Homozygosity for CHEK2 p.Gly167Arg leads to a unique cancer syndrome with multiple complex chromosomal translocations in peripheral blood karyotype.

Abstract

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.

• Authors: Tamar Paperna, Nitzan Sharon-Shwartzman, Alina Kurolap, Yael Goldberg, Nivin Moustafa, Yariv Carasso, Miora Feinstien, Adi Mory, Gili Reznick-Levi, Claudia Gonzaga-Jauregui, Alan R Shuldiner, Lina Basel-Salmon, Yishai Ofran, Elizabeth E Half, Hagit Baris Feldman
• Journal: Journal of medical genetics (J Med Genet) Vol. 57 Issue 7 Pg. 500-504 (07 2020) ISSN: 1468-6244 [Electronic] England
• PMID: 30858171 (Publication Type: Journal Article)
• Copyright: © Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.

Chemical References

• Checkpoint Kinase 2
• CHEK2 protein, human

Topics

• Adult
• Aged
• Checkpoint Kinase 2 (genetics, ultrastructure)
• Female
• Genetic Predisposition to Disease
• Homozygote
• Humans
• Karyotype
• Male
• Middle Aged
• Neoplasms (genetics, pathology)
• Pedigree
• Protein Conformation
• Translocation, Genetic (genetics)