Atypical UV Photoproducts Induce Non-canonical Mutation Classes Associated with Driver Mutations in Melanoma

Marian F Laughery,Alexander J Brown,Kaitlynne A Bohm,Smitha Sivapragasam,Haley S Morris,Mila Tchmola,Angelica D Washington,Debra Mitchell,Stephen Mather,Ewa P Malc,Piotr A Mieczkowski,Steven A Roberts,John J Wyrick

doi:10.1016/j.celrep.2020.108401

Marian F Laughery, Alexander J Brown + Show 11 more

Open Access

https://doi.org/10.1016/j.celrep.2020.108401

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Abstract

SUMMARYSomatic mutations in skin cancers and other ultraviolet (UV)-exposed cells are typified by C>T and CC>TT substitutions at dipyrimidine sequences; however, many oncogenic “driver” mutations in melanoma do not fit this UV signature. Here, we use genome sequencing to characterize mutations in yeast repeatedly irradiated with UV light. Analysis of ~50,000 UV-induced mutations reveals abundant non-canonical mutations, including T>C, T>A, and AC>TT substitutions. These mutations display transcriptional asymmetry that is modulated by nucleotide excision repair (NER), indicating that they are caused by UV photoproducts. Using a sequencing method called UV DNA endonuclease sequencing (UVDE-seq), we confirm the existence of an atypical thymine-adenine photoproduct likely responsible for UV-induced T>A substitutions. Similar non-canonical mutations are present in skin cancers, which also display transcriptional asymmetry and dependence on NER. These include multiple driver mutations, most prominently the recurrent BRAF V600E and V600K substitutions, suggesting that mutations arising from rare, atypical UV photoproducts may play a role in melanomagenesis.

Highlights

Exposure to ultraviolet (UV) light causes a unique signature of mutations in skin cancers and other UV-irradiated cells (Brash, 2015; Ikehata and Ono, 2011; Pfeifer et al, 2005)
Two of the most frequent driver mutations in melanoma are the NRAS Q61R and the BRAF V600E mutations. These are among the most recurrent mutations in melanoma and are associated with carcinogenesis, neither is a canonical UV signature mutation: NRAS Q61R is caused by a T>C mutation, while BRAF V600E is caused by a T>A mutation in a non-Dipyr context (Hodis et al, 2012; Pandiani et al, 2017; Sample and He, 2018)
T>C substitutions are primarily associated with TTA, TTC, TTG, and TTT sequences (i.e., TTN), as well as CTN trinucleotides (Figure 1D), and mostly occur in the 30 position of a Dipyr (Figure S1D), indicating that they likely arise from known UV photoproducts (e.g., cyclobutane pyrimidine dimers (CPDs) or 6-4PPs)

Summary

Introduction

Exposure to ultraviolet (UV) light causes a unique signature of mutations in skin cancers and other UV-irradiated cells (Brash, 2015; Ikehata and Ono, 2011; Pfeifer et al, 2005). Genome sequencing of mutations arising in mammalian cells following experimental UV exposure (typically a single low dose of UV) has confirmed that UVB or UVC light primarily induces UV signature mutations (Kucab et al, 2019; Nik-Zainal et al, 2015; Olivier et al, 2014). These studies have not provided insight into the origin of the atypical substitution

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