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UV-Induced DNA Damage Signature Linked to Better Melanoma Outcomes

NEW YORK (GenomeWeb) – An ultraviolet radiation-induced mutation signature is associated with better overall survival among melanoma patients, a new study has found.

A University of Manchester-led team sifted through melanoma genomes from the Cancer Genome Atlas and classified them based on their mutational signatures. There are about 91,270 new cases of melanoma each year in the US, according to the US National Cancer Institute. Melanoma has been linked to exposure to UV radiation (UVR).

The team led by Manchester's Richard Marais identified 10 recurrently mutated genes associated with both a UVR-related mutational signature and better overall survival. In a mouse model of melanoma, the researchers found that shortwave UVR exposure could induce this signature and that only a handful of exposures were needed to accelerate melanoma development.

"Our studies emphasize the importance of prevention and education strategies to highlight the dangers of UVR and its carcinogenic role in melanoma," the authors wrote today in Nature Medicine.

In cells, UVR exposure induces C-to-T nucleotide transitions at dipyrimidines, and when this occurs in a trinucleotide pattern, it becomes what's known as signature 7, a mutational signature common among UVR-linked skin cancers.

The team analyzed cutaneous melanoma genomes obtained from TCGA and separated them by whether or not they harbored signature 7. This generated a set of 372 tumors in which it was present and 47 tumors in which it was not. In addition to a higher number of C-to-T transitions at dipyrimidines, the signature 7 tumors had higher numbers of SNVs. Ten genes, including LRP1B, DNAH9, and TP53, were recurrently mutated among signature 7 tumors, the researchers reported.

Patients harboring signature 7 had both longer disease-free and better overall survival, the researchers reported. In addition, patients with tumors harboring mutations in any of the signature 7-associated genes had better overall survival than patients whose tumors lacked them. The researchers confirmed prognostic ability of these mutations in a separate cohort.

The researchers also exposed BRAF V600E mouse models of melanoma to different wavelengths of UV radiation. Within 24 hours of exposure, skin cells of mice exposed to broad UV and short UVB wavelengths of 310 nanometers to 315 nanometers exhibited increased thymine dimers and p53, though the skin cells of mice exposed to long UVA wavelengths of between 350 nanometers and 400 nanometers did not.

They also exposed mice to UV wavelengths of 280 nanometers to 380 nanometers four times. These mice, they found, developed tumors with a median latency of 13 weeks — more quickly than the chronically exposed mice — though the tumor burden the groups developed was similar. They also exposed mice to UV wavelengths of 280 nanometers to 380 nanometers four times prior to inducing BRAF V600E and found those mice also quickly developed melanoma.

Whole-exome sequencing of these mice found that all mice exposed chronically to UV wavelengths of 280 nanometers to 380 nanometers and all mice exposed to UVB wavelengths of 310 nanometers to 315 nanometers harbored signature 7 within their tumors.

The majority of tumors exposed short-term to UVR of wavelengths between 280 nanometers to 380 nanometers and BRAF-naïve tumors exposed to UVR of wavelengths between 280 nanometers and 380 nanometers also had this signature. The signature 7 mouse tumors, like the human ones, had more C-to-T transitions and more SNVs.

This, the researchers noted, suggests that signature 7 is associated with shortwave UV exposure, and that as few as four exposures can accelerate the development of melanoma.

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