Further Evidence for an Association of HLA-DR7 With Basal Cell Carcinoma on the Tropical Island of Saba

Bavinck, Jan Nico Bouwes; Bastiaens, Maarten T.; Marugg, M.E.; Beckers, R.; Westendorp, Rudi G.J.; Vermeer, B.J.; Claas, Frans H.J.

doi:10.1001/archderm.136.8.1019

Cited by 13 publications

(6 citation statements)

References 24 publications

(16 reference statements)

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“…Low levels or absence of expression of class I antigens may result in escape from regulation by cytotoxic T cells, which then facilitates tumor growth (73). Evidence for the involvement of HLA genes in the development of skin cancers was provided by Bouwes Bavinck et al These authors showed that the presence of HLA-DR7 and a decrease of HLA-DR4 are significantly associated with BCC (74). This corroborates the previous finding of Rompel et al that HLA-DR4 is decreased in BCC, especially in patients with multiple BCCs located on the trunk.…”

Section: Human Leukocyte Antigen (Hla)supporting

confidence: 75%

Etiology and pathogenesis of basal cell carcinoma

Mijušković¹

2013

Serbian Journal of Dermatology and Venerology

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Basal cell carcinoma (BCC) is the most common cancer among Caucasians. It generally occurs on sun-exposed areas of the body, mostly on the head and neck (80%), trunk (15%), rarely on arms and legs. Basal cell carcinoma is a good example of a disease caused by a combination of genetic and environmental factors. Ultraviolet (UV) radiation plays a dual role in the development of BCC: it causes DNA damage and immunosuppression. UVA and UVB rays damage the DNA via various mechanisms. UVB radiation directly damages DNA within skin cells, causing cytosine → thymine mutations at dipyrimidine sites, whereas UVA radiation is 10.000 times less mutagenic, but it is significantly more present in the natural UV radiation. Also, UVA photons have lower energy than UVB photons and do not induce mutations. UV radiation exerts immune suppression by decreasing the antigen presenting cells ability and by producing immunosuppressive cytokines, such as interleukin-10 (IL-10) and tumor necrosis factor alpha (TNF-α). Mediators of UV-induced immunosuppression are DNA and cis-urocanic acid. Several studies showed a significant association between the development of BCC and sun-exposure during childhood and adolescence, and a strong relation with family history of skin cancer. Exposure to ionizing radiation increases the risk of nonmelanoma skin cancers by three times, while the risk is proportional to the radiation dose. Chemical carcinogens, such as arsenic, tar, psoralen, and pesticides, increase risks for nonmelanoma skin cancers, predominantly for squamous cell carcinoma (SCC). Regarding genetic predisposition, there is glutathione S-transferase (GST) as an important part of cellular defense against endogenous and exogenous chemicals. Several polymorphisms in GST family members have been associated with impaired detoxification, thus influencing the risk for some cancers, including nonmelanoma skin cancers. Cytochrome P450 enzymes are involved in detoxification of photosensitizing agents, and thus involved in BCC carcinogenesis. PTCH is a tumor suppressor gene first identified in patients with Gorlin syndrome. Abnormal activation of this gene and its pathways result in various types of tumorigenesis. BCC is associated with homozygous PTCH gene deletion. With regard to acquired genetic mutations, it was found that aggressive BCCs are significantly associated with increased p53 protein expression, probably representing the mutated form, although that assertion could not be established with certainty. Considering the apparently limited contribution of DNA damage and chromosome instability to the expression of BCC phenotype, the relevance of p53 mutations for BCC growth remains to be demonstrated. Data on the role of Bcl-2 gene family in the development of BCC are scarce. It is unclear whether Bcl-2 has a functional role in the development of BCC, or it only indicates the level of gene expression in tumor stem cells. Activation of Ras gene may play an important role during early stages in the development of nonmelanoma skin cancers, and it is often found on UV-exposed skin in BCC, actinic keratosis and SCC. Concerning immunologic factors, studies have shown that tumor necrosis factor-α (TNF-α) is the critical mast cell product involved in ultraviolet-induced immunosuppression: mast cells contain high quantities of TNF-α which is released after activation; the level of TNF-α is increased in the skin exposed to UV radiation disrupting the morphology and function of Langerhans cells, the principal antigen-presenting cells of the skin. An animal study suggests that the degree of susceptibility to ultraviolet-B-induced local immunosuppression depends on TNF-α level within the epidermis after UVB. It has been established that mast cell-derived histamine stimulates prostaglandin E2 (PGE2) production from keratinocytes. PGE2 alters the cytokine balance in favor of the immunosuppressive interleukin-10 (IL-10) against the immunostimulatory IL-12; histamine also increases suppressor T-cell function by binding to the H2 receptors, which in turn release higher levels of immune suppressive cytokines including IL-10 and induce apoptosis of antigen-presenting cells. All this results in a shift of the immune response from T helper 1 (Th1) cytokine profile to T helper 2 (Th2) cytokine profile, inhibiting antigen-presenting cells to induce antitumor activity.

