DNA Repair: The Future In Our Fight Against Cancer

by Dr. Nick Plowman
9th Jul 2018

DNA contains the ‘life-code’ for all living creatures. Everybody knows that. If not medically, then certainly from films such as Jurassic Park!

But it goes so much deeper than that. For decades, it’s been widely understood that mutations in DNA can cause cancer by allowing cells to grow out-with the needs of the body – in contradistinction to normal cellular growth or division (i.e. mitosis), which is closely regulated to the body’s needs – the basal turnover or temporary raised activity to mend wounds etc.


But, did you know that mutations that lead to cancer either stimulate on-going (unchecked) mitosis activity or de-repress inhibitory or suppressive normal controls on that activity?

Or that DNA repair mechanisms play a vital role in minimising the risk of developing a cancer?


No? You’re not alone.

It’s widely publicised that cigarette tar is a carcinogen that induces DNA mutations and that cirrhotic livers are predisposed to developing primary liver cancer. Many people also know that prolonged HRT (hormone replacement therapy) predisposes older women to breast cancer – but why does this happen?


The same applies to inherited ‘bad genes.’ We know that they have the potential to predispose a person to developing cancer – but how?


The ‘Low-Down On Cellular Function.’


During mitosis, the DNA has to replicate such that the daughter cells inherit the same life-code. At this time, the DNA becomes vulnerable to replication errors, which is when problems can occur. However, occasionally the repair processes break down and mutations creep in. If this happens, the person may be born with DNA repair deficiencies (either inherited or acquired), resulting in a higher chance of them developing mutations throughout their lives and a higher risk of cancers at a young age (e.g. Ataxia Telangiectasia).


Do Certain Genes Put Me At Greater Risk Of Breast Cancer?


DID YOU KNOW… Approximately 5% of breast cancers occur in patients with the inherited BRCA mutation (i.e. erroneous BRCA gene encoding for a protein involved in DNA repair)?


This was widely popularised by Angelina Jolie; however, mutations in similar genes can also lead to hereditable breast cancer due to DNA repair fault mechanisms (e.g. Rad50, Rad51c, PALB2, BRIP1, CHEK2, NBN). Everybody’s body is different, which is why it’s so important to participate in regular health checks – even if you carry one of these hereditary predispositions, you don’t need to go straight to such drastic preventative measures as mastectomy. DNA, biology and risk of cancer is not a ‘one size fits all’ cause or solution – as much as the media may lead you to believe.
 

‘‘Faulty DNA repair leads to error prone mitosis and the acquisition of multiple mutations in the genome, eventually resulting in cancer. Even without intrinsic DNA repair faults, occasional mutations may ‘slip through’ and the more mitoses that occur, the greater the likelihood.’’
 


Why Does Prolonged HRT Use Increase My Risk Of Breast Cancer?

Most people don’t realise this but all breast cancers derive from the cells lining the milk ducts. Long-term oestrogen offered by HRT creates a constant stimulus for the milk duct cells to divide and, over time, any un-repaired DNA repair faults/mutations (caused from the shere weight of numbers of mitoses) accumulate until influential enough (in quantity or importance - i.e. in terms of affecting cellular division signalling)) to make the cells cancerous.



Why Does A ‘Toxic’ Lifestyle Encourage Cancerous Mutations?

Patients with cirrhosis have normal liver cells trying to repair the damage caused by an on-going toxic effect (e.g. alcohol or viral hepatitis inflammation). These normal cells are constantly undergoing regenerative mitosis activity, and errors of transcription ‘creep in’. Over time, the gradual accumulation of mutations in these cells’ progeny occurs and, similar to the HRT effect in the breast, this results in cancer.

However, this isn’t exclusive. The prolonged mitosis stimulation of a group of cells can induce other cancers too. For example, skin cancer adjacent to a prolonged wound (e.g. a varicose ulcer) and the induction of a lymphoma occurring in the thyroid that has been invaded by inflammatory (and dividing) lymphocytes constantly over many years (Hashimoto’s disease). By contrast, tissues that are non-dividing (e.g. muscle, neurones etc.) rarely become cancerous.



So What Is The Solution?

Ultimately, DNA repair faults are seminal to the cause and perpetuation of cancer and, whether by many opportunities for replication errors due to excessive mitoses or due to inherited or acquired DNA repair faults, it’s vital that more research is conducted to further enhance our understanding.

Together with Chris Parris (Anglia Ruskin University), we have spent the last 20 years studying these mechanisms, and have developed an assay that can quickly determine whether an individual has such a fault. Interestingly, this has important implications for therapy, as people with DNA repair faults (e.g. Ataxia Telangiectasia patients) are more sensitive to radiotherapy and chemotherapy – sometimes spectacularly so. As a result of this research, we have described two new DNA repair fault syndromes and are currently investigating in vitro the ability of new drugs (e.g. PARP inhibitors) to additively enhance the inability of cancer cells to repair damage.


If successful, this could revolutionise the treatment of cancer patients. Stay tuned!  


Nick Plowman MD is one of the world’s leading cancer specialists and Director of The Oncology Clinic, Harley Street. For more information visit www.canceradvice.co.uk




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