CANCER AS A GENETIC DISEASE
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:
- 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.