Signatures of epigenetic, biological and mitotic age acceleration and telomere shortening are associated with arsenic-induced skin lesions.

Chronic arsenic exposure is a global health hazard significantly associated with the development of deleterious cutaneous changes and increased keratinocyte cancer risk. Although arsenic exposure is associated with broad-scale cellular and molecular changes, gaps exist in understanding how these changes impact the skin and facilitate malignant transformation. Recently developed epigenetic "clocks" can accurately predict chronological, biological and mitotic age, as well as telomere length, on the basis of tissue DNA methylation state. Deviations of predicted from expected age (epigenetic age dysregulation) have been associated with numerous complex diseases, increased all-cause mortality and higher cancer risk. We investigated the ability of these algorithms to detect molecular changes associated with chronic arsenic exposure in the context of associated skin lesions. To accomplish this, we utilized a multi-algorithmic approach incorporating seven "clocks" (Horvath, Skin&Blood, PhenoAge, PCPhenoAge, GrimAge, DNAmTL and epiTOC2) to analyze peripheral blood of pediatric and adult cohorts of arsenic-exposed (n = 84) and arsenic-naïve (n = 33) individuals, among whom n = 18 were affected by skin lesions. Arsenic-exposed adults with skin lesions exhibited accelerated epigenetic (Skin&Blood: + 7.0 years [95% CI 3.7; 10.2], q = 6.8 × 10-4), biological (PhenoAge: + 5.8 years [95% CI 0.7; 11.0], q = 7.4 × 10-2, p = 2.8 × 10-2) and mitotic age (epiTOC2: + 19.7 annual cell divisions [95% CI 1.8; 37.7], q = 7.4 × 10-2, p = 3.2 × 10-2) compared to healthy arsenic-naïve individuals; and accelerated epigenetic age (Skin&Blood: + 2.8 years [95% CI 0.2; 5.3], q = 2.4 × 10-1, p = 3.4 × 10-2) compared to lesion-free arsenic-exposed individuals. Moreover, lesion-free exposed adults exhibited accelerated Skin&Blood age (+ 4.2 [95% CI 1.3; 7.1], q = 3.8 × 10-2) compared to their arsenic-naïve counterparts. Compared to the pediatric group, arsenic-exposed adults exhibited accelerated epigenetic (+ 3.1 to 4.4 years (95% CI 1.2; 6.4], q = 2.4 × 10-4-3.1 × 10-3), biological (+ 7.4 to 7.8 years [95% CI 3.0; 12.1] q = 1.6 × 10-3-2.8 × 10-3) and mitotic age (+ 50.0 annual cell divisions [95% CI 15.6; 84.5], q = 7.8 × 10-3), as well as shortened telomere length (- 0.23 kilobases [95% CI - 0.13; - 0.33], q = 2.4 × 10-4), across all seven algorithms. We demonstrate that lifetime arsenic exposure and presence of arsenic-associated skin lesions are associated with accelerated epigenetic, biological and mitotic age, and shortened telomere length, reflecting altered immune signaling and genomic regulation. Our findings highlight the usefulness of DNA methylation-based algorithms in identifying deleterious molecular changes associated with chronic exposure to the heavy metal, serving as potential prognosticators of arsenic-induced cutaneous malignancy.

Tree-Based Machine Learning to Identify Predictors of Psoriasis Incidence at the Neighborhood Level: A Populational Study from Quebec, Canada.

