Remember me
Research Article
Aksoy F.a· Tezcan Unlu H.b· Cecener G.b· Guney Eskiler G.c· Egeli U.b· Tunca B.b· Efendi Erdem E.b· Senol K.a· Gokgoz M.S.aaDepartment of General Surgery, Faculty of Medicine, Bursa Uludag University, Bursa, Turkey
bDepartment of Medical Biology, Faculty of Medicine, Bursa Uludag University, Bursa, Turkey
cDepartment of Medical Biology, Faculty of Medicine, Sakarya University, Sakarya, Turkey
Mustafa Sehsuvar Gokgoz, sehsuvar@uludag.edu.tr
AbstractIntroduction: The CHEK2 gene is known to be an important signal transducer involved in DNA repair, apoptosis, or cell cycle arrest in response to DNA damage. The mutations in this gene have been associated with a wide range of cancers, both sporadic and hereditary. Germline CHEK2 mutations are linked to an increased risk of breast cancer. Therefore, the aim of this study was to identify the prevalence of CHEK2 variants in BRCA1/2- and PALB2-negative early-onset patients with breast cancer and/or ovarian cancer in a Turkish population for the first time. Methods: The study included 95 patients with BRCA1/2- and PALB2-negative early-onset breast cancer and/or ovarian cancer and also 60 unaffected women. All the intron/exon boundaries and coding exons of CHEK2 were subjected to mutational analysis by heteroduplex analysis and DNA sequencing. Results: A total of 16 CHEK2 variants were found in breast cancer patients within the Turkish population. CHEK2 c.1100delC mutation most frequently studied in the CHEK2 gene was not detected in our study. The prevalence of variants of uncertain significance in CHEK2 was found to be 7.3% (n = 7) in BRCA1/2 and PALB2 mutation-negative Turkish patients with early-onset breast and/or ovarian cancer. Conclusion: The present study may shed light on alternative variations that could be significant for understanding the prevalence and clinical suitability of the CHEK2 gene.
© 2022 The Author(s). Published by S. Karger AG, Basel
References Apostolou P, Fostira F. Hereditary breast cancer: the era of new susceptibility genes. Biomed Res Int. 2013;2013:747318. Desrichard A, Bidet Y, Uhrhammer N, Bignon YJ. CHEK2 contribution to hereditary breast cancer in non-BRCA families. Breast Cancer Res. 2011;13:R119. Seal S, Thompson D, Renwick A, Elliott A, Kelly P, Barfoot R, et al. Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles. Nat Genet. 2006;38:1239–41. Godet I, Gilkes DM. BRCA1 and BRCA2 mutations and treatment strategies for breast cancer. Integr Cancer Sci Ther. 2017;4:1–7. Cecener G, Guney Eskiler G, Egeli U, Tunca B, Alemdar A, Gokgoz S, et al. Association of PALB2 sequence variants with the risk of early-onset breast cancer in patients from Turkey. Mol Biol Rep. 2016;43:1273–84. Fan Z, Ouyang T, Li J, Wang T, Fan Z, Fan T, et al. Identification and analysis of CHEK2 germline mutations in Chinese BRCA1/2-negative breast cancer patients. Breast Cancer Res Treat. 2018;169:59–67. Huszno JA, Budryk MB, Kolosza ZC, Tęcza K, Pamuła Piłat J, Nowara E, et al. A comparison between CHEK2 c.1100delC/I157T mutation carrier and noncarrier breast cancer patients: a clinicopathological analysis. Oncology. 2016;90:193–8. Ow GS, Ivshina AV, Fuentes G, Kuznetsov VA. Identification of two poorly prognosed ovarian carcinoma subtypes associated with CHEK2 germ-line mutation and non-CHEK2 somatic mutation gene signatures. Cell Cycle. 2014;13:2262–80. Cai Z, Chehab NH, Pavletich NP. Structure and activation mechanism of the CHK2 DNA damage checkpoint kinase. Mol Cell. 2009;35:818–29. Apostolou P, Fostira F, Papamentzelopoulou M, Michelli M, Panopoulos C, Fountzilas G, et al. CHEK2 c.1100delC allele is rarely identified in Greek breast cancer cases. Cancer Genet. 2015;208:129–34. Osorio A, Rodriguez-Lopez R, Diez O, de la Hoya M, Ignacio Martínez J, Vega A, et al. The breast cancer low-penetrance allele 1100delC in the CHEK2 gene is not present in Spanish familial breast cancer population. Int J Cancer. 2004;108:54–6. Vahteristo P, Bartkova J, Eerola H, Syrjäkoski K, Ojala S, Kilpivaara O, et al. A CHEK2 genetic variant contributing to a substantial fraction of familial breast cancer. Am J Hum Genet. 2002;71:432–8. Egeli U, Cecener G, Tunca B, Tasdelen I. Novel germline BRCA1 and BRCA2 mutations in Turkish women with breast and/or ovarian cancer and their relatives. Cancer Invest. 2006;24:484–91. Cecener G, Egeli U, Tunca B, Erturk E, Ak S, Gokgoz S, et al. BRCA1/2 germline mutations and their clinical importance in Turkish breast cancer patients. Cancer Invest. 