Skip to main content

Advertisement

SpringerLink
Log in

A novel founder MSH2 deletion in Ethiopian Jews is mainly associated with early-onset colorectal cancer

  • Original Article
  • Published:
Familial Cancer Aims and scope Submit manuscript

Abstract

Lynch syndrome is an inherited cancer predisposition syndrome caused by germline defects in any of the mismatch repair (MMR) genes. Diagnosis of carriers makes precision prevention, early detection, and tailored treatment possible. Herein we report a novel founder deletion of 18,758 bp, mediated by Alu repeats on both sides, detected in Ethiopian Jews. The deletion, which encompasses exon 9–10 of the MSH2 coding sequence, is associated mainly with early-onset MSH2/MSH6-deficient colorectal cancer (CRC) and liposarcoma. Testing of 35 members of 5 seemingly unrelated families of Ethiopian origin yielded 10/21 (48%) carriers, of whom 9 had CRC. Age at first tumor diagnosis ranged from 16 to 89 years. Carriers from the oldest generations were diagnosed after age 45 years (mean 57), and carriers from the younger generation were diagnosed before age 45 years (mean 30). Awareness of this founder deletion is important to improve patient diagnosis, institute surveillance from an early age, and refer patients for genetic counseling addressing the risk of bi-allelic constitutional MMR deficiency syndrome.

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.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Data availability

Data transparency.

References

  1. Chen S, Wang W, Lee S, Nafa K, Lee J, Romans K, Watson P, Gruber SB, Euhus D, Kinzler KW, Jass J, Gallinger S, Lindor NM, Casey G, Ellis N, Giardiello FM, Offit K, Parmigiani G, Registry CCF (2006) Prediction of germline mutations and cancer risk in the Lynch syndrome. JAMA 296(12):1479–1487. https://doi.org/10.1001/jama.296.12.1479

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Moreira L, Balaguer F, Lindor N, de la Chapelle A, Hampel H, Aaltonen LA, Hopper JL, Le Marchand L, Gallinger S, Newcomb PA, Haile R, Thibodeau SN, Gunawardena S, Jenkins MA, Buchanan DD, Potter JD, Baron JA, Ahnen DJ, Moreno V, Andreu M, Ponz de Leon M, Rustgi AK, Castells A, EPICOLON Consortium (2012) Identification of Lynch syndrome among patients with colorectal cancer. JAMA 308(15):1555–1565. https://doi.org/10.1001/jama.2012.13088

    Article  CAS  PubMed  Google Scholar 

  3. Møller P, Seppälä TT, Bernstein I, Holinski-Feder E, Sala P, Evans DG, Lindblom A, Macrae F, Blanco I, Sijmons RH, Jeffries J, Vasen HFA, Burn J, Nakken S, Hovig E, Rødland EA, Tharmaratnam K, de Vos Tot Nederveen Cappel WH, Hill J, Wijnen JT, Jenkins MA, Green K, Lalloo F, Sunde L, Mints M, Bertario L, Pineda M, Navarro M, Morak M, Renkonen-Sinisalo L, Valentin MD, Frayling IM, Plazzer JP, Pylvanainen K, Genuardi M, Mecklin JP, Moeslein G, Sampson JR, Capella G (2018) Cancer risk and survival in path_MMR carriers by gene and gender up to 75 years of age: a report from the Prospective Lynch Syndrome Database. Gut 67(7):1306–1316. https://doi.org/10.1136/gutjnl-2017-314057 (Erratum in: Gut 2020;69(6):e4)

    Article  PubMed  Google Scholar 

  4. Lynch HT, Smyrk TC, Watson P, Lanspa SJ, Lynch JF, Lynch PM, Cavalieri RJ, Boland CR (1993) Genetics, natural history, tumor spectrum, and pathology of hereditary nonpolyposis colorectal cancer: an updated review. Gastroenterology 104(5):1535–1549. https://doi.org/10.1016/0016-5085(93)90368-m

    Article  CAS  PubMed  Google Scholar 

  5. Ponti G, Castellsagué E, Ruini C, Percesepe A, Tomasi A (2015) Mismatch repair genes founder mutations and cancer susceptibility in Lynch syndrome. Clin Genet 87(6):507–516. https://doi.org/10.1111/cge.12529

    Article  CAS  PubMed  Google Scholar 

  6. Froggatt NJ, Joyce JA, Davies R, Gareth D, Evans R, Ponder BA, Barton DE, Maher ER (1995) A frequent hMSH2 mutation in hereditary non-polyposis colon cancer syndrome. Lancet 345(8951):727. https://doi.org/10.1016/s0140-6736(95)90900-1

    Article  CAS  PubMed  Google Scholar 

  7. Lynch HT, de la Chapelle A, Hampel H, Wagner A, Fodde R, Lynch JF, Okimoto R, Clark MB, Coronel S, Trowonou A, Fu YX, Haynatzki GR, Gong G (2006) American founder mutation for Lynch syndrome. Prevalence estimates and implications. Cancer 106(2):448–452. https://doi.org/10.1002/cncr.21624

