Intragenomic variability and extended sequence patterns in the mutational signature of ultraviolet light

Lindberg, Markus; Boström, Martin; Elliott, Kerryn; Larsson, Erik

doi:10.1073/pnas.1909021116

Cited by 24 publications

(18 citation statements)

References 44 publications

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“…3A, 3B, bottom panels). This finding indicates that the enrichment of dipyrimidine or trinucleotide sequences in the UVB-irradiated samples clearly reflects the known sequence specificity of CPD formation (Cadet et al, 2015;Lindberg et al, 2019;Mao et al, 2016;Pfeifer, 2020;Premi et al, 2019) and also indicates the high sensitivity and specificity of CD-seq. To identify broader sequence motifs for CPD formation, we obtained a base enrichment on twenty nucleotide regions around the gapped base-pair (Fig.…”

Section: Cd-seq For Genome-wide Mapping Of Uvb-induced Cyclobutane Pymentioning

confidence: 57%

Mapping of DNA damage genome-wide at nucleotide resolution by circle-damage-sequencing

Jin

Pettinga

Johnson

et al. 2020

Preprint

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ABSTRACTTo establish relationships between mutations, for example in cancer genomes, and possible mechanisms linked to DNA damage, it is necessary to know at what sequence positions of the genome the damage occurs. However, it has been challenging to specifically map DNA damage at the nucleotide level of resolution and genome-wide with high sensitivity. Here, we describe a new method, which we named circle damage sequencing (CD-seq), to accomplish this goal. The method is based on circularization of DNA molecules and DNA damage-selective cleavage of the circularized DNA followed by adapter ligation and sequencing. Based on the design of this approach, only DNA damage-containing molecules are sequenced. We conducted proof-of-principle studies to show that mapping of ultraviolet B-induced cyclobutane pyrimidine dimers (CPDs) can easily be achieved with high precision using pyrimidine dimer-specific DNA repair enzymes. Our approach shows strongly reduced levels of CPDs near transcription start sites and a spike of this damage near the transcription end sites of genes. We then show that 1,N6-etheno-deoxyadenosine DNA adducts created after treatment of cells with the lipid peroxidation product 4-hydroxynonenal can be mapped genome-wide at adenine positions and obtained a preferential sequence context of these adducts as 5’TAC/G3’. The CD-seq method can be adapted for a variety of DNA lesions for which specific excision enzymes are available and should prove useful for studies of DNA damage, DNA repair and cancer etiology.

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Section: Cd-seq For Genome-wide Mapping Of Uvb-induced Cyclobutane Pymentioning

confidence: 57%

Mapping of DNA damage genome-wide at nucleotide resolution by circle-damage-sequencing

Jin

Pettinga

Johnson

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…6E and fig. S7) ( 1 , 23 ). These signatures are highly enriched in melanoma genomes, where the classical signature 7 appears like a composite of SBS7a and SBS7b.…”

Section: Resultsmentioning

confidence: 99%

The major mechanism of melanoma mutations is based on deamination of cytosine in pyrimidine dimers as determined by circle damage sequencing

et al. 2021

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Sunlight-associated melanomas carry a unique C-to-T mutation signature. UVB radiation induces cyclobutane pyrimidine dimers (CPDs) as the major form of DNA damage, but the mechanism of how CPDs cause mutations is unclear. To map CPDs at single-base resolution genome wide, we developed the circle damage sequencing (circle-damage-seq) method. In human cells, CPDs form preferentially in a tetranucleotide sequence context (5′-Py-T<>Py-T/A), but this alone does not explain the tumor mutation patterns. To test whether mutations arise at CPDs by cytosine deamination, we specifically mapped UVB-induced cytosine-deaminated CPDs. Transcription start sites (TSSs) were protected from CPDs and deaminated CPDs, but both lesions were enriched immediately upstream of the TSS, suggesting a mutation-promoting role of bound transcription factors. Most importantly, the genomic dinucleotide and trinucleotide sequence specificity of deaminated CPDs matched the prominent mutation signature of melanomas. Our data identify the cytosine-deaminated CPD as the leading premutagenic lesion responsible for mutations in melanomas.

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“…Thus, and based on our experience with undifferentiated melanomas, none of the current cases qualifies for melanoma [6]. The potential value of actinic molecular signature in differentiating metastatic undifferentiated melanoma from rare NRAS-mutated NSCLC remains an issue of future studies [24][25][26].…”

Section: Discussionmentioning

confidence: 99%

Undifferentiated large cell/rhabdoid carcinoma presenting in the intestines of patients with concurrent or recent non-small cell lung cancer (NSCLC): clinicopathologic and molecular analysis of 14 cases indicates an unusual pattern of dedifferentiated metastases

et al. 2021

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Undifferentiated carcinoma metastatic to the bowel is uncommon in surgical pathology practice and might be confused with primary gastrointestinal carcinoma, melanoma, lymphoma, and others. We present 14 cases of uni- (n = 9) or multifocal (n = 5) undifferentiated large cell/rhabdoid carcinoma presenting in the bowel of patients with concurrent (n = 9) or recent (diagnosed 1 to 25 months earlier; median, 4) non-small cell lung cancer (NSCLC). Patients were 6 females and 8 males, aged 52 to 85 years. Primary NSCLC was verified histologically in 10 cases and by imaging in 4. The undifferentiated histology was present in the lung biopsy in 4/10 patients (as sole pattern in 3 and combined with adenocarcinoma in 1) and was limited to the intestinal metastases in the remainder. PDL1 was strongly expressed in 7/9 cases (CPS: 41 to 100). Loss of at least one SWI/SNF subunit was detected in 7/13 cases (54%). SMARCA2 loss (n = 6) was most frequent and was combined with SMARCA4 loss in one case. PBRM1 loss was observed in one tumor. Successful molecular testing of 11 cases revealed BRAF mutations in 4 (3 were non-V600E variants), KRAS mutations in 3, and wildtype in 4. None had EGFR mutations. Analysis of 4 paired samples revealed concordant KRAS (2) and BRAF (1) mutations or wildtype (1). Our study indicates that undifferentiated carcinoma within the intestines of patients with concurrent/recent NSCLC represents dedifferentiated metastasis from the NSCLC. Recognition of this unusual presentation is cardinal to avoid misdiagnosis with inappropriate therapeutic and prognostic implications.

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Intragenomic variability and extended sequence patterns in the mutational signature of ultraviolet light

Cited by 24 publications

References 44 publications

Mapping of DNA damage genome-wide at nucleotide resolution by circle-damage-sequencing

Mapping of DNA damage genome-wide at nucleotide resolution by circle-damage-sequencing

The major mechanism of melanoma mutations is based on deamination of cytosine in pyrimidine dimers as determined by circle damage sequencing

Undifferentiated large cell/rhabdoid carcinoma presenting in the intestines of patients with concurrent or recent non-small cell lung cancer (NSCLC): clinicopathologic and molecular analysis of 14 cases indicates an unusual pattern of dedifferentiated metastases

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