Mutations in either of two adjacent genes on chromosome 17q25 can cause epidermodysplasia verruciformis, a rare heritable disorder associated with increased susceptibility to human papillomavirus (HPV). Infection with certain HPV subtypes can lead to development of generalized nonresolving verrucous lesions, which develop into in situ and invasive SCCs in 30% to 60% of patients. Malignant transformation is thought to occur in about half of these lesions. Approximately 90% of these lesions are attributed to HPV types 5 and 8, although types 14, 17, 20, and 47 have occasionally been implicated. The association between HPV infection and increased risk of SCC has also been demonstrated in people without epidermodysplasia verruciformis; one case-control study found that HPV antibodies were found more frequently in the plasma of individuals with SCC (OR, 1.6; 95% CI, 1.2–2.3) than in plasma from cancer-free individuals.
The genes associated with this disorder, EVER1 and EVER2, were identified in 2002. The inheritance pattern of these genes appears to be autosomal recessive; however, autosomal dominant inheritance has also been reported.[119,120] Both of these gene products are transmembrane proteins localized to the endoplasmic reticulum, and they likely function in signal transduction. This effect may be through regulation of zinc balance; it has been shown that these proteins form a complex with the zinc transporter 1 (ZnT-1), which is, in turn, blocked by certain HPV proteins.
A recent case-control study examined the effect of a specific EVER2 polymorphism (rs7208422) on the risk of cutaneous SCC in 239 individuals with prior SCC and 432 controls. This polymorphism is a (A > T) coding single nucleotide polymorphism in exon 8, codon 306 of the EVER2 gene. The frequency of the T allele among controls was 0.45. Homozygosity for the polymorphism caused a modest increase in SCC risk, with an adjusted OR of 1.7 (95% CI, 1.1–2.7) relative to wild-type homozygotes. In this study, those with one or more of the T alleles were also found to have increased seropositivity for any HPV and for HPV types 5 and 8, as compared with the wild type.
Some evidence suggests nonallelic heterogeneity in epidermodysplasia verruciformis. Another susceptibility locus associated with this disorder has been identified at chromosome regions 2p21-p24 through linkage analysis of an affected consanguineous family. Unlike those with mutations in the EVER1 and EVER2 genes, affected individuals linked to this genomic region were infected with HPV 20 rather than the usual HPV subtypes associated with this disorder, and this family did not have a history of cutaneous SCC.
Fanconi anemia is a complex disorder that is characterized by increased incidence of hematologic and solid tumors, including SCC of the skin. Fanconi anemia is inherited as an autosomal recessive disease. It is a relatively rare syndrome with an estimated carrier frequency of one in 181 individuals in the United States (range: 1 in 156 to 1 in 209) and a carrier frequency of up to one in 100 individuals of Ashkenazi Jewish ancestry. Leukemia is the most commonly reported cancer in this population, but increased rates of gastrointestinal, head and neck, and gynecologic cancers have also been seen. By age 40 years, individuals affected with Fanconi anemia have an 8% risk per year of developing a solid tumor; the median age of diagnosis for solid tumors is 26 years. Multiple cases of cancers of the brain, breast, lung, and kidney (Wilms tumor) have been reported in this population. Data on the incidence of nonmelanoma skin cancers in this population are sparse; however, review of the literature suggests that the age of diagnosis is between the mid-20s and early 30s and that women seem to be affected more often than men.[126,127,128,129,130]
Individuals with this disease have increased susceptibility to DNA cross-linking agents (e.g., mitomycin-C or diepoxybutane) and ionizing and UV radiation. Cells from individuals with Fanconi anemia have shown decreased ability to excise pyrimidine dimers. The diagnosis of this disease is made by observing increased chromosomal breakage, rearrangements, or exchanges in cells after exposure to carcinogens such as diepoxybutane.
Thirteen complementation groups have been identified for Fanconi anemia; details regarding the genes associated with these groups are listed in Table 3 below.