Skip to main content

Small fraction of testicular cancer cases may be causatively related to CHEK2 inactivating germ-line mutations: evidence for somatic loss of the remaining CHEK2 allele in the tumor tissue

Familial Cancer volume 20, pages 49–53 (2021)Cite this article

Abstract

A recent study suggested a role of CHEK2 loss-of-function germ-line pathogenic variants in the predisposition to testicular cancer (TC) (AlDubayan et al. JAMA Oncol 5:514–522, 2019). We attempted to validate this finding relying on the high population frequency of recurrent CHEK2 pathogenic variants in Slavic populations. CHEK2 pathogenic alleles (c.1100delC (p.Thr367Metfs); del5395 [del ex9-10]; IVS2 + 1G > A [c.444 + 1G > A]) were detected in 7/280 (2.5%) TC patients vs. 3/424 (0.7%) healthy men and 6/1007 (0.6%) healthy women [OR 4.0 (95% CI 1.5–11), p = 0.009 for pooled control groups]. Somatic CHEK2 loss-of-heterozygosity (LOH) was detected in 4 out of 6 tumors available for analysis; strikingly all these instances of LOH involved inactivation of the wild-type allele. The CHEK2 c.470T > C (p.Ile157Thr) variant was detected in 21/280 (7.5%) affected vs. 22/424 (5.2%) non-affected men [OR 1.5 (95% CI 0.8–2.7), p = 0.3]. Somatic CHEK2 LOH was revealed only in 6 out of 21 tumors obtained from CHEK2 c.470T > C (p.Ile157Thr) carriers, with the C-allele lost in two cases and T-allele deleted in four tumors. The results of comparison of allele frequencies in TC patients versus population controls coupled with the data on CHEK2 LOH status in tumor tissues support the association of CHEK2 pathogenic variants with TC risk.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

References

  1. Litchfield K, Thomsen H, Mitchell JS, Sundquist J, Houlston RS, Hemminki K, Turnbull C (2015) Quantifying the heritability of testicular germ cell tumour using both population-based and genomic approaches. Sci Rep 5:13889

    Article  Google Scholar 

  2. Litchfield K, Levy M, Orlando G, Loveday C, Law PJ, Migliorini G, Holroyd A, Broderick P, Karlsson R, Haugen TB, Kristiansen W, Nsengimana J, Fenwick K, Assiotis I, Kote-Jarai Z, Dunning AM, Muir K, Peto J, Eeles R, Easton DF, Dudakia D, Orr N, Pashayan N, UK Testicular Cancer Collaboration, PRACTICAL Consortium, Bishop DT, Reid A, Huddart RA, Shipley J, Grotmol T, Wiklund F, Houlston RS, Turnbull C (2017) Identification of 19 new risk loci and potential regulatory mechanisms influencing susceptibility to testicular germ cell tumor. Nat Genet 49:1133–1140

    CAS  Article  Google Scholar 

  3. Wang Z, McGlynn KA, Rajpert-De Meyts E, Bishop DT, Chung CC, Dalgaard MD, Greene MH, Gupta R, Grotmol T, Haugen TB, Karlsson R, Litchfield K, Mitra N, Nielsen K, Pyle LC, Schwartz SM, Thorsson V, Vardhanabhuti S, Wiklund F, Turnbull C, Chanock SJ, Kanetsky PA, Nathanson KL, Testicular Cancer Consortium (2017) Meta-analysis of five genome-wide association studies identifies multiple new loci associated with testicular germ cell tumor. Nat Genet 49:1141–1147

    CAS  Article  Google Scholar 

  4. Hanna NH, Einhorn LH (2014) Testicular cancer–discoveries and updates. N Engl J Med 371:2005–2016

    Article  Google Scholar 

  5. Rajpert-De Meyts E, McGlynn KA, Okamoto K, Jewett MA, Bokemeyer C (2016) Testicular germ cell tumours. Lancet 387:1762–1774

    Article  Google Scholar 

  6. Cheng L, Albers P, Berney DM, Feldman DR, Daugaard G, Gilligan T, Looijenga LHJ (2018) Testicular cancer. Nat Rev Dis Primers 4:29

    Article  Google Scholar 

  7. AlDubayan SH, Pyle LC, Gamulin M, Kulis T, Moore ND, Taylor-Weiner A, Hamid AA, Reardon B, Wubbenhorst B, Godse R, Vaughn DJ, Jacobs LA, Meien S, Grgic M, Kastelan Z, Markt SC, Damrauer SM, Rader DJ, Kember RL, Loud JT, Kanetsky PA, Greene MH, Sweeney CJ, Kubisch C, Nathanson KL, Van Allen EM, Stewart DR, Lessel D, Regeneron Genetics Center (RGC) Research Team (2019) Association of inherited pathogenic variants in checkpoint kinase 2 (CHEK2) with susceptibility to testicular germ cell tumors. JAMA Oncol 5:514–522

