The genomic landscape of cutaneous SCC reveals drivers and a novel azathioprine associated mutational signature

Inman, Gareth J.; Wang, Jun; Nagano, A.; Alexandrov, Ludmil B.; Purdie, Karin J.; Taylor, Richard G.; Sherwood, Victoria; Thomson, J.; Hogan, Sarah; Spender, Lindsay C.; South, Andrew P.; Stratton, Michael R.; Chelala, Claude; Harwood, Catherine A.; Proby, Charlotte M.; Leigh, Irene M.

doi:10.1038/s41467-018-06027-1

Cited by 227 publications

(316 citation statements)

References 78 publications

(118 reference statements)

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“…The publicly available data fromPickering et al (2014) is filtered, which may also have an impact on signatures. Furthermore, the reduced effectiveness of repair mechanisms in the non-coding DNA(Budden and Bowden, 2013;Frigola et al, 2017) may also be reflected in signature analysis of WGS data.Consistent with recent work byInman et al ( 2018), case 06, who was under azathioprine treatment for rheumatoid arthritis, showed strong contribution of signature 32(Figure 2c).…”

supporting

confidence: 91%

Mutational Patterns in Metastatic Cutaneous Squamous Cell Carcinoma

Mueller

Gauthier

Ashford

et al. 2019

Journal of Investigative Dermatology

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Cutaneous squamous cell carcinoma from the head and neck typically metastasize to the lymph nodes of the neck and parotid glands. When a primary is not identified, they are difficult to distinguish from metastases of mucosal origin and primary salivary gland squamous cell carcinoma. UV radiation causes a mutation pattern that predominantly features cytosine to thymine transitions at dipyrimidine sites and has been associated with cutaneous squamous cell carcinoma. In this study, we used whole genome sequencing data from 15 cutaneous squamous cell carcinoma metastases and show that a UV mutation signature is pervasive across the cohort and distinct from mucosal squamous cell carcinoma. The mutational burden was exceptionally high and concentrated in some regions of the genome, especially insulator elements (mean 162 mutations/megabase). We therefore evaluated the likely impact of UVinduced mutations on the dipyrimidine-rich binding site of the main human insulator protein, CCCTCbinding factor, and the possible implications on CCCTC-binding factor function and the spatial organization of the genome. Our findings suggest that mutation signature analysis may be useful in determining the origin of metastases in the neck and the parotid gland. Furthermore, UV-induced DNA damage to insulator binding sites may play a role in the carcinogenesis and progression of cutaneous squamous cell carcinoma.

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supporting

confidence: 91%

Mutational Patterns in Metastatic Cutaneous Squamous Cell Carcinoma

Mueller

Gauthier

Ashford

et al. 2019

Journal of Investigative Dermatology

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“…Genomic profiling of 293 human skin basal cell carcinomas uncovered a strong UV damage-related mutational signature in almost all cases (Bonilla et al 2016). The majority of squamous cell carcinomas of the skin also carry a strong UV signature and a large number of such mutations (Durinck et al 2011;Pickering et al 2014;Inman et al 2018;Mueller et al 2019). Merkel cell carcinoma is a rare type of neuroendocrine skin tumor.…”

Section: Mutations In Skin Cancer Genomesmentioning

confidence: 99%

Mechanisms of UV-induced mutations and skin cancer

Pfeifer

2020

GENOME INSTAB. DIS.

