Genetic ancestry, skin pigmentation, and the risk of cutaneous squamous cell carcinoma in Hispanic/Latino and non-Hispanic white populations

Jorgenson, Eric; Choquet, Hélène; Yin, Jie; Hoffmann, Thomas J.; Banda, Yambazi; Kvale, Mark N.; Risch, Neil; Schaefer, Catherine; Asgari, Maryam M.

doi:10.1038/s42003-020-01461-8

Cited by 7 publications

(5 citation statements)

References 52 publications

(74 reference statements)

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“…Genetic studies to date have identified few syndromes associated with increased risk of SCC (including xeroderma pigmentosa, epidermolysis bullosa, Fanconi anaemia, oculocutaneous albinism and aging syndromes such as Werner syndrome), and BCC (Basal cell nevus syndrome), some higher risk genes which are primarily pigment related (MC1R, OCA2, HER2, TYR, ASIP, SCL45A2, IRF4) and HLA ( HLADQA1 ) 21,22 . More recently an ancestry gene effect in Hispanic and non‐Hispanic whites 23 was demonstrated. Like CLCN6, most of these variants show small effect sizes with typical odds ratios ranging from 1.15 to 1.5.…”

Section: Discussionmentioning

confidence: 99%

Genetic polymorphism in Methylenetetrahydrofolate Reductase chloride transport protein 6 (MTHFR CLCN6) gene is associated with keratinocyte skin cancer in a cohort of renal transplant recipients

Griffin

Akhurst

et al. 2022

Skin Health and Disease

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Background Renal transplant recipients (RTRs) are at increased risk of keratinocyte cancer (KC), especially cutaneous squamous cell carcinoma (cSCC). Previous studies identified a genetic variant of the Methylenetetrahydrofolate Reductase ( MTHFR ) gene, C677T, which conferred a risk for diagnosis of cSCC in Irish RTRs. Objective We sought to find further genetic variation in MTHFR and overlap genes that may be associated with a diagnosis of KC in RTRs. Methods Genotyping of a combined RTR population ( n = 821) from two centres, Ireland ( n = 546) and the USA ( n = 275), was performed. This included 290 RTRs with KC and 444 without. Eleven single nucleotide polymorphisms (SNPs) in the MTHFR gene and seven in the overlap gene MTHFR Chloride transport protein 6 ( CLCN6) were evaluated and association explored by time to event analysis (from transplant to first KC) using Cox proportional hazards model. Results Polymorphism at MTHFR CLCN6 (rs9651118) was significantly associated with KC in RTRs (HR 1.50, 95% CI 1.17–1.91, p < 0.00061) and cSCC (HR 1.63, 95% CI 1.14–2.34, p = 0.007). A separate SNP, MTHFR C677T, was also significantly associated with KC in the Irish population (HR 1.31, 95% CI 1.05–1.63, p = 0.016), but not American RTRs. Conclusions We report the association of a SNP in the MTHFR overlap gene, CLCN6 and KC in a combined RTR population. While the exact function of CLCN6 is not known, it is proposed to be involved in folate availability. Future applications could include incorporation in a polygenic risk score for KC in RTRs to help identify those at increased risk beyond traditional risk factor assessment.

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Section: Discussionmentioning

confidence: 99%

Genetic polymorphism in Methylenetetrahydrofolate Reductase chloride transport protein 6 (MTHFR CLCN6) gene is associated with keratinocyte skin cancer in a cohort of renal transplant recipients

Griffin

Akhurst

et al. 2022

Skin Health and Disease

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“…Even though phenotypic characteristics have been broadly described, the genetic structure of the population has rarely been highlighted, particularly in the quest to establish correlations between prevalence and geographic distribution [ 53 ]. Analyses of the rs357564 variant have been performed in several types of cancer and clinical conditions [ 54 , 55 , 56 , 57 ].…”

Section: Discussionmentioning

confidence: 99%

PTCH1 Gene Variants, mRNA Expression, and Bioinformatics Insights in Mexican Cutaneous Squamous Cell Carcinoma Patients

Zambrano-Román,

Padilla-Gutiérrez,

Valle

et al. 2024

Biology

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Background: Skin cancer is one of the most frequent types of cancer, and cutaneous squamous cell carcinoma (cSCC) constitutes 20% of non-melanoma skin cancer (NMSC) cases. PTCH1, a tumor suppressor gene involved in the Sonic hedgehog signaling pathway, plays a crucial role in neoplastic processes. Methods: An analytical cross-sectional study, encompassing 211 cSCC patients and 290 individuals in a control group (CG), was performed. A subgroup of samples was considered for the relative expression analysis, and the results were obtained using quantitative real-time PCR (qPCR) with TaqMan® probes. The functional, splicing, and disease-causing effects of the proposed variants were explored via bioinformatics. Results: cSCC was predominant in men, especially in sun-exposed areas such as the head and neck. No statistically significant differences were found regarding the rs357564, rs2236405, rs2297086, and rs41313327 variants of PTCH1, or in the risk of cSCC, nor in the mRNA expression between the cSCC group and CG. A functional effect of rs357564 and a disease-causing relation to rs41313327 was identified. Conclusion: The proposed variants were not associated with cSCC risk in this Mexican population, but we recognize the need for analyzing larger population groups to elucidate the disease-causing role of rare variants.

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“…European alleles were selected as the prevalence of cSCC is highest in individuals of European descent. 23 Overall, 24/149 patients (16.1%) contain a shared mutation that is predicted to bind well to MHC class I (Fig. 1d).…”

Section: Majority Of Mutations In Human Cscc Are Unique To Individual...mentioning

confidence: 99%

Distinct sets of molecular characteristics define tumor-rejecting neoantigens

Adams,

Macy,

Borden

et al. 2024

Preprint

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Challenges in identifying tumor-rejecting neoantigens limit the efficacy of neoantigen vaccines to treat cancers, including cutaneous squamous cell carcinoma (cSCC). A minority of human cSCC tumors shared neoantigens, supporting the need for personalized vaccines. Using a UV-induced mouse cSCC model which recapitulated the mutational signature and driver mutations found in human disease, we found that CD8 T cells constrain cSCC. Two MHC class I neoantigens were identified that constrained cSCC growth. Compared to the wild-type peptides, one tumor-rejecting neoantigen exhibited improved MHC binding and the other had increased solvent accessibility of the mutated residue. Across known neoantigens that do not impact MHC binding, structural modeling of the peptide/MHC complexes indicated that increased solvent accessibility, which will facilitate TCR recognition of the neoantigen, distinguished tumor-rejecting from non-immunogenic neoantigens. This work reveals characteristics of tumor-rejecting neoantigens that may be of considerable importance in identifying optimal vaccine candidates in cSCC and other cancers.

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Genetic ancestry, skin pigmentation, and the risk of cutaneous squamous cell carcinoma in Hispanic/Latino and non-Hispanic white populations

Cited by 7 publications

References 52 publications

Genetic polymorphism in Methylenetetrahydrofolate Reductase chloride transport protein 6 (MTHFR CLCN6) gene is associated with keratinocyte skin cancer in a cohort of renal transplant recipients

Genetic polymorphism in Methylenetetrahydrofolate Reductase chloride transport protein 6 (MTHFR CLCN6) gene is associated with keratinocyte skin cancer in a cohort of renal transplant recipients

PTCH1 Gene Variants, mRNA Expression, and Bioinformatics Insights in Mexican Cutaneous Squamous Cell Carcinoma Patients

Distinct sets of molecular characteristics define tumor-rejecting neoantigens

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