The Versatile Cancer Genes

Elsewhere in this blog, I have referred to how DNA damage can be repaired through a combination of homologous recombination and base excision repair. The well known mediators of homologous recombination are BRCA1 & BRCA2. Women who carry defective BRACA 1 or 2 allele are at increased risk of breast, and in the case of BRCA2 loss, breast and ovarian cancer. Men who have lost a wild type BRCA2 allele are also at increased risk of breast cancer.

It is thought that breast or ovarian cancer develops when the remaining healthy allele becomes mutated in the adult- a process called somatic mutation, to differentiate it from germline mutations, which are inherited.

Those with defects in both alleles of BRCA1 are thought unlikely to survive beyond a very early stage of their life- perhaps succumbing in utero or in early childhood. But what happens to those with two defective BRCA2 alleles at birth?

We didn't know, until now.

An illuminating article in the New England Journal of Medicine reveals that BRCA2 is in fact identical to FANCD1, one of the twenty proteins for whom defective genes have been found in Fanconi's anaemia, an autosomal recessive childhood onset severe anaemia with reduction of other cell lines as well, resulting in an aplastic picture.

It is thought that patients with Fanconi's anaemia are very susceptible to DNA damage through cross linking, such as by exposure to radiation. These patients are also susceptible to neoplastic processes such as acute leukaemias, which are curiously much more sensitive to agents such as cisplatin than ordinary leukaemias. It is thought that this is because of their cross linked DNA.

The twenty defective genes in Fanconi's anaemia are thought be responsible for DNA repair through homologous recombination. The process is started off by coming together of two proteins called FANCD2 and FANCI, which then associate with other downstream proteins, one of which is FANCD1....or BRCA2.

It is now realised that those with loss of both BRCA2 alleles through germline mutations develop Fanconi's anaemia, while those with loss of one allele are at increased risk of breast and ovarian cancer in life. Both processes are due to an inherent defect in DNA repair through homologous recombination.

Not surprisingly, defects in some of the twenty genes responsible for Fanconi's anaemia have also been described in other cancers. An innovative way of increasing the susceptibility of such cancers to cisplatin like chemotherapeutic agents is to expose such cells to DNA cross linking agents, as was demonstrated in Fanconi's anaemia.

Another disorder that epitomises the consequences of defective DNA repair is ataxia-telangiectasia, in which the fault lies with a gene described as ataxia-tengiectasia-mutated. Such patients present with immunodeficiency in addition to the obvious symptoms of ataxia & telangiectasia.

It's quite clear that some cancer genes give rise to more than one phenotype...and not just cancers either.