Cutaneous squamous cell carcinoma andp53 codon 72 polymorphism: A need for screening?

Increased noise as an effect of haploinsufficiency of the tumor-suppressor gene neurofibromatosis type 1 in vitro

“…They may be caused in a similar way as the café-au-lait macules in NF1 by the reduced activity of another gene relevant for melanocytes and, hence, by increased noise in a signal transduction chain. Variants of the melanocortin-1-receptor gene with a reduced gene activity were found in persons with this skin type (51). Increased noise may also explain the highly variable cell size of NF1 keratinocytes in vitro (33).…”

Human melanocortin 1 receptor (MC1R) gene variants alter melanoma cell growth and adhesion to extracellular matrix

“…In addition, subjects who are homozygous or heterozygous for MC1R variants are at increased risk of melanoma as well as nonmelanoma skin cancer, with homozygotes at greater risk than heterozygotes (Valverde et al, 1996;Palmer et al, 2000;Bastiaens et al, 2001;Kennedy et al, 2001;van der Velden et al, 2001;Box et al, 2001a,b). The higher risk of melanoma in these subjects may be due to alterations in the melanin content in human skin (or in the precursor melanocyte), for example eumelanin is thought to protect against ultraviolet radiation, and less eumelanin may permit more sun-induced DNA damage in the melanocyte, leading to neoplasia (Kaidbey et al, 1979;Crombie, 1979).…”

“…In humans, MC1R variants (in particular the Arg151Cys, Arg160Trp, and Asp294His alterations) are a frequent cause of red hair and fair skin, with recent evidence from transgenic mouse studies that these variants result in the preferential synthesis of red/ yellow phaeomelanin rather than brown/black eumelanin in vivo (Valverde et al, 1995;Box et al, 1997;Smith et al, 1998;Healy et al, 2000Healy et al, , 2001Harding et al, 2000). Not surprisingly, considering the widespread recognition of skin type and red hair as a risk factor for skin cancer, associations between MC1R variants and melanoma (as well as non-melanoma skin cancer) have been reported (Valverde et al, 1996;Palmer et al, 2000;Bastiaens et al, 2001;Kennedy et al, 2001;van der Velden et al, 2001;Box et al, 2001a,b). In addition, MC1R variants have been documented as a modifier of risk for melanoma development in individuals from kindreds with p16INK4/CDKN2 alterations, who are prone to familial melanoma (van der Velden et al, 2001;Box et al, 2001b).…”

“…Despite the causal nature of MC1R variants in red hair and fair skin, the studies reporting an association between MC1R variants and skin cancer have documented that the elevated risk ratio attributable to MC1R variants remains after controlling for skin type and hair colour in the analysis (Valverde et al, 1996;Palmer et al, 2000;Bastiaens et al, 2001;Kennedy et al, 2001;van der Velden et al, 2001;Box et al, 2001a). This finding could result from inherent difficulties in pigmentation phenotyping, for example skin typing based on historical data, provided by the study subject, is prone to error (Rampen et al, 1988;Weinstock et al, 1991).…”

Polymorphisms in the p53 pathway

“…Several groups have reported an association between the R72 p53 variant (binds and inactivates p73 better) and increased risk for epithelial cancer, including gastric cancer and cancer of the breast (Langerod et al, 2002;Bonafe et al, 2003;Buyru et al, 2003;Ohayon et al, 2005), ovary (Pegoraro et al, 2002), esophagus (Kawaguchi et al, 2000), skin (Dokianakis et al, 2000;Bastiaens et al, 2001;Shen et al, 2003;De Oliveira et al, 2004), lung , bladder (Soulitzis et al, 2002), prostate (Henner et al, 2001), and larynx (Sourvinos et al, 2001). In other studies, however, authors have found the opposite correlation, instead demonstrating an association between the P72 (lesser apoptotic) variant and increased risk for other cancer types, including cancer of the thyroid (Granja et al, 2004), nasopharynx (Tsai et al, 2002a, b;Tiwawech et al, 2003), prostate (Suzuki et al, 2003), skin (Chen et al, 2003), urogenital region (Kuroda et al, 2003), and lung Fan et al, 2000;Zhang et al, 2003).…”