Skin cancer type
Cutaneous basal cell carcinoma
Basal cell nevus syndrome (BCNS)
Squamous cell carcinoma
Oculocutaneous albinism type 1
Oculocutaneous albinism type 2
Dystrophic epidermolysis bullosa (DEB)
Junctional epidermolysis bullosa (JEB)
Cutaneous malignant melanoma (CMM)
XP is a rare autosomal recessive hereditary disorder affecting approximately one in one million individuals in the USA and Europe but is more common in Japan, North Africa, and the Middle East. XP is caused by dysfunction of nucleotide excision repair that results in cutaneous malignancies in the first decade of life. Affected individuals have an increased sensitivity to sunlight, resulting in a markedly increased risk of SCC, BCC, and melanoma. One report found that nonmelanoma skin cancer was increased 150-fold in individuals with XP; for those younger than 20 years, the prevalence was almost 5,000 times the general population incidence . Seven complementation groups plus one variant form of XP are based on the underlying genetic cause of the disease. Complementation group A, due to mutations in XPA, accounts for approximately 10 % of cases . Approximately 40 % of the XP cases in complementation group C are due to mutations in the XPC gene. ERCC2 (XPD) mutations are present in about 20 % of the affected individuals and constitute complementation group D. Other mutated genes in this disorder include ERCC3 (XP group B), DDB2 (XP group E), ERCC4 (XP group F), and ERCC5 (XP group G). Carriers of a mutation in one XP gene are generally asymptomatic. Founder mutations in XPA (R228A) and XPC (V548A fs X572) have been identified in North African populations, and direct screening for these mutations has been proposed for this group of patients . The variant form of XP, or type V XP, is caused by mutations in the POLH gene, which encodes a polymerase required in S-phase of the cell cycle.
Ferguson-Smith syndrome is an autosomal dominant disorder characterized by invasive skin tumors that are histologically identical to sporadic cutaneous SCC, which resolve spontaneously without intervention. Linkage analysis of affected families has shown loss of the long arm of chromosome 9, and haplotype analysis has localized this gene to 9q22.3 between D9S197 and D9S1809. PTCH (mutated in BCNS) and XPA are among the candidate genes located in this chromosomal region; however, neither one of these genes has been found to be mutated in the families affected with Ferguson-Smith syndrome. Two fructose bisphosphatase genes (FBP1 and FBP2), a possible membrane alanine aminopeptidase (C9orf3), and three other genes of unknown function (AL133071, FLJ14753, and CDC14B) are additional candidates [14, 15].
Two types of oculocutaneous albinism are associated with increased risk of SCC of the skin. Oculocutaneous albinism type 1, or tyrosinase-related albinism, is caused by mutations in the tyrosinase gene, TYR, located on the long arm of chromosome 11. The OCA2 gene, also known as the P gene, is mutated in oculocutaneous albinism type 2, or tyrosinase-positive albinism. Both disorders have an autosomal recessive inheritance pattern, with frequent compound heterozygosity . Mutations in the genes MATP (OCA4) and TYRP1 (tyrosinase-related protein) are associated with less common types of oculocutaneous albinism. Several other albinism syndromes such as Hermansky-Pudlak syndrome also are inherited in an autosomal recessive manner but may have a pseudodominant inheritance pattern in Puerto Rican families, due to its high prevalence in this population. The underlying cause is believed to be a defect in melanosome and lysosome transport in skin cells. A number of mutations at disparate loci have been associated with this syndrome, including HPS1, HPS3, HPS4, HPS5, HPS6, HPS7 (DTNBP1), and HPS8 (BLOC1S3) .
Two autosomal recessive syndromes, Chediak-Higashi syndrome and Griscelli syndrome, are caused by mutations in the LYST and MYO5A genes, respectively . Approximately 95 % of individuals with the heritable disorder dystrophic epidermolysis bullosa have a detectable germline mutation in the gene COL7A1, located at 3p21.3, which is expressed in the basal keratinocytes of the epidermis and encodes for type VII collagen .
