A normal DNA repair process can become a major source of mutations in
cancer

Date:
August 4, 2020
Source:
Institute for Research in Biomedicine (IRB Barcelona)
Summary:
The mechanism unveiled triggers a mutation fog, causing hundreds of
mutations in each tumor, which spread through the genome of lung,
head- and-neck and breast cancers. Researchers have identified
the antiviral APOBEC3A enzyme as the major cause of this new type
of hypermutation.

Published in Nature Genetics, the study shows how the mutation
fog process generates many oncogenic ''cancer driver'' mutations,
thus accelerating tumour development.



FULL STORY ========================================================================== Hypermutation is an unusual occurence that can lead to many nearby
mutations at once, severely damaging our genetic material and potentially causing cancer.

The best known type of local hypermutation, called a mutation shower or thunderstorm, is quite uncommon and it leads to many mutations accumulated
in a small area, e.g. a single gene.


========================================================================== Researchers from IRB Barcelona's Genome Data Science Lab, led by the
ICREA researcher Fran Supek, have discovered a new type of hypermutation
called mutation fog, which can generate hundreds of mutations in every
cell. Such mutations are widely distributed, but accumulate in the
most important regions of the genome, where genes reside (the so-called euchromatin). The fact that these mutations are spread around explains
why they have remained undetected until now.

Surprisingly, the scientists have also identified that the newly
discovered hypermutation type is related to a normal DNA repair
process. When cells sense a mismatch in their DNA, they undergo a DNA
repair reaction, in order to preserve genetic information. Remarkably,
this reaction can become coupled to the APOBEC enzyme-typically used
by human cells to defend against viruses and having an important role
in fighting hepatitis and HIV. The work by the Genome Data Science Lab indicates that, in some cases, when both the APOBEC enzymes and the DNA
repair process are active at the same time, APOBEC hijacks the DNA repair, generating the mutation fog.

"We think that this APOBEC-driven mutation fog has a mutagenic potential
that matches or even exceeds that of well-known strong carcinogens, such
as tobacco smoke or ultraviolet radiation," Fran Supek explains. Recent
work by other research groups suggests that the process appears to be more active in late- stage metastatic cancers: it helps the cancer evolve,
enabling it to resist drugs and radiation. "This finding makes APOBEC
an attractive target for treating cancer, removing its ability to evolve
and to become more aggressive," adds Supek.

The origin of a half of the mutations in some lung and breast cancers
A thorough analysis of more than 6,000 human cancer genomes, including
lung tumours, breast tumours and melanomas, among others, led to the
finding that the mutation fog is a common phenomenon. "More than half
of all APOBEC mutations in some lung or breast cancers are generated by
the hypermutation mechanism that we have found," says David Mas-Ponte,
first author of the study and PhD student in the Genome Data Lab.

Some types of cancer, such as cervical or some head-and-neck cancers,
are known to be due to viruses. However, this study has found mutations
caused by this APOBEC system not only in these tumours but also in cancers
that are not currently known to be virus-related. Further work should
clarify what triggers the APOBEC system. "Understanding APOBEC better
could have broad implications for cancer treatment," adds Mas-Ponte.

The HyperClust statistical method Mas-Ponte and Supek designed a
statistical method, called HyperClust, that can rapidly analyse large
amounts of human genomic data to find unusual mutational processes that
can lead to simultaneous mutations, such as these cases of mutation
fog. This statistical method is described in the article, which has been published in Nature Genetics, and is also available as an open-source
software in a Github repository.

This work has been funded by the ERC Starting Grant "HYPER-INSIGHT"
awarded to Fran Supek; ICREA reaearcher and EMBO Young Investigator;
and the Severo Ochoa grant awarded to IRB Barcelona. David Mas-Ponte
was the recipient of an FPI-SO fellowship.


========================================================================== Story Source: Materials provided by Institute_for_Research_in_Biomedicine_(IRB_Barcelona).

Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. David Mas-Ponte, Fran Supek. DNA mismatch repair promotes APOBEC3-
mediated diffuse hypermutation in human cancers. Nature Genetics,
2020; DOI: 10.1038/s41588-020-0674-6 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/08/200804111505.htm

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