BACKGROUND: Psoriasis is a major global health burden affecting ~ 60 million people worldwide. Existing studies on psoriasis focused on individual-level health behaviors (e.g. diet, alcohol consumption, smoking, exercise) and characteristics as drivers of psoriasis risk. However, it is increasingly recognized that health behavior arises in the context of larger social, cultural, economic and environmental determinants of health. We aimed to identify the top risk factors that significantly impact the incidence of psoriasis at the neighborhood level using populational data from the province of Quebec (Canada) and advanced tree-based machine learning (ML) techniques. METHODS: Adult psoriasis patients were identified using International Classification of Disease (ICD)-9/10 codes from Quebec (Canada) populational databases for years 1997-2015. Data on environmental and socioeconomic factors 1 year prior to psoriasis onset were obtained from the Canadian Urban Environment Health Consortium (CANUE) and Statistics Canada (StatCan) and were input as predictors into the gradient boosting ML. Model performance was evaluated using the area under the curve (AUC). Parsimonious models and partial dependence plots were determined to assess directionality of the relationship. RESULTS: The incidence of psoriasis varied geographically from 1.6 to 325.6/100,000 person-years in Quebec. The parsimonious model (top 9 predictors) had an AUC of 0.77 to predict high psoriasis incidence. Amongst top predictors, ultraviolet (UV) radiation, maximum daily temperature, proportion of females, soil moisture, urbanization, and distance to expressways had a negative association with psoriasis incidence. Nighttime light brightness had a positive association, whereas social and material deprivation indices suggested a higher psoriasis incidence in the middle socioeconomic class neighborhoods. CONCLUSION: This is the first study to highlight highly variable psoriasis incidence rates on a jurisdictional level and suggests that living environment, notably climate, vegetation, urbanization and neighborhood socioeconomic characteristics may have an association with psoriasis incidence.

The Ultraviolet Irradiation of Keratinocytes Induces Ectopic Expression of LINE-1 Retrotransposon Machinery and Leads to Cellular Senescence.

Retrotransposons have played an important role in evolution through their transposable activity. The largest and the only currently active human group of mobile DNAs are the LINE-1 retrotransposons. The ectopic expression of LINE-1 has been correlated with genomic instability. Narrow-band ultraviolet B (NB-UVB) and broad-band ultraviolet B (BB-UVB) phototherapy is commonly used for the treatment of dermatological diseases. UVB exposure is carcinogenic and can lead, in keratinocytes, to genomic instability. We hypothesize that LINE-1 reactivation occurs at a high rate in response to UVB exposure on the skin, which significantly contributes to genomic instability and DNA damage leading to cellular senescence and photoaging. Immortalized N/TERT1 and HaCaT human keratinocyte cell lines were irradiated in vitro with either NB-UVB or BB-UVB. Using immunofluorescence and Western blotting, we confirmed UVB-induced protein expression of LINE-1. Using RT-qPCR, we measured the mRNA expression of LINE-1 and senescence markers that were upregulated after several NB-UVB exposures. Selected miRNAs that are known to bind LINE-1 mRNA were measured using RT-qPCR, and the expression of miR-16 was downregulated with UVB exposure. Our findings demonstrate that UVB irradiation induces LINE-1 reactivation and DNA damage in normal keratinocytes along with the associated upregulation of cellular senescence markers and change in miR-16 expression.

Understanding the Perceived Relationship between Sun Exposure and Melanoma in Atlantic Canada: A Consensual Qualitative Study Highlighting a "Sunscreen Paradox".

Globally, cutaneous melanoma (CM) incidence is increasing, with sun exposure identified as a key modifiable risk factor. The Atlantic provinces of Canada display varied CM incidence rates: New Brunswick aligns with the national average, while Nova Scotia and Prince Edward Island exceed it, and Newfoundland and Labrador fall below this benchmark. We investigated the relationship between sun exposure and CM in these provinces. Twenty-two focus groups encompassing 95 Atlantic Canada residents were conducted and transcribed. A thematic analysis was conducted in MAXQDA using the social-ecological model as a framework. Residents of high-CM incidence provinces demonstrated greater sun exposure awareness, consulting UV indices, and using sunscreen and sun-protective clothing. However, they received greater UV exposure due to warmer climates and outdoor work and cultural activities. Conversely, those in low-incidence provinces used sunscreen and sun-protective clothing less often, engaged in occupations and hobbies affording less sun exposure, and lived in cooler climates. Our data supports a possible "sunscreen paradox", whereby increased sunscreen use is correlated with augmented sun exposure, leading to a deceptive sense of security. Public health initiatives in Atlantic Canada promoting sun safety must address this paradox while integrating community-specific behaviors and norms in order to develop tailored campaigns.

