Skip to main content

Advertisement

SpringerLink
Log in

Re-evaluating cancer risks associated with the CHEK2 p.Ser428Phe Ashkenazi Jewish founder pathogenic variant

  • Short Communication
  • Published:
Familial Cancer Aims and scope Submit manuscript

Abstract

A missense variant (p.Ser428Phe [S428F]) in the CHEK2 gene is reportedly associated with a 2–3 fold increase in breast cancer risk in Ashkenazi Jews. This study aimed to re-evaluate cancer risks conferred by the CHEK2 S428F variant in Ashkenazi Jews. De-identified data from CHEK2 S428F variant carriers sequenced with multigene panels were analyzed. Overall, 486/341,531 (0.14%) cases of all ethnicities diagnosed with any cancer type were CHEK2 S428F carriers, of whom 243/9980 self-identified as Ashkenazi Jews and carried this risk variant only. Compared with ethnically matched non-cancer controls, across all cancer cases, this variant was not more prevalent (p = 0.271). Specifically, variant prevalence was not different in breast cancer cases compared with controls. Though the variant was shown to be enriched in pancreatic cancer cases (p = 0.008), sample size was small. The CHEK2 S428F variant was not overrepresented in Ashkenazi Jews with breast cancer and most other cancer types analyzed, except for pancreatic cancer, compared with ethnically matched non- cancer controls. These findings should prompt reevaluating ethnic-specific CHEK2 S428F cancer attributable risk.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Data availability

Irrelevant.

References

  1. Apostolou P, Papasotiriou I (2017) Current perspectives on CHEK2 mutations in breast cancer. Breast Cancer (Dove Med Press) 9:331–335. https://doi.org/10.2147/BCTT.S111394

    Article  CAS  Google Scholar 

  2. Schmidt MK, Hogervorst F, van Hien R, Cornelissen S, Broeks A, Adank MA, Meijers H, Waisfisz Q, Hollestelle A, Schutte M, van den Ouweland A, Hooning M, Andrulis IL, Anton-Culver H, Antonenkova NN, Antoniou AC, Arndt V, Bermisheva M, Bogdanova NV, Bolla MK, Brauch H, Brenner H, Brüning T, Burwinkel B, Chang-Claude J, Chenevix-Trench G, Couch FJ, Cox A, Cross SS, Czene K, Dunning AM, Fasching PA, Figueroa J, Fletcher O, Flyger H, Galle E, García-Closas M, Giles GG, Haeberle L, Hall P, Hillemanns P, Hopper JL, Jakubowska A, John EM, Jones M, Khusnutdinova E, Knight JA, Kosma VM, Kristensen V, Lee A, Lindblom A, Lubinski J, Mannermaa A, Margolin S, Meindl A, Milne RL, Muranen TA, Newcomb PA, Offit K, Park-Simon TW, Peto J, Pharoah PD, Robson M, Rudolph A, Sawyer EJ, Schmutzler RK, Seynaeve C, Soens J, Southey MC, Spurdle AB, Surowy H, Swerdlow A, Tollenaar RA, Tomlinson I, Trentham-Dietz A, Vachon C, Wang Q, Whittemore AS, Ziogas A, van der Kolk L, Nevanlinna H, Dörk T, Bojesen S, Easton DF (2016) Age- and tumor subtype-specific breast cancer risk estimates for CHEK2*1100delC carriers. J Clin Oncol 34(23):2750–2760. https://doi.org/10.1200/JCO.2016.66.5844

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Liang M, Zhang Y, Sun C, Rizeq FK, Min M, Shi T, Sun Y (2004) Association between CHEK2*1100delC and breast cancer: a systematic review and meta-analysis. Mol Diagn Ther 22:397–407. https://doi.org/10.1007/s40291-018-0344-x

    Article  CAS  Google Scholar 

  4. 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. doi:https://doi.org/10.1086/426403

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Ma X, Zhang B, Zheng W (2013) Genetic variants associated with colorectal cancer risk: comprehensive research synopsis, meta-analysis, and epidemiological evidence. Gut 63:326–336. doi:https://doi.org/10.1136/gutjnl-2012-304121

    Article  CAS  PubMed  Google Scholar 

  6. Wu Y, Yu H, Zheng SL, Na R, Mamawala M, Landis T, Wiley K, Petkewicz J, Shah S, Shi Z, Novakovic K, McGuire M, Brendler CB, Ding Q, Helfand BT, Carter HB, Cooney KA, Isaacs WB, Xu J (2018) A comprehensive evaluation of CHEK2 germline mutations in men with prostate cancer. Prostate 78:607–615. doi:https://doi.org/10.1002/pros.23505

