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In some cases, there is a clear link between an inherited or germline mutation and elevated risk of cancer.

As already mentioned;

  • XP patients have an extreme sensitivity to sunlight-induced skin cancer;
  • and HNPCC (hereditary non-polyposis colon cancer) patients, with a defect in mismatch repair (See chapter 8 DNA repair), are very prone to colon cancer.

Other examples are:

  • Retinoblastoma
  • BRCA1/2 (breast cancer) genes

A more subtle effect is seen with various genetic polymorphisms (i.e. variations in sequence from the wild type gene, occuring at >1% in the population). For example, a polymorphism in the base excision repair gene OGG1, is associated with elevated risk of lung cancer, and this is true also for genes involved in phase I and phase II metabolism.

The inherited form of retinoblastoma has a mutation in the RB1 gene on chromosome 13. For the disease to appear, since RB is a tumour suppressor protein, the other allele must be inactivated, and this usually involves spontaneous loss of the part of this chromosome containing the functional allele – known as ‘loss of heterozygosity’.


Photo Retinoblastoma patient with affected eye to the left

The phase II enzyme GST (See chapter 7 Modulation of DNA damage) is particularly important in modifying the response to DNA-damaging agents. There are several isoforms of the enzyme, and genetic variants are well represented in the human population.

  • GSTM1 is either null or +
  • GSTT1 is either null or +
  • GSTP1 has a common polymorphism; genotypes are described as a/a, a/b, b/b.

Different genotypes are linked with different risks of cancer.

  • Lack of GSTM1 enzyme may result in deficient detoxification of tobacco smoke carcinogens leading to a slight increase in risk of lung cancer.
  • The GSTP1b genotype is associated with increased incidence of bladder and testicular cancer.