The mutations in DNA repair genes that increase the susceptibility of carriers to cancer are usually inherited. However, as we’ve seen, the broader class of tumour suppressor genes can also carry mutations from generation to generation and, although the cancers that develop from these mutations only represent about 10% of all cancers, they have been remarkably informative about what happens as tumours evolve. This is mainly due to the fact that families carrying mutant genes have been intensively studied, including members who have not shown any symptoms and this has helped to build a model of the stages of tumour development.
Breast cancer is perhaps the best known of the cancers that ‘run in families’, that is, show ‘familial aggregation’. It is about twice as common in first-degree relatives of women with the disease than it is in the general population. About 5% of all female breast cancers (men can get the disease too but very rarely – about 1% of all breast cancers) arise from inherited mutations. In the 1990s the genes BRCA1 and BRCA2 were identified and studies of large populations showed that inherited mutations in either gene confer a lifetime risk of the disease of over 50%, compared with an average risk of breast cancer for women of ~10%. Since then variants in a number of other genes (CHEK2, ATM, BRIP1 and PALB2) have been shown to increase the risk by about two-fold. Like BRCA1 and BRCA2, these are all tumour suppressor genes and they all play roles in DNA repair. Nevertheless, taken together, they only account for about 25% of the risk factors, which means that in three-quarters of the cases of familial breast cancer the genetic cause, or causes, are unknown. This rather depressing situation is not for want of effort: it is simply that studies trying to link mutations in specific genes to inherited breast cancer have failed to come up with anything. It seems very probable, therefore, that rather than there being more BRCA-type genes waiting to be discovered, inherited susceptibility to breast cancer usually results from the combined effect of lots of genetic variants (single-nucleotide polymorphisms), each making but a small contribution to a polygenic disease.
Cancers of the bowel have perhaps been the most informative as far as the pattern of mutations required for tumour development. This is particularly true of familial adenomatous polyposis (FAP): this hereditary syndrome is characterised by the presence of hundreds of adenomatous lesions (polyps) in the colon at an early age, any one of which can, over time, convert into a malignant adenocarcinoma. It is relatively easy to examine the lining of the bowel (by endoscopy) and thus screen individuals from susceptible families and, if premalignant polyps are detected, the condition can usually be treated by surgery. Only if one of the polyps develops beyond the adenoma stage, penetrating the underlying basement membrane and thus allowing tumour cells to pass into the circulation, does the condition becomes malignant and hence life-threatening (Fig. 1).
1. Progression of familial adenomatous polyposis.
In the majority of FAP cases, the predisposition arises from a defective APC (adenomatosis polyposis coli) gene. Cells from transgenic mice show very beautifully that the APC protein plays a part in the separation of duplicated chromosomes during mitosis and that APC mutations disrupt this process. Damaged APC causes chromosomes to be torn apart in an unregulated fashion as cells divide. This destabilises the genomic integrity of a cell, giving rise to the characteristic of cancers. For obvious reasons, this form of genetic instability is referred to as chromosomal instability (CIN). Mutations in APC, therefore, prime the cell to acquire yet more mutations and, from studies of families with such mutations, it has emerged that very frequently the oncogene KRAS2 is mutated and subsequently P53 function is lost – a kind of mutational signature. Other mutations occur but we have already seen why these two genes are often involved in cancer and they are a very good example of mutations in different signalling pathways having convergent effects in driving the development of cancer.