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.

Synthetic Lethality- Strategies To Target Cancer

One way of targeting cancer cells is to aim for an antigen that's only present in cancer tissue and not in healthy tissues, for example with monoclonal antibodies to the epidermal growth factor called Her/neu present in certain breast cancers, through a now well known agent called Herceptin (Trastuzumab). However, this approach only works with a few cancers. Another ingenious approach is to exploit a phenomenon called Synthetic Lethality.

The DNA we all are made of undergoes thousands of breakages in every cell cycle. If this is not repaired, sooner or later, we'll all develop cancer. To ensure that this doesn't happen, nature has introduced more than one mechanism, a sort of backup that is termed redundancy in medicine. If one mechanism fails, there will be another that will repair the damaged DNA. Redundancy has to be there, because otherwise we'll simply cease to exist.

Here's where the opportunity for fighting cancer comes in. Nature's two most important methods of repairing DNA are through an enzyme called PARP1, which removes the defective DNA base pairs, allowing the defective bit to be repaired, and through a process called homologous recombination, where new DNA is generated from existing DNA. Remember, DNA has two strands, and all the info required to generate a fully functional DNA ribbon is present in any one strand.

This is no big deal and is not unique to human beings. For thousands of years, bacteria have repaired faults through homologous recombination. In 2007, two American & one British scientist were awarded the Nobel Prize in Medicine for describing this phenomenon and its applications in more detail.

Now we come to the nity-gritty. Most people will know by now that one of the biggest risk factors for breast and ovarian cancers is the presence of mutations in two vital genes called BRCA1 and BRCA2. These tend to run in families and increase the risk of these cancers severalfold.

How do you think the BRCA gene works? It codes for homologous recombination. "Defective" families carry one copy of the faulty gene and one healthy copy (called the "wild type allele"- in genetics, "wild" refers to the natural, healthy copy.) They only develop cancer when the healthy gene somehow undergoes a new mutation. The lifetime risk of such cancer is around 40% for carriers of the BRACA1 gene and around 20% for the BRCA2 gene. In desperation, many such poor women undergo "preventative" mastectomy or oophorectomy at a relatively young age for peace of mind.

Yet, now a study suggests that there is a way out of such terrible solutions. Remember the PARP1 enzyme I mentioned, the other part of the double act of DNA repair? When cancer develops in the BRCA mutation carriers because of an acquired defect in the remaining wild type gene, the cancerous cells become totally dependent on the PARP1 enzyme for DNA repair. Yet, the other, non-cancerous cells in the cancer sufferer are not dependent on PARP1 alone because they still have one functioning, healthy copy of the BRCA gene. Therefore, it follows that if you can target the PARP-1 in these women through a pharmacological agent, the cancer cells, having no means to repair their DNA, will die, while the healthy cells will be unaffected.

That's what synthetic lethality means. Two genes are said to be in a synthetic lethal relationship if defect in one can be compensated by the other. However, if both are defective, the cell will die.

Hats off to the cancer researchers. In a few years, it seems, we'll be able to beat familial breast & ovarian cancer, a task that once seemed insurmountable.