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APOBEC-Linked Mutational Signatures Drive Skin Cancer in Recessive Dystrophic Epidermolysis Bullosa

NEW YORK (GenomeWeb) – Mutational signatures linked to the APOBEC family drive the development of early-onset squamous cell carcinomas of the skin among individuals with a rare genetic disorder condition.

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare genetic disorder caused by COL7A1 mutations that leads to skin fragility, tissue damage, and inflammation. Wounds that people with the condition develop don't heal well, which causes scarring and fibrosis, and the condition is linked to an increased risk of early-onset, highly malignant squamous cell carcinoma (SCC) with a five-year survival rate near zero.

An international team of researchers conducted a molecular analysis of 27 RDEB SCC tumors to tease out mutational signatures from within the tumors. As they reported today in Science Translational Medicine, the researchers found that apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC) mutational signatures dominate RDEB SCC tumors and could represent a means of preventing tumor development.

"Our findings reveal a cause for cancers arising at sites of persistent inflammation and identify potential therapeutic avenues to treat RDEB SCC," senior author Andrew South from Thomas Jefferson University and his colleagues wrote in their paper.

The researchers sequenced the exomes of 27 different SCC tumors from 26 RDEB patients to a mean 217-fold coverage and compared them to published data on 38 UV-induced SCC and 279 head and neck SCC (HNSCC) samples.

The RDEB SCC tumors harbored an average 147 nonsynonymous mutations, and commonly mutated genes include TP53, CDKN2A, and CASP8.

The researchers uncovered three de novo mutational signatures within these tumors. These signatures were either known Catalog of Somatic Mutations in Cancer (COSMIC) mutational signatures or mixtures of known COSMIC signatures.

The RDEB SCC mutational signatures overlapped with COSMIC mutational signatures related to UV damage and APOBEC editing, among others, but the APOBEC-associated mutational signature was found in all RDEB SCC tumors.

The researchers estimated that APOBEC mutational processes account for about 42 percent of RDEB SCC tumor mutations. By contrast, fewer than 2 percent of mutations in UV-induced SCC tumors were linked to APOBEC mutational processes. They also noted that DNA repair processes appear intact in RDEB SCC tumors, which indicates the increased mutagenesis is largely due to APOBEC activity.

When the researchers examined samples collected from different region of the same five tumors, they found the APOBEC mutational signature is present in both the "trunk" and the "branches" of the tumors, suggesting it is active throughout tumor development.

APOBEC inhibitors, the researchers noted, could represent a potential treatment approach.

The transcriptomes of RDEB SCC tumors, meanwhile, were similar to those of the basal and mesenchymal subtypes of HNSCC, suggesting APOBEC processes could also influence other SCC subtypes. At the same time, it indicated to the researchers that treatments that are effective in HNSCC should be evaluated for use in RDEB SCC.

Pathway analysis of the RDEB SCC transcriptomes also uncovered an enrichment of inflammatory processes. This, the researchers said, could reflect a role for an inflammatory tumor microenvironment in tumor development.

For one patient, the researchers examined the mutational landscape of two separate RDEB SCC tumors to find that that the suite of affected genes was similar — both had mutations in genes like CASP8 and NOTCH1 — though the actual mutations differed. This could mean, the researchers said, that the genetics of RDEB SCC tumors are recurrently influenced by host genetics, a highly inflammatory microenvironment, or microbial colonization.

"Collectively, these data suggest that use of targeted therapies in RDEB SCC may have greater efficacy than with polyclonal tumors that have acquired the ability to adapt to selective treatment pressures," the researchers wrote.

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