Cutaneous Malignant Melanoma

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CMM is the most serious cutaneous malignancy and is increasing in frequency among most Caucasian populations, where the most important risk factor is exposure to ultraviolet light.97 Relatively little is known of the genetic factors that mediate susceptibility to and prognosis in sporadic CMM, although polymorphisms associated with the melanocortin-1 receptor (MCR1),98," CDKN2A,100 XRCC3 DNA repair gene101 and glutathione S-transferase Mu phenotype (GSTM1)102 may be associated with susceptibility to CMM. Polymorphisms associated with the Vitamin D receptor and the cytochrome P450 CYP2D6 genes have been implicated in modulating prognosis in this tumor.103,104 In addition, several lines of evidence suggest that CMM patients develop an immune response to their tumors105 (supported by variable HLA-DQB1 allellic associations with CMM susceptibility and prognosis106,107), although in individuals with CMM, this anti-tumor immune response is insufficient to abrogate tumor development.

Based on the above, and to distinguish whether high constitutive levels of IL-10 have a tumor-promoting or anti-tumor influence in CMM, we have shown that the IL-10 -1082 AA genotype, associated with low IL-10 expression in vitro is associated with both susceptibility to CMM (OR = 1.78) and is a risk factor for more advanced (OR = 2.24) , and poorer prognosis disease, as evidenced by tumor Breslow thickness (OR = 3.67)74 IL-10 -1082, -819, -592 haplotypes associated with low IL-10 expression (ACC/ACC, ACC/ATA and ATA/ATA) were also associated with greater tumor Breslow thickness (OR = 3.63), which is the single most important prognostic indicator in CMM.108 In addition, the IL-10 -1082 GG genotype and IL-10 -1082, -819, -592 GCC/GCC 'high expression' haplotype were associated with noninvasive tumor growth (ORs = 2.42 and 2.31 for noninvasive growth respectively). This study was performed in British Caucasian CMM cases and controls. Some support for these findings is provided by the small, independent study of Martinez-Escribano et al, 5 who showed

Table 2. IL-10 polymorphisms and cancer

Disease

IL-10

Polymorphism Cases Controls

Association

Genotype, Allele or Haplotype

Refs.

Cutaneous -1082, -819, 153 malignant -592

melonoma

Cutaneous malignant melonoma

Prostate cancer

Breast cancer

Breast cancer

Cervical cancer

Cervical cancer

Gastric carcinoma

Gastric carcinoma

Gastric carcinoma

-1082

Myelodysplasia Acute myeloid leukemia

247 144 125 77 144

Squamous -1082, -819, cell carcinoma -592 of skin (post renal transplant) Multiple IL-10G, myeloma IL-10R

microsatellites

NonHodgkins -1082, -819, 126 lymphoma -592

Acute -1082 135

lymphoblastic leukemia

158 Susceptibility, advanced stage of disease, greater tumor thickness Greater tumor thickness Noninvasive growth phase Noninvasive growth phase

48 Survival (shorter)

263 Susceptibility 263 No

100 Susceptibility

69 Susceptibility

179 No

230 Susceptibility, advanced stage

220 Association with EBV—negative gastric carcinoma

212 Susceptibility (non cardia gastric cancer)

70 Susceptibility

Protection

109 Susceptiblity

Protection No up to 1000

1082 AA

ACC/ACC, ACC/ ATA, ATA/ATA 1082 GG

GCC/GCC ACC/ATA

Howell et al74

-1082 AA

-1082 AA -1082 AG

Martinez-Escribano et al75

McCarron et al76 Howell et al77

Giordani et al78

Stanczuk et al79 Roh et al80

GCC (1 or 2 Wu et al81 copies)

-1082 G allele Wu et al82

ATA haplotype El-Omar et al83

GCC haplotype Alamartine ATA haplotype et al84

Zheng et al85

Gowans et al86

Susceptibility to -1082 AA, ATA,Cunningham aggressive disease ACC haplotypes et al87

Protection from -1082 GG Lauten poor response to et al88

Prednisone that in Italian CMM patients, the IL-10 -1082, -819, -592 ACC/ATA 'low expression' haplo-type was also associated with greater tumor Breslow thickness and was a risk factor for poorer survival. Finally, it should be noted that results from these genetic studies are in accordance with the effects of IL-10 gene transfection in animal models of malignant melanoma, which suggests that intratumor expression of IL-10 abrogates tumor development.36

Although the influence of IL-10 on CMM development is likely to be complex, these results support recent findings that IL-10 has an anti-tumor effect in CMM, possibly via inhibition of VEGF expression and angiogenesis.17 In agreement with this, we have also obtained evidence that gene polymorphisms associated with differential expression of other angiogenic cytokines (in particular, VEGF) may also play a role in predisposition to and tumor growth in CMM.109

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