INTRODUCTION: Breast cancer is the most prevalent malignancy among women worldwide. A significant portion of patients possess homologous recombination deficiency (HRD), often caused by BRCA1/2 mutations, which may sensitize tumors to PARP inhibitors and platinum-based chemotherapy through synthetic lethality. Since mutations in BRCA genes have been previously suggested in association with impaired biology of telomeres, in the present study we investigated leukocyte telomere length (LTL) to evaluate its potential utility as a biomarker for BRCA1 mutations and HRD. METHODOLOGY: LTL was measured using multiplex monochrome real-time qPCR in four groups: breast cancer patients with pathogenic hereditary BRCA1 mutations (n = 99), age-matched non-cancerous controls carrying the same BRCA1 mutations (n = 99), breast cancer patients with wild-type BRCA1 (n = 105), and age-matched non-cancerous controls with wild-type BRCA1 (n = 107). BRCA1 mutations were tested by the DNA sequencing approach. RESULTS: A significant negative correlation between age and LTL was observed across all studied groups, except in breast cancer patients carrying pathogenic hereditary BRCA1 mutations. Interestingly, after adjusting for age, BRCA1 mutation carriers had shorter LTL compared to non-carriers, regardless of the presence of cancer (P = 0.024). CONCLUSION: LTL shortening is associated with BRCA1 mutations, regardless of cancer status. Further validation studies are needed.

2nd Faculty of Medicine Charles University 5 Úvalu 84 150 06 Prague Czech Republic

Biomedical Centre Faculty of Medicine in Pilsen Charles University Alej Svobody 76 323 00 Pilsen Czech Republic

Department of Genetics and Pathology Pomeranian Medical University in Szczecin Szczecin Poland

Department of Molecular Biology of Cancer Institute of Experimental Medicine of the Czech Academy of Sciences Videnska 1083 142 20 Prague Czech Republic

Department of Physiology Faculty of Science Charles University Prague Czech Republic

German Cancer Research Center D 69120 Heidelberg Germany

Institute of Biology and Medical Genetics 1st Faculty of Medicine Charles University Albertov 4 128 00 Prague Czech Republic

Zobrazit více v PubMed

Arnold M, Morgan E, Rumgay H, et al. Current and future burden of breast cancer: global statistics for 2020 and 2040. Breast. 2022;66:15–23. 10.1016/j.breast.2022.08.010. PubMed DOI PMC

Huszno J, Kołosza Z, Grzybowska E. BRCA1 mutation in breast cancer patients: analysis of prognostic factors and survival. Oncol Lett. 2019;17:1986–95. 10.3892/ol.2018.9770. PubMed DOI PMC

Mutter RW, Riaz N, Ng CK, et al. Bi-allelic alterations in DNA repair genes underpin homologous recombination DNA repair defects in breast cancer. J Pathol. 2017;242:165–77. 10.1002/path.4890. PubMed DOI PMC

Mekonnen N, Yang H, Shin YK. Homologous recombination deficiency in Ovarian, Breast, Colorectal, Pancreatic, Non-Small cell lung and prostate Cancers, and the mechanisms of resistance to PARP inhibitors. Front Oncol. 2022;12:880643. 10.3389/fonc.2022.880643. PubMed DOI PMC

Wagener-Ryczek S, Merkelbach-Bruse S, Siemanowski J. Biomarkers for homologous recombination deficiency in cancer. J Pers Med. 2021;11:612. 10.3390/jpm11070612. PubMed DOI PMC

Srinivas N, Rachakonda S, Kumar R. Telomeres and telomere length: A general overview. Cancers (Basel). 2020;12:E558. 10.3390/cancers12030558. PubMed DOI PMC

Chen L, Tan KML, Gong M, et al. Variability in newborn telomere length is explained by inheritance and intrauterine environment. BMC Med. 2022;20:20. 10.1186/s12916-021-02217-9. PubMed DOI PMC

Schneider CV, Schneider KM, Teumer A, Rudolph KL, Hartmann D, Rader DJ, Strnad P. Association of telomere length with risk of disease and mortality. JAMA Intern Med. 2022;182:291–300. 10.1001/jamainternmed.2021.7804. PubMed DOI PMC

Akincilar SC, Unal B, Tergaonkar V. Reactivation of telomerase in cancer. Cell Mol Life Sci. 2016;73:1659–70. 10.1007/s00018-016-2146-9. PubMed DOI PMC

Ballal RD, Saha T, Fan S, Haddad BR, Rosen EM. BRCA1 localization to the telomere and its loss from the telomere in response to DNA damage. J Biol Chem. 2009;284:36083–98. 10.1074/jbc.M109.025825. PubMed DOI PMC

Uziel O, Yerushalmi R, Zuriano L, et al. BRCA1/2 mutations perturb telomere biology: characterization of structural and functional abnormalities in vitro and in vivo. Oncotarget. 2016;7:2433–54. 10.18632/oncotarget.5693. PubMed DOI PMC

Tanaka H, Phipps EA, Wei T, et al. Altered expression of telomere-associated genes in leukocytes among BRCA1 and BRCA2 carriers. Mol Carcinog. 2018;57:567–75. 10.1002/mc.22773. PubMed DOI PMC

