14. Cancer Predisposition Syndromes

• cisplatin and nitrogen mustard create an inter-strand crosslink which acts as a chemotherapy
• fanconi anaemia = issues with properly repairing interstrand cross-links

  • microcephaly, bone marrow failure, predisposition to cancer
  • autosomal recessive inheritance
  • 22 genes identified - only need mutation in one
• patients with fanconi anaemia often develop myelodysplastic syndrome, which is a pre-malignant state for acute myeloid leukaemia

  • carriers have high predisposition for breast/ovarian cancer
• intercross strand repair

  • replication forks meet at the icl
  • fanconi anaemia complex activated
  • recruits nucleases that make incisions on either side
  • cross link flipped out - need to repair cross link area and break in one of the strands
• if interstrand crosslinks aren't repaired, DNA can't be fully replicated and an anaphase bridge forms when chromosomes try and replicate

  • mitotic catastrophe
  • contributes to chromosomal breakage
  • formation of multi-radial chromosomes (NHEJ used to repair breaks and stick chromosomes together - kills the cell)
• interstrand crosslinks are vary rare to develop naturally

  • aldehydes can induce them
  • e.g. from alcohol or after histone demethylation