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Section: Human Leukocyte Antigen (Hla)supporting

confidence: 75%

Etiology and pathogenesis of basal cell carcinoma

Mijušković¹

2013

Serbian Journal of Dermatology and Venerology

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“…The association between various HLA antigens and BCC risk has been reported by a number of publications (Bavinck et al 2000; Bouwes Bavinck et al 1997; Bouwes Bavinck et al 1991; Cerimele et al 1988; Czarnecki et al 1991; Myskowski et al 1985). However, the association of this pathway was not validated using the skin eQTLs and is upon further replication.…”

Section: Discussionmentioning

confidence: 87%

Integrating pathway analysis and genetics of gene expression for genome-wide association study of basal cell carcinoma

et al. 2011

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Genome-wide association studies (GWASs) have primarily focused on marginal effects for individual markers and have incorporated external functional information only after identifying robust statistical associations. We applied a new approach combining the genetics of gene expression and functional classification of genes to the GWAS of basal cell carcinoma (BCC) to identify potential biological pathways associated with BCC. We first identified 322,324 expression-associated single-nucleotide polymorphisms (eSNPs) from two existing GWASs of global gene expression in lymphoblastoid cell lines (n=995), and evaluated the association of these functionally annotated SNPs with BCC among 2,045 BCC cases and 6,013 controls in Caucasians. We then grouped them into 99 KEGG pathways for pathway analysis and identified two pathways associated with BCC with p-value < 0.05 and false discovery rate (FDR) < 0.5: the autoimmune thyroid disease pathway (mainly HLA class I and II antigens, p < 0.001, FDR = 0.24) and JAK-STAT signaling pathway (p = 0.02, FDR = 0.49). Seventy nine (25.7%) out of 307 eSNPs in the JAK-STAT pathway were associated with BCC risk (p < 0.05) in an independent replication set of 278 BCC cases and 1,262 controls. In addition, the association of JAK-STAT signaling pathway was marginally validated by using 16,691 eSNPs identified from 110 normal skin samples (p = 0.08). Based on the evidence of biological functions of the JAK-STAT pathway on oncogenesis, it is plausible that this pathway is involved in BCC pathogenesis.

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“…The low levels or absence of expression of class I antigens may result in escape from recognition by cytotoxic T cells, which then facilitates tumour growth. 159 Evidence for the involvement of HLA genes in the development of skin cancer was provided by Bouwes Bavinck et al 160 These authors showed that the presence of HLA-DR7 and a decrease of HLA-DR4 are significantly associated with BCC. This corroborates the previous finding of Rompel et al 161 that HLA-DR4 is decreased in BCC, especially in patients with multiple BCCs located on the trunk.…”

Section: Human Leucocyte Antigen (Hla) Haplotypesmentioning

confidence: 99%

Molecular aetiology and pathogenesis of basal cell carcinoma

et al. 2005

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Summary Recent insights into the cell biology of the epidermis and its appendages are transforming our understanding of the pathogenesis of basal cell carcinoma (BCC). The significant progress that has been made warrants a comprehensive review of the molecular and cellular pathology of BCC. The items addressed include environmental and genetic risk factors, the biology of the putative precursor cell(s), and the contribution of aberrations in processes such as apoptosis, cell proliferation, differentiation and signalling to carcinogenesis. Furthermore, established and novel treatment modalities are discussed with particular attention to future biological approaches.

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Further Evidence for an Association of HLA-DR7 With Basal Cell Carcinoma on the Tropical Island of Saba

Cited by 13 publications

References 24 publications

Etiology and pathogenesis of basal cell carcinoma

Etiology and pathogenesis of basal cell carcinoma

Integrating pathway analysis and genetics of gene expression for genome-wide association study of basal cell carcinoma

Molecular aetiology and pathogenesis of basal cell carcinoma

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