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Homozygosity for CHEK2 p.Gly167Arg leads to a unique cancer syndrome with multiple complex chromosomal translocations in peripheral blood karyotype
  1. Tamar Paperna1,
  2. Nitzan Sharon-Shwartzman1,
  3. Alina Kurolap1,2,
  4. Yael Goldberg3,
  5. Nivin Moustafa1,
  6. Yariv Carasso4,
  7. Miora Feinstien3,
  8. Adi Mory1,
  9. Gili Reznick-Levi1,
  10. Claudia Gonzaga-Jauregui5,
  11. Alan R Shuldiner5,
  12. Lina Basel-Salmon3,6,7,8,
  13. Yishai Ofran2,4,
  14. Elizabeth E Half2,9,
  15. Hagit Baris Feldman1,2
  1. 1 The Genetics Institute, Rambam Health Care Campus, Haifa, Israel
  2. 2 The Ruth and Bruce Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, Haifa, Israel
  3. 3 Raphael Recanati Genetics Institute, Rabin Medical Center - Beilinson Hospital, Petah Tikva, Israel
  4. 4 Department of Haematology and Bone Marrow Transplantation, Rambam Health Care Campus, Haifa, Israel
  5. 5 Regeneron Genetics Center, Tarrytown, New York, USA
  6. 6 Pediatric Genetics Clinic, Schneider Children’s Medical Center of Israel, Petach Tikva, Israel
  7. 7 Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
  8. 8 Felsenstein Medical Research Cente, Rabin Medical Center, Petach Tikva, Israel
  9. 9 Department of Gastroenterology, Rambam Health Care Campus, Haifa, Israel
  1. Correspondence to Dr Hagit Baris Feldman, The Genetics Institute, Rambam Health Care Campus, Haifa 3109601, Israel; hb_feldman{at}


Background Chromosomal instability, as reflected by structural or copy-number changes, is a known cancer characteristic but are rarely observed in healthy tissue. Mutations in DNA repair genes disrupt the maintenance of DNA integrity and predispose to hereditary cancer syndromes.

Objective To clinically characterise and genetically diagnose two reportedly unrelated patients with unique cancer syndromes, including multiorgan tumourogenesis (patient 1) and early-onset acute myeloid leukaemia (patient 2), both displaying unique peripheral blood karyotypes.

Methods Genetic analysis in patient 1 included TruSight One panel and whole-exome sequencing, while patient 2 was diagnosed by FoundationOne Heme genomic analysis; Sanger sequencing was used for mutation confirmation in both patients. Karyotype analysis was performed on peripheral blood, bone marrow and other available tissues.

Results Both patients were found homozygous for CHEK2 c.499G>A; p.Gly167Arg and exhibited multiple different chromosomal translocations in 30%–60% peripheral blood lymphocytes. This karyotype phenotype was not observed in other tested tissues or in an ovarian cancer patient with a different homozygous missense mutation in CHEK2 (c.1283C>T; p.Ser428Phe).

Conclusions The multiple chromosomal translocations in patient lymphocytes highlight the role of CHK2 in DNA repair. We suggest that homozygosity for p.Gly167Arg increases patients' susceptibility to non-accurate correction of DNA breaks and possibly explains their increased susceptibility to either multiple primary tumours during their lifetime or early-onset tumourigenesis.

  • chek2
  • multi-organ tumorigenesis
  • acute myeloid leukemia
  • chromosomal translocations
  • Dna breakage

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  • TP, NS-S and AK contributed equally.

  • Contributors The first three authors (TP, NS-S and AK) contributed equally to this work. TP, NS-S and AK collected patient data and summarized clinical and genetic findings. TP, AK, CG-J, AM and ARS participated in genetic analyses, bioinformatics and data interpretation. NS-S, YG, YC, MF, GR-L, YO and EEH followed and treated the patients. NM and LB-S performed the karyotype analyses and interpreted karyotyping results. LB-S performed the chromosomal microarray analysis. TP, NS-S, AK and HBF drafted the manuscript. All coauthors critically reviewed the manuscript and approved the final submitted version.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Ethics approval The Helsinki Ethics Committee of Rambam Health Care Campus.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement All data regarding this study is available upon request.

  • Patient consent for publication Obtained.