Pooley KA, McGuffog L, Barrowdale D, et al. Lymphocyte telomere length is long in BRCA1 and BRCA2 mutation carriers regardless of cancer-affected status. Cancer Epidemiol Biomarkers Prev. 2014;23:1018–24. 10.1158/1055-9965.EPI-13-0635-T. PubMed DOI PMC

Leibowitz BD, Dougherty BV, Bell JSK, et al. Validation of genomic and transcriptomic models of homologous recombination deficiency in a real-world pan-cancer cohort. BMC Cancer. 2022;22:587. 10.1186/s12885-022-09669-z. PubMed DOI PMC

Kroupa M, Rachakonda SK, Liska V, et al. Relationship of telomere length in colorectal cancer patients with cancer phenotype and patient prognosis. Br J Cancer. 2019;121:344–50. 10.1038/s41416-019-0525-3. PubMed DOI PMC

Kroupa M, Kubecek O, Tomasova K, et al. The dynamics of telomere length in primary and metastatic colorectal cancer lesions. Sci Rep. 2023;13:9097. 10.1038/s41598-023-35835-9. PubMed DOI PMC

Kroupa M, Rachakonda S, Vymetalkova V, et al. Telomere length in peripheral blood lymphocytes related to genetic variation in telomerase, prognosis and clinicopathological features in breast cancer patients. Mutagenesis. 2020;35:491–7. 10.1093/mutage/geaa030. PubMed DOI

Kroupa M, Tomasova K, Kavec M, Skrobanek P, Buchler T, Kumar R, Vodickova L, Vodicka P. TElomeric repeat-containing RNA (TERRA): physiological functions and relevance in cancer. Front Oncol. 2022;12:913314. 10.3389/fonc.2022.913314. PubMed DOI PMC

Sedic M, Kuperwasser C. BRCA1-hapoinsufficiency: unraveling the molecular and cellular basis for tissue-specific cancer. Cell Cycle. 2016;15:621–7. 10.1080/15384101.2016.1141841. PubMed DOI PMC

Alhareeri AA, Archer KJ, Fu H, et al. Telomere lengths in women treated for breast cancer show associations with chemotherapy, pain symptoms, and cognitive domain measures: a longitudinal study. Breast Cancer Res. 2020;22:137. 10.1186/s13058-020-01368-6. PubMed DOI PMC

Vodenkova S, Kroupa M, Polivkova Z, et al. Chromosomal damage and telomere length in peripheral blood lymphocytes of cancer patients. Oncol Rep. 2020;44:2219–30. 10.3892/or.2020.7774. PubMed DOI

Benites-Zapata VA, Ulloque-Badaracco JR, Alarcón-Braga EA, Fernández-Alonso AM, López-Baena MT, Pérez-López FR. Telomerase activity and telomere length in women with breast cancer or without malignancy: A systematic review and meta-analysis. Maturitas. 2024;180:107882. 10.1016/j.maturitas.2023.107882. PubMed DOI

Killick E, Tymrakiewicz M, Cieza-Borrella C, et al. Telomere length shows no association with BRCA1 and BRCA2 mutation status. PLoS ONE. 2014;9:e86659. 10.1371/journal.pone.0086659. PubMed DOI PMC

Martinez-Delgado B, Yanowsky K, Inglada-Perez L, Domingo S, Urioste M, Osorio A, Benitez J. Genetic anticipation is associated with telomere shortening in hereditary breast cancer. PLoS Genet. 2011;7:e1002182. 10.1371/journal.pgen.1002182. PubMed DOI PMC

Thorvaldsdottir B, Aradottir M, Stefansson OA, Bodvarsdottir SK, Eyfjörd JE. Telomere length is predictive of breast cancer risk in BRCA2 mutation carriers. Cancer Epidemiol Biomarkers Prev. 2017;26:1248–54. 10.1158/1055-9965.EPI-16-0946. PubMed DOI

Gielen M, Hageman GJ, Antoniou EE, et al. Body mass index is negatively associated with telomere length: a collaborative cross-sectional meta-analysis of 87 observational studies. Am J Clin Nutr. 2018;108:453–75. 10.1093/ajcn/nqy107. PubMed DOI PMC

Mathur MB, Epel E, Kind S, Desai M, Parks CG, Sandler DP, Khazeni N. Perceived stress and telomere length: A systematic review, meta-analysis, and methodologic considerations for advancing the field. Brain Behav Immun. 2016;54:158–69. 10.1016/j.bbi.2016.02.002. PubMed DOI PMC

Sánchez-González JL, Sánchez-Rodríguez JL, Varela-Rodríguez S, et al. Effects of physical exercise on telomere length in healthy adults: systematic Review, Meta-Analysis, and Meta-Regression. JMIR Public Health Surveill. 2024;10:e46019. 10.2196/46019. PubMed DOI PMC

Tempaku P, Hirotsu C, Mazzotti D, et al. Long sleep duration, insomnia, and insomnia with short objective sleep duration are independently associated with short telomere length. J Clin Sleep Med. 2018;142037–2045. 10.5664/jcsm.7532. PubMed PMC