    Article  CAS  PubMed  Google Scholar 

  7. Zhan W, Shelton CA, Greer PJ, Brand RE, Whitcomb DC (2018) Germline variants and risk for pancreatic cancer: a systematic review and emerging concepts. Pancreas 47:924–936. https://doi.org/10.1097/MPA.0000000000001136

    Article  PubMed  PubMed Central  Google Scholar 

  8. Shaag A, Walsh T, Renbaum P, Kirchhoff T, Nafa K, Shiovitz S, Mandell JB, Welcsh P, Lee MK, Ellis N, Offit K, Levy-Lahad E, King MC (2005) Functional and genomic approaches reveal an ancient CHEK2 allele associated with breast cancer in the Ashkenazi Jewish population. Hum Mol Genet 14:555–563. doi:https://doi.org/10.1093/hmg/ddi052

    Article  CAS  PubMed  Google Scholar 

  9. Walsh T, Mandell JB, Norquist BM, Casadei S, Gulsuner S, Lee MK, King MC (2017) Genetic predisposition to breast cancer due to mutations other than BRCA1 and BRCA2 founder Alleles among Ashkenazi Jewish women. JAMA Oncol 3:1647–1653. https://doi.org/10.1001/jamaoncol.2017.1996

    Article  PubMed  PubMed Central  Google Scholar 

  10. Lincoln SE, Kobayashi Y, Anderson MJ, Yang S, Desmond AJ, Mills MA, Nilsen GB, Jacobs KB, Monzon FA, Kurian AW, Ford JM, Ellisen LW (2015) A systematic comparison of traditional and multigene panel testing for hereditary breast and ovarian cancer genes in more than 1000 patients. J Mol Diagn 17:533–544. https://doi.org/10.1016/j.jmoldx.2015.04.009

    Article  PubMed  Google Scholar 

  11. Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M, Invitae Clinical Genomics Group, Topper S (2017) Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. Genet Med 19:1105–1117. https://doi.org/10.1038/gim.2017.37 (Erratum in: Genet Med. 2020 Jan;22(1):240-242)

    Article  PubMed  Google Scholar 

Download references

Funding

No funding was available for this study.

Author information

Author notes

  1. Edward D. Esplin

    Present address: Invitae, San Francisco, CA, USA

  2. Rinat Bernstein-Molho

    Present address: The Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel

  3. Yael Laitman and Sarah M. Nielsen have contributed equally to this work.

Authors and Affiliations

  1. The Oncogenetics Unit, Institute of Human Genetics, Sheba Medical Center, 52621, Tel-Hashomer, Israel

    Yael Laitman, Rinat Bernstein-Molho & Eitan Friedman

  2. The Breast Cancer Unit, Oncology Institute, Tel-Hashomer, Israel

    Rinat Bernstein-Molho

  3. Invitae, San Francisco, CA, USA

    Sarah M. Nielsen, Kathryn E. Hatchell & Rebecca Truty

  4. The Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel

    Eitan Friedman

Authors
  1. Yael Laitman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sarah M. Nielsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kathryn E. Hatchell
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rebecca Truty
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Rinat Bernstein-Molho
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Edward D. Esplin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Eitan Friedman
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The study was conceptualized by YL, RBM and EF; SMN, KEH, RT and EDE generated the aggregate data; YL, SMN and KEH performed the statistical analyses, the initial draft was written by YL and EF. All authors have seen and approved the raw data and were involved in data interpretation. All authors have read and approved the final manuscript.

Corresponding author

Correspondence to Eitan Friedman.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest. SMN, KEH, RT and EDE are all employees and shareholders of the Invitae Corporation.

Ethical approval and consent to participate

The Institutional Review Board of the Sheba Medical center approved the study.

Consent to participate

irrelevant.

Consent for publication

Irrelevant.

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

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Laitman, Y., Nielsen, S.M., Hatchell, K.E. et al. Re-evaluating cancer risks associated with the CHEK2 p.Ser428Phe Ashkenazi Jewish founder pathogenic variant. Familial Cancer 21, 305–308 (2022). https://doi.org/10.1007/s10689-021-00278-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10689-021-00278-6

Keywords

Search

Navigation