    Article  Google Scholar 

  8. Sokolenko AP, Rozanov ME, Mitiushkina NV, Sherina NY, Iyevleva AG, Chekmariova EV, Buslov KG, Shilov ES, Togo AV, Bit-Sava EM, Voskresenskiy DA, Chagunava OL, Devilee P, Cornelisse C, Semiglazov VF, Imyanitov EN (2007) Founder mutations in early-onset, familial and bilateral breast cancer patients from Russia. Fam Cancer 6:281–286

    CAS  Article  Google Scholar 

  9. Sokolenko AP, Bogdanova N, Kluzniak W, Preobrazhenskaya EV, Kuligina ES, Iyevleva AG, Aleksakhina SN, Mitiushkina NV, Gorodnova TV, Bessonov AA, Togo AV, Lubiński J, Cybulski C, Jakubowska A, Dörk T, Imyanitov EN (2014) Double heterozygotes among breast cancer patients analyzed for BRCA1, CHEK2, ATM, NBN/NBS1, and BLM germ-line mutations. Breast Cancer Res Treat 145:553–562

    CAS  Article  Google Scholar 

  10. Szymanska-Pasternak J, Szymanska A, Medrek K, Imyanitov EN, Cybulski C, Gorski B, Magnowski P, Dziuba I, Gugala K, Debniak B, Gozdz S, Sokolenko AP, Krylova NY, Lobeiko OS, Narod SA, Lubinski J (2006) CHEK2 variants predispose to benign, borderline and low-grade invasive ovarian tumors. Gynecol Oncol 102:429–431

    CAS  Article  Google Scholar 

  11. Han FF, Guo CL, Liu LH (2013) The effect of CHEK2 variant I157T on cancer susceptibility: evidence from a meta-analysis. DNA Cell Biol 32:329–335

    CAS  Article  Google Scholar 

  12. Yanus GA, Akhapkina TA, Ivantsov AO, Preobrazhenskaya EV, Aleksakhina SN, Bizin IV, Sokolenko AP, Mitiushkina NV, Kuligina ES, Suspitsin EN, Venina AR, Holmatov MM, Zaitseva OA, Yatsuk OS, Pashkov DV, Belyaev AM, Togo AV, Imyanitov EN, Iyevleva AG (2018) Spectrum of APC and MUTYH germ-line mutations in Russian patients with colorectal malignancies. Clin Genet 93:1015–1021

    CAS  Article  Google Scholar 

  13. Yanus GA, Belyaeva AV, Ivantsov AO, Kuligina ESh, Suspitsin EN, Mitiushkina NV, Aleksakhina SN, Iyevleva AG, Zaitseva OA, Yatsuk OS, Gorodnova TV, Strelkova TN, Efremova SA, Lepenchuk AY, Ochir-Garyaev AN, Paneyah MB, Matsko DE, Togo AV, Imyanitov EN (2013) Pattern of clinically relevant mutations in consecutive series of Russian colorectal cancer patients. Med Oncol 30:686

    Article  Google Scholar 

  14. Suspitsin EN, Yanus GA, Sokolenko AP, Yatsuk OS, Zaitseva OA, Bessonov AA, Ivantsov AO, Heinstein VA, Klimashevskiy VF, Togo AV, Imyanitov EN (2014) Development of breast tumors in CHEK2, NBN/NBS1 and BLM mutation carriers does not commonly involve somatic inactivation of the wild-type allele. Med Oncol 31:828

    Article  Google Scholar 

  15. Sokolenko AP, Suspitsin EN, Kuligina ESh, Bizin IV, Frishman D, Imyanitov EN (2015) Identification of novel hereditary cancer genes by whole exome sequencing. Cancer Lett 369:274–288

    CAS  Article  Google Scholar 

  16. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, ACMG Laboratory Quality Assurance Committee (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17:405–424

    Article  Google Scholar 

  17. Cybulski C, Górski B, Huzarski T, Masojć B, Mierzejewski M, Debniak T, Teodorczyk U, Byrski T, Gronwald J, Matyjasik J, Zlowocka E, Lenner M, Grabowska E, Nej K, Castaneda J, Medrek K, Szymańska A, Szymańska J, Kurzawski G, Suchy J, Oszurek O, Witek A, Narod SA, Lubiński J (2004) CHEK2 is a multiorgan cancer susceptibility gene. Am J Hum Genet 75:1131–1135

    CAS  Article  Google Scholar 

  18. Schwarz JK, Lovly CM, Piwnica-Worms H (2003) Regulation of the Chk2 protein kinase by oligomerization-mediated cis- and trans-phosphorylation. Mol Cancer Res 1:598–609