Morphea, Eosinophilic Fasciitis and Cancer: A Scoping Review.

Morphea is an autoimmune fibrotic skin disease. Eosinophilic fasciitis (EF) is considered to belong to the severe spectrum of morphea. We conducted a scoping review assessing the risk of secondary cancer among morphea/EF patients, paraneoplastic morphea/EF and morphea/EF developing secondary to cancer therapy. The search was conducted using MEDLINE, Embase, Cochrane databases for articles published from inception to September 2022 following the Preferred Reporting Items for Systematic reviews and Meta-Analyses for Scoping Reviews (PRISMA-ScR) guidelines with no language or date restrictions. Two hundred and one studies were included. Of these, 32 studies reported on secondary cancer in morphea/EF patients, 45 on paraneoplastic morphea/EF and 125 on cancer-treatment-induced morphea/EF. While the current evidence remains limited, data suggest an increased risk of secondary cutaneous and possibly pancreatic malignancy in morphea patients, particularly the generalized subtype. There were insufficient data for EF. On the other hand, paraneoplastic morphea was anecdotal, whereas several observational studies suggested that ~10% of EF cases may be paraneoplastic, primarily in the context of hematologic malignancies. Radiotherapy-induced morphea is rare, seen in ~0.2% of treated patients and is usually localized to the treatment site, except in patients with pre-existing autoimmunity. While chemotherapy-induced cases are reported, immunotherapy morphea/EF cases are emerging and are preferentially seen with PD-1 and not CTLA-4 inhibitors. This study is limited by the type of articles included (case reports, case series and observational studies), and hence, additional research on this important topic is needed.

Burden and geographic distribution of oral cavity and oropharyngeal cancers in the Russian Federation.

Background: The global incidence of lip and oral cavity cancers (OCCs) and oropharyngeal cancers (OPCs) is steadily increasing. While tobacco and alcohol consumption are established risk factors, a considerable proportion of these cancers has become attributed to human papilloma virus (HPV) infection. We aimed to describe the occurrence and identify potential risk factors of OCCs and OPCs across the Russian Federation during 2007-2018. Methods: We conducted an ecological analysis using publicly accessible data from the P.A. Herzen Moscow Oncology Research Institute. Incidence and mortality rates by jurisdiction were mapped for geospatial analysis. We pre-defined 11 potential contributing risk factors and used univariable and multivariable Poisson regression model with backwards stepwise variable selection to identify associated factors with OCC and OPC. Results: A total of 190,585 individuals were diagnosed with OCCs and OPCs in Russia between 2007-2018. Non-uniform geographic distribution of cancer cases was noted where the Far Eastern Federal District had the highest rate of OCC and the Central Federal District of OPCs. Districts with high weekly alcohol consumption had significantly higher incidence and mortality rates in both sexes. Districts with high rates of daily smoking had higher incidence of OCC among females, and those with low smoking trends had lower mortality rates for OCCs and OPCs. Conclusion: We detail the burden of OCCs and OPCs across Russia, with the aim of elucidating modifiable risk factors and proposing evidence-based prevention strategies. Tobacco/alcohol sales control measures and smoking/drinking cessation programs should continue to be prioritized as public health measures, especially for females.

National trends in incidence and geographic distribution of melanoma and keratinocyte carcinoma in the Russian Federation.

