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DNA Sequencing Uncovers Mutational Signature Linked to Aflatoxin Exposure

NEW YORK (GenomeWeb) – DNA mutations induced by the fungal aflatoxin can be detected by sequencing shortly after exposure, according to a new study.

Aflatoxin exposure is one of the main causes of liver cancer. In Southeast Asia and sub-Saharan Africa, it is thought to cause some 80 percent of liver cancers. The toxin, which is produced by the fungus Aspergillus flavus, is consumed by people when they eat contaminated grains.

As they reported in the Proceedings of the National Academy of Sciences, researchers from the Massachusetts Institute of Technology used high-fidelity DNA sequencing to find that mutations induced by aflatoxin exposure could be detected within as little as 10 weeks in a mouse model, and that many of those alterations fell in a certain codon context. They also found that these mutations were present within the tumors the mice later developed as well as within some human liver tumors.

These mutations could be used to gauge exposure and risk of developing liver cancer, the researchers added.

"What we're doing is creating a fingerprint," senior author John Essigmann from MIT said in a statement. "It's really a measure of prior exposure to something that causes cancer."

Essigmann and his colleagues used duplex sequencing to uncover mutations that cropped up in mice exposed to aflatoxin. Duplex sequencing — in which complementary DNA strands are barcoded before sequencing — is some 1,000 times to 10,000 times more accurate than other sequencing approaches as results from both strands can be analyzed, the researchers said. This, they added, provides greater assurance that rare mutations are not mistakes.

The researchers dosed mice with aflatoxin, or DMSO as a control, four days after birth and collected liver samples from them at 10 weeks before tumors developed or at 72 weeks of age after tumors had developed. They conducted duplex sequencing on these samples to a median depth of coverage of about 15,000 reads per base.

Mice exposed to aflatoxin had an 11-fold higher frequency of mutations than control mice. At 10 weeks, the exposed mice had many more G:C to T:A transversion mutations than the control mice, which had a more diverse array of mutations. G:C to T:A mutations are known to occur in response to aflatoxin exposure, the researchers noted, because of how it intercalates with DNA.

Further, the researchers noted that 25 percent of these mutations occurred in the same three-base context of CGC, in which the middle G undergoes the mutation. This hotspot was present in each of the four mice exposed to aflatoxin and analyzed at 10 weeks.

"Even at 10 weeks, a very distinct mutational signature comes up," Essigmann said. "It's very early onset, and you don't see it with other carcinogens, to our knowledge."

In tumors collected from the mice at 72 weeks, the researchers reported that this signature was still present, though diluted by the presence of additional mutations. Non-tumor cells from that time point also harbored the signature.

Essigmann and his colleagues also analyzed a set of 314 human hepatocellular carcinoma samples. They reported that about a dozen of these human tumor samples harbored this signature. These patients were mostly from Southeast Asia and sub-Saharan Africa and were thought to have been exposed to aflatoxin through their diet.

Essigmann and his colleagues suggested that this signature could be used to gauge aflatoxin exposure. According to MIT, the researchers are hoping to develop it into a blood test and said that people who test positive on such a test could be encouraged to undergo regular liver cancer screenings.

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