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. 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.[120,121,122,123,124]
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.
Table 3. Genes Associated with Fanconi Anemia (FA)
AR = autosomal recessive; FA = Fanconi anemia; XLR = X-linked recessive.
|Gene||Locus||Approximate Incidence Among FA Patients (%)||Pattern of Disease Transmission|
|FANCA (OMIM)||16q24.3 ||~70||AR|
|FANCB (OMIM) ||Xp22.31 ||Rare|| XLR|
|FANCC (OMIM) ||9q22.3||~10||AR|
|FANCD1 (BRCA2) (OMIM) ||13q12.3||Rare|| AR|
|FANCD2 (OMIM) ||3p25.3||Rare||AR|
|FANCE (OMIM) ||6p21.3||~10||AR|
|FANCF (OMIM) ||11p15||Rare||AR|
|FANCG (XRCC9) (OMIM) ||9p13||~10||AR|
|FANCI (KIAA1794) (OMIM) ||15q25-26||Rare||AR|
|FANCJ (BACH1/BRIP1) (OMIM) ||17q22.3||Rare||AR|
|FANCL (PHF9/POG) (OMIM)||2p16.1||Rare||AR|
|FANCM (Hef) (OMIM) ||14q21.3||Rare||AR|
|FANCN (PALB2) (OMIM) ||16p12.1||Rare||AR|
The proteins involved with DNA crosslink repairs have been termed the FANC pathway due to their involvement with Fanconi anemia. They interact with several other proteins associated with hereditary cancer risk, including those for Bloom syndrome and ataxia-telangiectasia. Further investigation has revealed that FANCD1 is the same gene as BRCA2, a gene that causes predisposition to breast and ovarian cancer. Other Fanconi anemia genes, FANCJ (BRIP1) and FANCN (PALB2), have also been identified as rare breast cancer susceptibility genes. (Refer to the PDQ summary on Genetics of Breast and Ovarian Cancer for more information on BRCA2, BRIP1, and PALB2.) Individuals who are heterozygous carriers of other Fanconi anemia-associated mutations do not appear to have an increased risk of cancer, with the possible exception of a twofold increase in breast cancer incidence in FANCC mutation carriers.