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Ultraviolet (UV) irradiation causes various types of DNA damage, which leads to specific mutations and the emergence of skin cancer in humans, often decades after initial exposure. Different UV wavelengths cause the formation of prominent UV-induced DNA lesions. Most of these lesions are removed by the nucleotide excision repair pathway, which is defective in rare genetic skin disorders referred to as xeroderma pigmentosum. A major role in inducing sunlight-dependent skin cancer mutations is assigned to the cyclobutane pyrimidine dimers (CPDs). In this review, we discuss the mechanisms of UV damage induction, the genomic distribution of this damage, relevant DNA repair mechanisms, the proposed mechanisms of how UV-induced CPDs bring about DNA replication-dependent mutagenicity in mammalian cells, and the strong signature of UV damage and mutagenesis found in skin cancer genomes.Keywords Ultraviolet · UV · Cyclobutane pyrimidine dimer · (6-4) Photoproduct · Mutations · DNA repair · Skin cancer · Melanoma Abbreviations UV light Ultraviolet light CPD Cyclobutane pyrimidine dimer (6-4)PP Pyrimidine (6-4) pyrimidone photoproduct 8-oxo-dG 8-Oxo-7,8-dihydro-2′-deoxyguanosine XP Xeroderma pigmentosum NER Nucleotide excision repair 5mC 5-Methylcytosine

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“…Photosensitizing or other DNA-damaging effects of immunosuppressive medications may be the major factors contributing to development of skin cancers in SOTRs, because there are several lines of evidence suggesting direct carcinogenic mechanisms [42][43][44][45] and skin cancer incidence is much less elevated in people with AIDS (ie, relative risk of 4.2 for individuals with CD4 counts < 200 cells/mm 3 compared to HIV-uninfected people). 46 Melanoma is much less common, and incidence is only modestly increased in SOTRs and HIV-infected individuals (SIRs 1.2-2, Supplemental Table S1).…”

Section: Engelsmentioning

confidence: 99%

Epidemiologic perspectives on immunosuppressed populations and the immunosurveillance and immunocontainment of cancer

Engels

2019

American Journal of Transplantation

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The advent in the last several years of effective immunotherapy for cancer has renewed interest in the role of the immune system in controlling cancer. The idea that the immune system can help control cancer has a long history. Solid organ transplant recipients (SOTRs) as well as human immunodeficiency virus (HIV)-infected people are affected by cell-mediated immune dysfunction. Epidemiologic studies of these populations reveal a pattern characterized by a strongly increased incidence of virus-related cancers (eg, Kaposi sarcoma, non-Hodgkin lymphoma, and anogenital cancers). In addition, recent epidemiologic studies have evaluated cancer-specific mortality among SOTRs and HIV-infected people following a cancer diagnosis. For a wider range of cancers-not limited to those caused by viruses, and including melanoma and cancers of the colorectum, lung, and breast-these immunosuppressed cancer patients have higher cancer-specific mortality than other cancer patients. This latter group of cancers somewhat mirrors those for which immunotherapy with checkpoint inhibitors is approved. These epidemiologic observations suggest that there are 2 distinct immune selection processes in humans: immunosurveillance directed against premalignant cells before cancer diagnosis (most relevant for preventing virus-related cancers), and "immunocontainment" directed against established cancers. These processes thus appear relevant for different groups of malignancies and may have different mechanisms. K E Y W O R D Scancer/malignancy/neoplasia, cancer/malignancy/neoplasia: registry/incidence, cancer/ malignancy/neoplasia: risk factors, clinical research/practice, epidemiology, hematology/ oncology, immune deficiency, immunosuppression/immune modulation, translational research/science | INTRODUC TI ONThe advent in the last several years of effective immunotherapy for cancer has renewed interest in the role of the immune system in controlling cancer. 1-3 The field of cancer immunotherapy has long drawn support from the observation that immunosuppressed individuals, including solid organ transplant recipients (SOTRs), have an elevated risk of developing cancer. 2 In this Personal

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The genomic landscape of cutaneous SCC reveals drivers and a novel azathioprine associated mutational signature

Cited by 227 publications

References 78 publications

Mutational Patterns in Metastatic Cutaneous Squamous Cell Carcinoma

Mutational Patterns in Metastatic Cutaneous Squamous Cell Carcinoma

Mechanisms of UV-induced mutations and skin cancer

Epidemiologic perspectives on immunosuppressed populations and the immunosurveillance and immunocontainment of cancer

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