Junctional epidermolysis bullosa (JEB) is an autosomal recessive type of epidermolysis bullosa. JEB results in considerable mortality with approximately 50 % of cases dying within the first year of life. Mutations in any of the genes encoding the three basic subunits of laminin 332, previously known as laminin 5 or COL17A1, can result in this syndrome .
Fanconi anemia is a complex disorder that is characterized by increased incidence of hematologic and solid tumors, including SCC of the skin. Thirteen complementation groups defined by the underlying causative genetic factors have been identified for Fanconi anemia, of which Fanconi anemia complementation group A (FANCA) is the most common . Individuals with dyskeratosis congenita have an incidence of SCC of approximately 1.5 %, and the median age at diagnosis is 21 years. These SCCs are generally managed as any other SCC of the skin. Several genes associated with telomere function (including DKC1, TERC, TINF2, NHP2, NOP10, and TERT) have been implicated in dyskeratosis congenita .
Rothmund-Thomson syndrome, also known as poikiloderma congenitale, is a heritable disorder characterized by chromosomal instability. The precise increased risk of skin cancer is not well characterized, but the point prevalence of nonmelanoma skin cancer, including both BCC and SCC, is 2–5 % in young individuals affected by this syndrome. A mutation in the RECQL4 gene, located at 8q24.3, is present in 66 % of clinically affected individuals and has an autosomal recessive inheritance pattern. RECQL4 encodes the ATP-dependent DNA helicase Q4, which promotes DNA unwinding to allow for cellular processes such as replication, transcription, and repair . Loss of genomic stability is also the major cause of Bloom syndrome (BLM gene) and Werner syndrome (WRN gene). Approximately 20 % of the cancers reported in these syndromes are cutaneous, with melanoma and SCC of the skin accounting for 14 % and 5 %, respectively .
Susceptibility loci for several forms of familial cutaneous malignant melanoma (CMM) have been mapped, including CMM1 on chromosome 1p36. Other familial CMM susceptibility loci include CMM2 which has been found to be affected by mutations in the CDKN2A gene on chromosome 9p21 and CMM3 by mutations in the CDK4 gene on chromosome 12q14. CMM4 has been mapped to chromosome 1p22. Susceptibility to melanoma has been associated with polymorphisms in the MC1R (CMM5) and XRCC3 (CMM6) genes. The melanocortin 1 receptor (MC1R or alpha melanocyte-stimulating hormone receptor) is a key protein regulating skin and hair pigmentation. CMM7 has been mapped to chromosome 20q11.22. The CDKN2A gene encodes proteins that regulate two critical cell cycle regulatory pathways, the TP53 pathway and the RB1 pathway. Through the use of shared coding regions and alternative reading frames, the CDKN2A gene produces two major proteins: p16 (INK4), which is a cyclin-dependent kinase inhibitor, and p14 (ARF), which binds the p53-stabilizing protein MDM2 . Sporadic somatic mutations causing malignant melanoma have also been identified in several genes, including BRAF, STK11, PTEN, TRRAP, DCC, GRIN2A, ZNF831, and BAP1. A large percentage of melanomas (40–60 %) carry an activating somatic mutation in the BRAF gene, most often the missense mutation V600E  (Table 27.2).
Skin cancer types, known genes, and common mutations
Skin cancer type
Common mutations or variants
Cutaneous basal cell carcinoma
R402Q, rs1126809[A], rs1042602[C]
1 mutation within the catalytic domain and 4 mutations within the C-terminal SH2 region
c.1291delC, c.2619C>A, c.2196_2197delCT, c.863G>A, c.3499G>A, c.3440 T>G, c.3244_3246dup, c.1347+6G>A, c.1504-1G>A, c.2251-3C>G, c.2560+1G>T
c.536C>T, c.IVS537+18C>T, c.582A>G
8818A>G, rs1015362[G], rs4911414[T]
Squamous cell carcinoma
V548A fs X572
ERCC2 (XPD), ERCC3 (XPB), DDB2 (XPE), ERCC4 (XPF), ERCC5 (XPG)
K751Q ( rs13181)
OCA2 ( P gene)
HPS1, HPS3, HPS4, HPS5, HPS6, HPS7 (DTNBP1), and HPS8 (BLOC1S3)
DKC1, TERC, TINF2, NHP2, NOP10, TERT
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