Germline mutation contribution to chromosomal instability

  1. Joanne Ngeow1,2
  1. 1Division of Medical Oncology, Cancer Genetics Service, National Cancer Centre Singapore, Singapore
  2. 2Oncology Academic Clinical Program, Duke-NUS Medical School Singapore, Singapore
  1. Correspondence should be addressed to J Ngeow; Email: Joanne.Ngeow.Y.Y{at}
  1. Figure 1

    Defects at cell cycle checkpoints in which germline mutations have been found to be associated with chromosomal instability. Defective DNA damage response and repair, particularly in the mismatch and DNA double-strand breaks (DSBs) repair results in chromosomal aberrations such as deletions, amplifications, inversions and translocations. Impaired spindle assembly checkpoint (SAC) signaling, uncorrected kinetochore–microtubule (k-MT) mis-attachments, multipolar spindles due to supernumerary centrosomes resulting from dysregulated centrosome duplication contribute to lagging chromosomes in anaphase, resulting in chromosomal mis-segregation. These abnormalities combine to predispose the cell to chromosomal instability. HR, homologous recombination; NHEJ, non-homologous end joining.

  2. Figure 2

    CIN can promote both tumor progression and tumor suppression. Germline mutations affecting the mitotic checkpoint, kinetochore–microtubule (k-MT) dynamics and DNA damage response can predispose to CIN as a result of insufficient delays in mitotic arrest to repair aberrations such as merotelic attachments, chromosomal mis-orientations and DNA damage. Consequently, unbalanced and broken DNA persists over subsequent mitoses, generating daughter cells with ever-increasing levels of chromosomal instability. Further loss of critical tumor suppressors (or amplification of oncogenes) coupled with selective growth advantage and clonal expansion leads to tumorigenesis. However, CIN beyond tolerable levels is non-viable and often leads to cell death. By tipping the balance of CIN in the cell, such as using targeted drugs that is synthetic lethal to the existing germline defect, it is possible to exploit this vulnerability to promote tumor suppression as a therapeutic strategy.

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