1007/s10549-008-9906-7
Germani A, Petrucci S, De Marchis L, et al. Beyond BRCA1 and BRCA2: deleterious variants in DNA repair path- way genes in italian families with breast/ovarian and pancreatic cancers. J Clin Med. 2020;9(9):3003.doi:10.3390/ jcm9093003
Fanale D, Incorvaia L, Filorizzo C, et al. Detection of germline mutations in a cohort of 139 patients with bilateral breast cancer by multi-gene panel testing: impact of pathogenic variants in other genes beyond BRCA1/2. Can cers. 2020;12:2415. doi:10.3390/cancers12092415
Girardi A, Magnoni F, Vicini E, et al. CDH1 germline mutations in families with hereditary lobular breast cancer.
Eur J Cancer Prev. 2022;31(3):274-278. doi: 10.1097/CEJ.0000000000000688
Gamble LA, Rossi A, Fasaye GA, et al. Association between hereditary lobular breast cancer due to CDH1vari- ants and gastric cancer risk. JAMA Surg. 2022;157(1):18-22. doi:10.1001/jamasurg.2021.5118
López M, Cervera-Acedo C, Santibáñez P, et al. A novel mutation in the CDH1 gene in a Spanish family with hereditary diffuse gastric cancer. Springerplus. 2016;5:1181. doi: 10.1186/s40064-016-2852-7
Corso G, Figueiredo J, De Angelis SP, et al. E-cadherin deregulation in breast cancer. J Cell Mol Med. 2020;24:5930- 5936. doi: 10.1111/jcmm.15140
Asiaf A, Ahmad ST, Aziz SA, et al. Loss of expression and aberrant methylation of the CDH1 (E-cadherin) gene in breast cancer patients from Kashmir. Asian Pac J Cancer Prev. 2014;15:6397-6403. doi: 10.7314/ apjcp.2014.15.15.6397
Kurian AW, Hughes E, Handorf EA, et al. Breast and ovarian cancer penetrance estimates derived from germline multiple-gene sequencing results in women. JCO Precis Oncol. 2017;1:1-12. doi: 10.1200/PO.16.00066
Bono M, Fanale D, Incorvaia L, et al. Impact of deleterious variants in other genes beyond BRCA1/2 detected in breast/ovarian and pancreatic cancer patients by NGS-based multi-gene panel testing: looking over the hedge. ESMO Open. 2021;6(4):100235. doi: 10.1016/j.esmoop.2021.100235
Neben CL, Zimmer AD, Stedden W, et al. Multi-gene panel testing of 23,179 individuals for hereditary cancer risk identifies pathogenic variant carriers missed by current genetic testing guidelines. J Mol Diagn. 2019;21(4):646- 657. doi: 10.1016/j.jmoldx.2019.03.001
Stjepanovic N, Moreira L, Carneiro F, et al. Hereditary gastrointestinal cancers: ESMO Clinical Practice Guide- lines for diagnosis, treatment and follow-up†. Ann Oncol. 2019;30(10):1558-1571 doi: 10.1093/annonc/mdz233
Biasini M, Bienert S, Waterhouse A, et al. SWISS-MODEL: Modelling protein tertiary and quaternary structure using evolutionary information. Nucleic Acids Res. 2014;42:W252-W258. doi: 10.1093/nar/gku340
Liu S, Wang H, Zhang L, et al. Rapid detection of genetic mutations in individual breast cancer patients by next- generation DNA sequencing. Hum Genomics. 2015;9:2. doi: 10.1186/s40246-015-0024-4
Halder S, Mallick D, Mondal P, et al. Detection and significance of human epidermal growth factor receptor 2 expression in gastric adenocarcinoma. Indian J Med Paediatr Oncol. 2017;38:153-157. doi: 10.4103/ijmpo.ijm- po_159_16
Kim SA, Inamura K, Yamauchi M, et al. Loss of CDH1 (E-cadherin) expression is associated with infiltrative tumour growth and lymph node metastasis. Br J Cancer. 2016;114:199-206. doi: 10.1038/bjc.2015.347
Sunami E, Shinozaki M, Sim MS, et al. Estrogen receptor and HER2/neu status affect epigenetic differences of tumor-related genes in primary breast tumors. Breast Cancer Res. 2008;10:R46. doi: 10.1186/bcr2098
Salahshor S, Haixin L, Huo H, et al. Low frequency of E-cadherin alterations in familial breast cancer. Breast Cancer Res. 2001;3:199-207. doi: 10.1186/bcr295
Jakubowska A, Ławniczak M, Wojnarska B, et al. CDH1 gene mutations do not contribute in hereditary diffuse gastric cancer in Poland. Fam Cancer. 2010;9(4):605-608. doi.org/10.1007/s10689-010-9381-2
Heck JW, Cheung SK, Hampton RY. Cytoplasmic protein quality control degradation mediated by parallel ac- tions of the E3 ubiquitin ligases Ubr1 and San1. Proc Natl Acad Sci U S A. 2010;107:1106-1111. doi: 10.1073/ pnas.0910591107
Melo S, Figueiredo J, Fernandes MS, et al. Predicting the functional impact of CDH1 missense mutations in hereditary diffuse gastric cancer. Int J Mol Sci. 2017;18:2687. doi: 10.3390/ijms18122687
Shenoy S. CDH1 (E-cadherin) mutation and gastric cancer: Genetics, molecular mechanisms and guidelines for management. Cancer Manag Res. 2019;11:10477-10486. doi.org/10.2147/CMAR.S208818. doi: 10.2147/CMAR. S208818
Zylberberg HM, Sultan K, Rubin S. Hereditary diffuse gastric cancer: One family’s story. World J Clin Cases. 2018;6:1-5. doi: 10.12998/wjcc.v6.i1.1
Submitted: November 11, 2021
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2023 Experimental Oncology
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.