Keratinocyte Carcinomas (KC), including basal cell and cutaneous squamous cell carcinomas, are the most common skin cancers in Fitzpatrick phototype I-III individuals, while melanoma is one of the deadliest skin cancer types. The incidence of both melanoma and KC is increasing in Russia. KCs' incidence increases from north-to-south across the Russian Federation. In contrast, while melanoma's incidence increases from north-to-south in the eastern part of the country, in the west of Russia a reverse latitude gradient trend is noted, where northern more affluent regions of Russia display higher rates of melanoma than the southern jurisdictions. Furthermore, our detailed analysis of incidence by jurisdiction highlights that affluent northern capital cities have higher rates of melanoma than the surrounding regions. The observed melanoma incidence trends in the western portion of Russia are similar to the findings in the western Europe and opposite of the findings in Canada.

Gene-Environment Analyses in a UK Biobank Skin Cancer Cohort Identifies Important SNPs in DNA Repair Genes That May Help Prognosticate Disease Risk.

BACKGROUND: Despite well-established relationships between sun exposure and skin cancer pathogenesis/progression, specific gene-environment interactions in at-risk individuals remain poorly-understood. METHODS: We leveraged a UK Biobank cohort of basal cell carcinoma (BCC, n = 17,221), cutaneous squamous cell carcinoma (cSCC, n = 2,331), melanoma in situ (M-is, n = 1,158), invasive melanoma (M-inv, n = 3,798), and healthy controls (n = 448,164) to quantify the synergistic involvement of genetic and environmental factors influencing disease risk. We surveyed 8,798 SNPs from 190 DNA repair genes, and 11 demographic/behavioral risk factors. RESULTS: Clinical analysis identified darker skin (RR = 0.01-0.65) and hair (RR = 0.27-0.63) colors as protective factors. Eleven SNPs were significantly associated with BCC, three of which were also associated with M-inv. Gene-environment analysis yielded 201 SNP-environment interactions across 90 genes (FDR-adjusted q < 0.05). SNPs from the FANCA gene showed interactions with at least one clinical factor in all cancer groups, of which three (rs9926296, rs3743860, rs2376883) showed interaction with nearly every factor in BCC and M-inv. CONCLUSIONS: We identified novel risk factors for keratinocyte carcinomas and melanoma, highlighted the prognostic value of several FANCA alleles among individuals with a history of sunlamp use and childhood sunburns, and demonstrated the importance of combining genetic and clinical data in disease risk stratification. IMPACT: This study revealed genome-wide associations with important implications for understanding skin cancer risk in the context of the rapidly-evolving field of precision medicine. Major individual factors (including sex, hair and skin color, and sun protection use) were significant mediators for all skin cancers, interacting with >200 SNPs across four skin cancer types.

Assessing Skin Cancer Risk Factors, Sun Safety Behaviors and Melanoma Concern in Atlantic Canada: A Comprehensive Survey Study.

BACKGROUND: The incidence of cutaneous melanoma (CM) is increasing at an alarming rate in Canada and elsewhere around the world. Significant regional differences in CM incidence have been identified in Atlantic provinces. The goal of this study is to compare ultraviolet exposure, sun protective behaviours, level of worry and baseline CM knowledge in provinces with a high versus low incidence of CM as well, as between various demographic groups. METHODS: A cross-sectional survey study was conducted in Atlantic provinces between July 2020 and August 2022. All participants aged ≥ 16 years with a completed survey were eligible. Survey responses were summarized using frequency counts, percentages, and means. Two-sided Z-tests for equality of proportions and logistic regression models were used to compare the survey results between geographic and demographic groups. RESULTS: In total, 7861 participants were included (28.0% men; mean age 61.3 years; response rate 28%). Our results (gender- and age-adjusted odds ratio, 95% confidence interval) show that high-incidence provinces for CM (Prince Edward Island and Nova Scotia) had significantly more sunburns (OR 2.00, 1.72-2.31), total sun exposure (OR 2.05, 1.68-2.50), recreational sun exposure (OR 1.95, 1.61-2.35) and tans (OR 1.77, 1.53-2.05) than individuals in low-incidence provinces (Newfoundland and Labrador). However, individuals in high-incidence provinces displayed more protective behaviors: there were less tanning bed users (OR 0.82, 0.71-0.95), they checked their skin more frequently for new moles (OR 1.26, 1.06-1.51) and practiced more sun protection overall. Additional analyses are presented based on education, income, sexual orientation and gender. DISCUSSION: These findings suggest that future efforts aimed at reducing the CM burden in Atlantic Canada should be tailored for target geographic and/or demographic groups. LIMITATIONS: the study participants are not representative of the population in Atlantic Canada due to recruitment strategies.

