Study reveals why DNA damage from smoking and UV rays may cause cancer in some people but not others | University of Cambridge
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Study reveals why DNA damage from smoking and UV rays may cause cancer in some people but not others
Scientists have found the first direct evidence of the powerful role our genetic makeup plays in influencing our risk of cancer, with inherited genes interacting with acquired genetic mutations to shape how tumours evolve.
We’ve been able to show for the first time the extent to which genetic background influences both the mutation processes and the pathways leading to tumour development
Duncan Odom
The findings could explain why some people are more susceptible to cancer than others in the same environment and suggest that future cancer prevention and screening strategies may need to account more carefully for inherited genetics and population diversity.<br>The research, published today in Nature and carried out in mice, suggests that responses to DNA-damaging cancer treatments could differ depending on a patient's background genetics, strengthening the case for a more personalised approach to treatment.<br>Tumours arise when our DNA accumulates errors, or mutations, causing the cells to grow faster and ignore signals that would otherwise instruct damaged cells to die before they can cause harm. Environmental exposures – for example, cigarette smoke or sunlight – influence how much DNA damage occurs, and inherited genetic alterations can alter how many mutations accumulate.<br>Not everyone exposed to the same environmental risk factors will develop cancer, however. Most smokers do not develop lung cancer – and some non-smokers develop lung cancer. The reason why is almost certainly related to our inherited genetic makeup, but finding direct evidence has proved challenging in patient cohort studies. Even though many studies have suggested that inherited genetic differences affect cancer risk, proving this link has been difficult because individuals within – and between – human populations vary in lifestyle, environment, and exposure history.<br>The study is the result of years of international collaboration, between the University of Cambridge, University of Edinburgh, and others around Europe and the US, and was co-led by Professor Duncan Odom, Dr Sarah Aitken, and Professor Martin Taylor.<br>In experiments largely carried out at the Cancer Research UK (CRUK) Cambridge Institute at the University of Cambridge, scientists developed an experimental approach that allowed them to control environmental factors experimentally and show that genetic background itself can alter how tumours arise and evolve.<br>The team bred four strains of mice with varying susceptibility to liver cancer, spanning a level of genetic diversity comparable to that seen in human populations. They then exposed the mice to a single dose of the liver carcinogen diethylnitrosamine (DEN). DEN is found in tobacco smoke and some processed foods and is known to cause DNA damage in liver cells, leading to mutations that can initiate tumour growth.<br>Because every mouse received the same dose at the same age – 15 days of age – under controlled conditions, the researchers were able to eliminate the environmental variation that confounds studies in humans.<br>They then sequenced the genomes of almost 600 tumours and analysed the gene activity that developed as well as examining the untreated mice to compare spontaneous tumour formation across strains. Using this data, they were able to reconstruct how each tumour evolved from its original cancer-causing mutation.<br>Across all mouse strains, cancers nearly always acquired a cancer-driving mutation that activated the same cancer-promoting signalling system, called the MAPK pathway. This is a multi-step cascade of molecular signals that controls important life processes, including cell growth and cell differentiation, and plays a key...