New Delhi: A study has found the first direct evidence of how one’s genetic makeup can influence DNA damage through exposures such as cigarette smoke or sunlight and alter how many mutations accumulate.
Findings published in the journal Nature could explain aspects including why most smokers do not develop lung cancer, while some non-smokers develop lung cancer.
Researchers, including those at the University of Cambridge, said 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, they said.
Senior author Duncan Odom, who led the research while at the Cancer Research UK (CRUK) Cambridge Institute at the University of Cambridge, said, “Cancer does not arise entirely by chance. Although tumours often reach the same biological endpoint, the path to that endpoint is determined by an individual’s genetic background.”
“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,” Odom said.
The researchers said the findings have implications for cancer screening and precision medicine, adding that prevention and screening strategies may need to account more carefully for inherited genetics and population diversity.
The researchers bred four strains of mice with a varying susceptibility to liver cancer, spanning a level of genetic diversity comparable to that seen in human populations.
The mice were then exposed to a single dose of the liver carcinogen diethylnitrosamine (DEN). DEN is found in tobacco smoke and certain processed foods and is known to cause DNA damage in liver cells, leading to mutations that can initiate tumour growth, the researchers said.
Because every mouse received the same dose at the same age – 15 days of age – under controlled conditions, the team eliminated the environmental variation that confounds studies in humans.
They then sequenced genomes of almost 600 tumours and analysed gene activity that developed, along with examining the untreated mice to compare spontaneous tumour formation across strains. Using the data, the researchers reconstructed how each tumour evolved from its original cancer-causing mutation.
Across all mouse strains, cancers nearly always acquired a cancer-driving mutation that activated the same cancer-promoting signalling system, called the MAPK pathway — a multi-step cascade of molecular signals that controls important life processes, including cell growth, and plays a key role in numerous types of cancer.
However, depending on the genetics of a mouse, the acquired mutation altered the activity of other signalling pathways associated with cancer, and also caused a striking tendency for a duplication of the whole-genome — where an organism gets an extra set of all its chromosomes and extra gene copies are free to mutate and take on new jobs.