    Article  PubMed  Google Scholar 

  8. Pérez-Cabornero L, Flores EB, Sanz MI, Sampedro EV, Becares AA, Aras EL, González JC, Riu MP, Munar CG, Pino CM, Domínguez DM (2011) Characterization of new founder Alu-mediated rearrangements in MSH2 gene associated with a Lynch syndrome phenotype. Cancer Prev Res 4(10):1546–1555

    Article  Google Scholar 

  9. Shirts BH, Casadei S, Jacobson AL, Lee MK, Gulsuner S, Bennett RL, Miller M, Hall SA, Hampel H, Hisama FM, Naylor LV, Goetsch C, Leppig K, Tait JF, Scroggins SM, Turner EH, Livingston R, Salipante SJ, King MC, Walsh T, Pritchard CC (2016) Improving performance of multigene panels for genomic analysis of cancer predisposition. Genet Med 18(10):974–981. https://doi.org/10.1038/gim.2015.212

    Article  CAS  PubMed  Google Scholar 

  10. Nord AS, Lee M, King MC, Walsh T (2011) Accurate and exact CNV identification from targeted high-throughput sequence data. BMC Genomics 12:184. https://doi.org/10.1186/1471-2164-12-184

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Tomashov-Matar R, Biran G, Lagovsky I, Kotler N, Stein A, Fisch B, Sapir O, Shohat M (2012) Severe combined immunodeficiency (SCID): from the detection of a new mutation to preimplantation genetic diagnosis. J Assist Reprod Genet 29(7):687–692. https://doi.org/10.1007/s10815-012-9765-3

    Article  PubMed  PubMed Central  Google Scholar 

  12. Dominguez-Valentin M, Sampson JR, Møller P, Seppälä TT, Collaborators PLSD (2021) Analysis in the Prospective Lynch Syndrome Database identifies sarcoma as part of the Lynch syndrome tumor spectrum. Int J Cancer 148(2):512–513. https://doi.org/10.1002/ijc.33214

    Article  CAS  PubMed  Google Scholar 

  13. Warthin AS (1925) The further study of a cancer family. J Cancer Res 9:279–286

    Google Scholar 

  14. Westphalen AA, Russell AM, Buser M, Berthod CR, Hutter P, Plasilova M, Mueller H, Heinimann K (2005) Evidence for genetic anticipation in hereditary non-polyposis colorectal cancer. Hum Genet 116(6):461–465. https://doi.org/10.1007/s00439-005-1272-5

    Article  CAS  PubMed  Google Scholar 

  15. von Salomé J, Boonstra PS, Karimi M, Silander G, Stenmark-Askmalm M, Gebre-Medhin S, Aravidis C, Nilbert M, Lindblom A, Lagerstedt-Robinson K (2017) Genetic anticipation in Swedish Lynch syndrome families. PLoS Genet 13(10):e1007012. https://doi.org/10.1371/journal.pgen.1007012

    Article  CAS  Google Scholar 

  16. Stella A, Surdo NC, Lastella P, Barana D, Oliani C, Tibiletti MG, Viel A, Natale C, Piepoli A, Marra G, Guanti G (2007) Germline novel MSH2 deletions and a founder MSH2 deletion associated with anticipation effects in HNPCC. Clin Genet 71(2):130–139. https://doi.org/10.1111/j.1399-0004.2007.00745.x

    Article  CAS  PubMed  Google Scholar 

  17. Ten Broeke SW, Rodríguez-Girondo M, Suerink M, Aretz S, Bernstein I, Capellá G, Engel C, Gomez-Garcia EB, van Hest LP, von Knebel DM, Lagerstedt-Robinson K, Letteboer TGW, Moller P, van Os TA, Pineda M, Rahner N, Olderode-Berends MJW, von Salomé J, Schackert HK, Spruijt L, Steinke-Lange V, Wagner A, Tops CMJ, Nielsen M (2019) The apparent genetic anticipation in PMS2-associated Lynch syndrome families is explained by birth-cohort effect. Cancer Epidemiol Biomark Prev 28(6):1010–1014. https://doi.org/10.1158/1055-9965.EPI-18-0576

    Article  Google Scholar 

  18. Talseth-Palmer BA, Wijnen JT, Grice DM, Scott RJ (2013) Genetic modifiers of cancer risk in Lynch syndrome: a review. Fam Cancer 12(2):207–216. https://doi.org/10.1007/s10689-013-9614-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Bozzao C, Lastella P, Stella A (2011) Anticipation in Lynch syndrome: where we are where we go. Curr Genomics 12(7):451–465. https://doi.org/10.2174/138920211797904070

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ansari R, Mahdavinia M, Sadjadi A, Nouraie M, Kamangar F, Bishehsari F, Fakheri H, Semnani S, Arshi S, Zahedi MJ, Darvish-Moghadam S, Mansour-Ghanaei F, Mosavi A, Malekzadeh R (2006) Incidence and age distribution of colorectal cancer in Iran: results of a population-based cancer registry. Cancer Lett 240(1):143–147. https://doi.org/10.1016/j.canlet.2005.09.004