The Role of Sex and Gender in Dermatology - From Pathogenesis to Clinical Implications.

BACKGROUND: Sex and gender have increasingly been recognized as significant risk factors for many diseases, including dermatological conditions. Historically, sex and gender have often been grouped together as a single risk factor in the scientific literature. However, both may have a distinct impact on disease incidence, prevalence, clinical presentation, severity, therapeutic response, and associated psychological distress. OBJECTIVES AND PROJECT DESCRIPTION: The mechanisms that underlie differences in skin diseases between males, females, men, and women remain largely unknown. The specific objectives of this review paper are:To highlight the biological differences between males and females (sex), as well as the sociocultural differences between men and women (gender) and how they impact the integumentary system.To perform a literature review to identify important sex- and gender-related epidemiological and clinical differences for various skin conditions belonging to a range of disease categories and to discuss possible biological and sociocultural factors that could explain the observed differences.To discuss dermatological skin conditions and gender-affirming treatments within the transgender community, a population of individuals who have a gender identity which is different than the gender identity they were assigned at birth. FUTURE IMPACT: With the rising number of individuals that identify as non-binary or transgender within our increasingly diverse communities, it is imperative to recognize gender identity, gender, and sex as distinct entities. By doing so, clinicians will be able to better risk-stratify their patients and select treatments that are most aligned with their values. To our knowledge, very few studies have separated sex and gender as two distinct risk factors within the dermatology literature. Our article also has the potential to help guide future prevention strategies that are patient-tailored rather than using a universal approach.

Skin Cancer Prevention across the G7, Australia and New Zealand: A Review of Legislation and Guidelines.

Incidence rates of melanoma and keratinocyte skin cancers have been on the rise globally in recent decades. While there has been a select focus on personal sun protection awareness, to our knowledge, there is a paucity of legislation in place to help support citizens' efforts to protect themselves from the harmful effects of ultraviolet radiation (UVR). Given this, we conducted a comprehensive review of legislation and guidelines pertaining to a variety of sun protection-related topics in countries of the Group of Seven (G7), Australia and New Zealand. Australia was the only country to have banned tanning beds for individuals of all ages, while other select countries have instituted bans for minors. In workplace policy, there is very little recognition of the danger of occupational UVR exposure in outdoor workers, and thus very few protective measures are in place. With regard to sports and recreation, certain dermatological/professional associations have put forward recommendations, but no legislation was brought forward by government bodies outside of Australia and New Zealand. With regard to youth, while there are various guidelines and frameworks in place across several countries, adherence remains difficult in the absence of concrete legislation and standardization of procedures. Finally, only Australia and a few select jurisdictions in the United States have implemented sales tax exemptions for sunscreen products. In light of our findings, we have made several recommendations, which we anticipate will help reduce the rates of melanoma and keratinocyte cancers in years to come. However, minimizing UVR exposure is not without risk, and we, therefore, suggest the promotion of vitamin D supplementation in conjunction with sun protective practices to limit potential harm.

Investigation of incidence and geographic distribution of gliomas in Canada from 1992 to 2010: a national population-based study highlighting the importance of exposure to airport operations.