2014;32:375–87. Goidescu IG, Caracostea G, Eniu DT, Stamatian FV. Prevalence of deleterious mutations among patients with breast cancer referred for multigene panel testing in a Romanian population. Clujul Med. 2018;91:157–65. Rashid MU, Muhammad N, Faisal S, Amin A, Hamann U. Constitutional CHEK2 mutations are infrequent in early-onset and familial breast/ovarian cancer patients from Pakistan. BMC Cancer. 2013;13:312. Thompson D, Seal S, Schutte M, McGuffog L, Barfoot R, Renwick A, et al. A multicenter study of cancer incidence in CHEK2 1100delC mutation carriers. Cancer Epidemiol Biomarkers Prev. 2006;15:2542–5. Adank MA, Jonker MA, Kluijt I, Van Mil SE, Oldenburg RA, Mooi WJ, et al. CHEK2 c.1100delC homozygosity is associated with a high breast cancer risk in women. J Med Genet. 2011;48:860–3. Iniesta MD, Merajver SD. CHEK2 screening: do not think so globally yet. J Clin Oncol. 2008;26:3092. Offit K, Garber JE. Time to check CHEK2 in families with breast cancer? J Clin Oncol. 2008;26:519–20. Manguoglu E, Guran S, Yamac D, Simsek M, Akdeniz S, Colak T, et al. Genomic large rearrangement screening of BRCA1 and BRCA2 genes in high-risk Turkish breast/ovarian cancer patients by using multiplex ligation-dependent probe amplification assay. Cancer Invest. 2011;29:73–7. Wang N, Ding H, Liu C, Li X, Wei L, Yu J, et al. A novel recurrent CHEK2 Y390C mutation identified in high-risk Chinese breast cancer patients impairs its activity and is associated with increased breast cancer risk. Oncogene. 2015;34:5198–205. Lindor NM, Guidugli L, Wang X, Vallée MP, Monteiro AN, Tavtigian S, et al. A review of a multifactorial probability-based model for classification of BRCA1 and BRCA2 variants of uncertain significance (VUS). Hum Mutat. 2012;33:8–21. Gomez-Garcia EB, Ambergen T, Blok MJ, van den Wijngaard A. Patients with an unclassified genetic variant in the BRCA1 or BRCA2 genes show different clinical features from those with a mutation. J Clin Oncol. 2005;23:2185–90. Slavin TP, Manjarrez S, Pritchard CC, Gray S, Weitzel JN. The effects of genomic germline variant reclassification on clinical cancer care. Oncotarget. 2019;10:417–23. Havranek O, Kleiblova P, Hojny J, Lhota F, Soucek P, Trneny M, et al. Association of germline CHEK2 gene variants with risk and prognosis of non-hodgkin lymphoma. PLoS One. 2015;10:e0140819. Yurgelun MB, Allen B, Kaldate RR, Bowles KR, Judkins T, Trneny M, et al. Identification of a variety of mutations in cancer predisposition genes in patients with suspected lynch syndrome. Gastroenterology. 2015;149:604–13. Kukita Y, Okami J, Yoneda-Kato N, Nakamae I, Kawabata T, Higashiyama M, et al. Homozygous inactivation of CHEK2 is linked to a familial case of multiple primary lung cancer with accompanying cancers in other organs. Cold Spring Harb Mol Case Stud. 2016;2:a001032. Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho Y-Y, et al. Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. Genet Med. 2017;19:1105–17. Kuusisto KM, Bebel A, Vihinen M, Schleutker J, Sallinen SL. Screening for BRCA1, BRCA2, CHEK2, PALB2, BRIP1, RAD50, and CDH1 mutations in high-risk Finnish BRCA1/2-founder mutation-negative breast and/or ovarian cancer individuals. Breast Cancer Res. 2011;13:R20. Byrnes GB, Southey MC, Hopper JL. Are the so-called low penetrance breast cancer genes, ATM, BRIP1, PALB2 and CHEK2, high risk for women with strong family histories? Breast Cancer Res. 2008;10:208. Gronwald J, Cybulski C, Piesiak W, Suchy J, Huzarski T, Byrski T, et al. Cancer risks in first-degree relatives of CHEK2 mutation carriers: effects of mutation type and cancer site in proband. Br J Cancer. 2009;100:1508–12. Cybulski C, Wokolorczyk D, Jakubowska A, Huzarski T, Byrski T, Gronwald J, et al. Risk of breast cancer in women with a CHEK2 mutation with and without a family history of breast cancer. J Clin Oncol. 2011;29:3747–52. Article / Publication DetailsFirst-Page Preview
Received: October 13, 2021
Accepted: November 25, 2021
Published online: January 06, 2022
Number of Print Pages: 13
Number of Figures: 6
Number of Tables: 7
ISSN: 0001-5652 (Print)
eISSN: 1423-0062 (Online)
For additional information: https://www.karger.com/HHE
Figures
Tables
Open Access License / Drug Dosage / Disclaimer
This article is licensed under the Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC). Usage and distribution for commercial purposes requires written permission. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
Comments (0)