    CAS  PubMed  Google Scholar 

  19. Cai Z, Chehab NH, Pavletich NP (2009) Structure and activation mechanism of the CHK2 DNA damage checkpoint kinase. Mol Cell 35:818–829

    CAS  Article  Google Scholar 

  20. Imyanitov EN, Togo AV, Hanson KP (2004) Searching for cancer-associated gene polymorphisms: promises and obstacles. Cancer Lett 204:3–14

    CAS  Article  Google Scholar 

  21. Litchfield K, Loveday C, Levy M, Dudakia D, Rapley E, Nsengimana J, Bishop DT, Reid A, Huddart R, Broderick P, Houlston RS, Turnbull C (2018) Large-scale Sequencing of Testicular Germ Cell Tumour (TGCT) cases excludes major TGCT predisposition gene. Eur Urol 73:828–831

    CAS  Article  Google Scholar 

  22. Loveday C, Law P, Litchfield K, Levy M, Holroyd A, Broderick P, Kote-Jarai Z, Dunning AM, Muir K, Peto J, Eeles R, Easton DF, Dudakia D, Orr N, Pashayan N, UK Testicular Cancer Collaboration, The PRACTICAL Consortium, Reid A, Huddart RA, Houlston RS, Turnbull C (2018) Large-scale analysis demonstrates familial testicular cancer to have polygenic aetiology. Eur Urol 74:248–252

    Article  Google Scholar 

  23. Loveday C, Sud A, Litchfield K, Levy M, Holroyd A, Broderick P, Kote-Jarai Z, Dunning AM, Muir K, Peto J, Eeles R, Easton DF, Dudakia D, Orr N, Pashayan N, UK Testicular Cancer Collaboration, PRACTICAL Consortium, Reid A, Huddart RA, Houlston RS, Turnbull C (2019) Runs of homozygosity and testicular cancer risk. Andrology 7:555–564

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We are cordially thankful to Dr. Barbara Vona (University of Tuebingen) for critical reading of this manuscript.

Funding

This work has been supported by the Russian Foundation for Basic Research [Grant Number 18-29-09090]. The funder had no role in study design, data collection and analysis, decision to publish, or the preparation of the manuscript.

Author information

Affiliations

  1. N.N. Petrov Institute of Oncology, Leningradskaya, 68, Pesochny-2, St.-Petersburg, Russia, 197758

    Valeriya I. Ni, Alexandr O. Ivantsov, Mariya A. Kotkova, Sofia V. Baskina, Svetlana N. Aleksakhina, Anna P. Sokolenko & Evgeny N. Imyanitov

  2. St.-Petersburg Pediatric Medical University, St.-Petersburg, Russia, 194100

    Alexandr O. Ivantsov, Anna P. Sokolenko & Evgeny N. Imyanitov

  3. City Oncological Dispensary, St.-Petersburg, Russia, 198255

    Elena V. Ponomareva, Rashida V. Orlova & Eldar E. Topuzov

  4. City Cancer Center, St.-Petersburg, Russia, 197758

    Kirill K. Kryukov, Kseniya V. Shelekhova & Evgeny N. Imyanitov

  5. I.I. Mechnikov North-Western Medical University, St.-Petersburg, Russia, 191015

    Evgeny N. Imyanitov

Authors
  1. Valeriya I. Ni
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alexandr O. Ivantsov
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mariya A. Kotkova
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sofia V. Baskina
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Elena V. Ponomareva
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rashida V. Orlova
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Eldar E. Topuzov
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kirill K. Kryukov
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Kseniya V. Shelekhova
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Svetlana N. Aleksakhina
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Anna P. Sokolenko
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Evgeny N. Imyanitov
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

ENI, APS and SNA designed the study with input from the co-authors. EVP, RVO, EET, KKK and KVS collected patient material and analyzed clinical records. AOI performed morphological analysis. VIN, MAK, SVB and SNA carried out molecular genetic analysis. ENI wrote the first draft of the manuscript. All authors revised the manuscript for intellectual content, approved the version to be published, and agree to be accountable for all aspects of the work in ensuring that questions related to the integrity of any part of the work are appropriately investigated and resolved.

Corresponding author

Correspondence to Evgeny N. Imyanitov.

Ethics declarations

Conflicts of interest

All authors declare no conflict of interest.

Ethical approval

All procedures performed were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Ni, V.I., Ivantsov, A.O., Kotkova, M.A. et al. Small fraction of testicular cancer cases may be causatively related to CHEK2 inactivating germ-line mutations: evidence for somatic loss of the remaining CHEK2 allele in the tumor tissue. Familial Cancer 20, 49–53 (2021). https://doi.org/10.1007/s10689-020-00190-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10689-020-00190-5

Keywords

  • CHEK2 mutation
  • Loss of heterozygosity
  • Testicular cancer