Background: Gliomas account for over two-thirds of all malignant brain tumors and have few established risk factors beyond family history and exposure to ionizing radiation. Importantly, recent studies highlighted the exposure to ultrafine particles (UFP) as a putative risk factor for malignant brain tumors. Methods: Clinical and geographic data encompassing all provinces and territories from 1992 to 2010 was obtained from the Canadian Cancer Registry and Le Registre Québécois du Cancer. Linear regression and joinpoint analyses were performed to assess incidence trends. Significantly higher and lower incidence postal codes were then interrogated using Standard Industrial Classification codes to detect significant industrial activity. Results: In Canada, between 1992 and 2010, there were ~32,360 cases of glioma. Of these, 17,115 (52.9%) were glioblastoma. The overall crude incidence rates of 5.45 and 2.87 cases per 100,000 individuals per year for gliomas and glioblastomas, respectively, were identified. Our findings further revealed increasing crude incidence of gliomas/glioblastomas over time. A male predominance was observed. Provinces leading in glioma incidence included Quebec, Nova Scotia, and New Brunswick. Significantly lower crude incidence of glioma was found in Nunavut, Northwest Territories, Ontario, and Alberta. A putative regional clustering of gliomas was observed, with higher incidence rates in postal code areas correlating with industrial activity related to airport operations. Conclusion: This study describes the geographic distribution of the glioma disease burden and, potentially, identifies industrial activity related to airport operations as potentially being associated with higher incidence of this cancer.

Ectopically Expressed Meiosis-Specific Cancer Testis Antigen HORMAD1 Promotes Genomic Instability in Squamous Cell Carcinomas.

Genomic instability is a prominent hallmark of cancer, however the mechanisms that drive and sustain this process remain elusive. Research demonstrates that numerous cancers with increased levels of genomic instability ectopically express meiosis-specific genes and undergo meiomitosis, the clash of mitotic and meiotic processes. These meiotic genes may represent novel therapeutic targets for the treatment of cancer. We studied the relationship between the expression of the meiosis protein HORMAD1 and genomic instability in squamous cell carcinomas (SCCs). First, we assessed markers of DNA damage and genomic instability following knockdown and overexpression of HORMAD1 in different cell lines representing SCCs and epithelial cancers. shRNA-mediated depletion of HORMAD1 expression resulted in increased genomic instability, DNA damage, increased sensitivity to etoposide, and decreased expression of DNA damage response/repair genes. Conversely, overexpression of HORMAD1 exhibited protective effects leading to decreased DNA damage, enhanced survival and decreased sensitivity to etoposide. Furthermore, we identified a meiotic molecular pathway that regulates HORMAD1 expression by targeting the upstream meiosis transcription factor STRA8. Our results highlight a specific relationship between HORMAD1 and genomic instability in SCCs, suggesting that selectively inhibiting HORMAD1, possibly, through STRA8 signaling, may provide a new paradigm of treatment options for HORMAD1-expressing SCCs.

Investigation of the Incidence and Geographic Distribution of Bone and Soft Tissue Sarcomas in Canada: A National Population-Based Study.

Sarcomas are a heterogeneous group of mesenchymal malignancies with various genetic and environmental risk factors. This study analyzed the epidemiology of sarcomas to gain insight into the incidence and mortality rates of these cancers in Canada, as well as to elucidate their potential environmental risk factors. Data for this study were obtained from le Registre Québécois du Cancer (LRQC) and from the Canadian Cancer Registry (CCR) for the period from 1992 to 2010. Mortality data were obtained from the Canadian Vital Statistics (CVS) database for the period from 1992 to 2010 using the International Classification of Diseases for Oncology, ICD-O-3, ICD-9, or ICD-10 codes, for all subtypes of sarcomas. We found that the overall sarcoma incidence in Canada decreased during the study period. However, there were select subtypes with increasing incidence. Peripherally located sarcomas were found to have lower mortality rates compared to axially located sarcomas, as expected. Clustering of Kaposi sarcoma cases in self-identified LGBTQ+ communities and in postal codes with a higher proportion of African-Canadian and Hispanic populations was observed. Forward Sortation Area (FSA) postal codes with a lower socioeconomic status also had higher Kaposi sarcoma incidence rates.