    Article  CAS  PubMed  Google Scholar 

  21. Bishehsari F, Mahdavinia M, Vacca M, Malekzadeh R, Mariani-Costantini R (2014) Epidemiological transition of colorectal cancer in developing countries: environmental factors, molecular pathways, and opportunities for prevention. World J Gastroenterol 20(20):6055–6072. https://doi.org/10.3748/wjg.v20.i20.6055

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Timotewos G, Solomon A, Mathewos A, Addissie A, Bogale S, Wondemagegnehu T, Aynalem A, Ayalnesh B, Dagnechew H, Bireda W, Kroeber ES, Mikolajczyk R, Bray F, Jemal A, Kantelhardt EJ (2018) First data from a population based cancer registry in Ethiopia. Cancer Epidemiol 53:93–98. https://doi.org/10.1016/j.canep.2018.01.008

    Article  PubMed  Google Scholar 

  23. The Israeli National Cancer Registry (2017) Colorectal cancer in Israel. Update incidence and mortality data, 2017. Ministry of Health, Israel. https://www.health.gov.il/English/MinistryUnits/ICDC/Chronic_Diseases/Cancer/Pages/default.aspx

Download references

Funding

Partial funding was provided by the Israel Cancer Association.

Author information

Author notes

  1. I. Kedar and L. Walsh have contributed equally to this work.

Authors and Affiliations

  1. The Raphael Recanati Genetics Institute, Rabin Medical Center – Beilinson Hospital, 39 Jabotinsky St., 4941492, Petach Tikva, Israel

    I. Kedar, S. Naftaly Nathan, I. Lagovsky, R. Tomashov-Matar, M. Goldenberg, L. Basel-Salmon & Y. Goldberg

  2. Departments of Medicine and Genome Sciences, University of Washington, Seattle, WA, USA

    L. Walsh, T. Walsh & M. C. King

  3. The Genetics Institute, Rambam Health Care Campus, Haifa, Israel

    G. Reznick Levi

  4. Medical Genetics Institute, Shaare Zedek Medical Center, Jerusalem, Israel

    S. Lieberman

  5. Department of Internal Medicine, Carmel Medical Center, Haifa, Israel

    A. Abu Shtaya

  6. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    L. Basel-Salmon, Z. Levi, I. Laish & Y. Goldberg

  7. Department of Gastroenterology and Hepatology, Hadassah Medical Center, Jerusalem, Israel

    L. Katz

  8. Genetics Institute, Emek Medical Center, Afula, Israel

    O. Aleme

  9. Sharett Institute of Oncology, Hebrew University-Hadassah Medical Center, Jerusalem, Israel

    T. Yablonski Peretz

  10. Gastrointestinal Cancer Center, Sharett Institute of Oncology, Hebrew University-Hadassah Medical Center, Jerusalem, Israel

    A. Hubert

  11. Ramat Hasharon, Israel

    D. Rothstein

  12. Gastroenterology Department, Institut D’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Hospital Clínic, Barcelona, Spain

    S. Castellvi-Bel

  13. Department of Laboratory Medicine, University of Washington, Seattle, WA, USA

    C. C. Pritchard

  14. Division of Gastroenterology, Rabin Medical Center – Beilinson Hospital, Petach Tikva, Israel

    Z. Levi

  15. Department of Gastroenterology, Rambam Health Care Campus, Haifa, Israel

    E. Half

  16. Gastroenterology Institute, Chaim Sheba Medical Center, Tel Hashomer, Israel

    I. Laish

Authors
  1. I. Kedar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. L. Walsh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. G. Reznick Levi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S. Lieberman
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A. Abu Shtaya
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. S. Naftaly Nathan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. I. Lagovsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. R. Tomashov-Matar
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. M. Goldenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. L. Basel-Salmon
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. L. Katz
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. O. Aleme
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. T. Yablonski Peretz
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. A. Hubert
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. D. Rothstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. S. Castellvi-Bel
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. T. Walsh
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. M. C. King
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. C. C. Pritchard
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Z. Levi
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. E. Half
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. I. Laish
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Y. Goldberg
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Every author of the manuscript has made substantial contributions to the planning of the work that led to the manuscript: IK, LW, GR, SL, AAS, SNN, IL, RTM, MG, LK, OA, AH, TW, CP, EH, IL, YG, substantially contributed to acquisition of data. CP, MCK, and, ZL, TYP, LBS, YG, contributed critical revision of the manuscript. IK, SL, DR, SCB, TW, YG substantially contributed to study concept and design, acquisition of data; analysis and interpretation of data as well as drafting of the manuscript and critical revision of the manuscript.

Corresponding author

Correspondence to Y. Goldberg.

Ethics declarations

Conflict of interest

All authors declare that they have no conflict of interest.

Ethical approval

6826 RMC. 0161-17 RMC.

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

Kedar, I., Walsh, L., Levi, G.R. et al. A novel founder MSH2 deletion in Ethiopian Jews is mainly associated with early-onset colorectal cancer. Familial Cancer 21, 181–188 (2022). https://doi.org/10.1007/s10689-021-00249-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10689-021-00249-x

Keywords

Search

Navigation