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Squamous Cell Carcinoma

Table 3. Genes Associated with Fanconi Anemia (FA) continued...

Mutations in the WRN gene on chromosome 8p12-p11.2 have been identified in approximately 90% of individuals with this syndrome; no other genes are known to be associated with Werner syndrome.[174,178,179,180,181] Inheritance of this gene is believed to be autosomal recessive. The product of the WRN gene is a multifunctional protein including a DNA exonuclease and an ATP-dependent DNA helicase belonging to the RecQ subfamily. This protein may play a role in processes such as DNA repair, recombination, replication, transcription, and combined DNA functions.[182,183,184,185,186,187,188,189,190] Telomere dysfunction has been associated with premature aging and cancer susceptibility.[191] Other helicases with similar function are altered in other chromosomal instability syndromes, such as BLM in Bloom syndrome and RecQL4 in Rothmund-Thomson syndrome.

Deleterious mutations described in the WRN gene include all types of mutations; however, the 1136C→T mutation is the most common and is found in 20% to 25% of the Japanese and white populations.[192,193] In the Japanese population, a founder mutation (IVS 25-1G→C) is present in 60% of affected individuals.[194]

Mutation in the WRN gene causes loss of nuclear localization of the gene product. Intracellular levels of the mRNA and protein associated with the mutated gene are also markedly decreased, compared with those of the wild-type. Half-lives of the mRNA and protein associated with the mutated gene are also shorter than those associated with the wild-type mRNA and protein.[193,195]

Characteristics of the major hereditary syndromes associated with a predisposition to SCC are described in Table 4 below.

Table 4. Hereditary Syndromes Associated with Squamous Cell Carcinoma of the Skin

ConditionGene(s)Clinical Testing AvailabilityaPathway
a For more information on genetic testing laboratories, seeGeneTests: Laboratory Directory.
Xeroderma pigmentosum (complementationgroup A,group B,group C,group D,group E,group F, andgroup G)XPA,XPB/ERCC3,XPC,XPD/ERCC2,XPE/DDB2 ,XPF/ERCC4,XPG/ERCC5XPA, XPCNucleotide excision repair
Xeroderma pigmentosum variantPOLH (XP-V)NoError-prone polymerase
Multiple self-healing squamous epithelioma (Ferguson-Smith syndrome)TGFBR1NoGrowth factor signalling
Oculocutaneous albinism (type IA,type IB,type II,type III, andtype IV)TYR,OCA2,MATP/OCA4,TYRP1TYR, OCA2, TYRP1Melanin synthesis
Hermansky-Pudlak syndromeHPS1,HPS3,HPS4,HPS5,HPS6,HPS7/DTNBP1,HPS8/BLOC1S3HPS1, HPS3, HPS4, HPS7Melanosomal and lysosomal storage
Hermansky-Pudlak syndrome, Type 2AP3B1NoMelanosomal and lysosomal storage
Chediak-Higashi syndromeLYSTLYSTLysosomal transport regulation
Griscelli syndrome (type 1,type 2, andtype 3)MYO5A,RAB27A,MLPHRAB27APigment granule transport
Elejalde DiseaseMYO5ANoPigment granule transport
Dystrophic epidermolysis bullosa (dominantandautosomal recessivesubtypes)COL7A1COL7A1Collagen anchor of basement membrane to dermis
Junctional epidermolysis bullosaLAMA3,LAMB3,LAMC2 ,COL17A1LAMA3, LAMB3, LAMC2, COL17A1Connective tissue
Epidermodysplasia verruciformisEVER1,EVER2NoSignal transduction in endoplasmic reticulum
Dyskeratosis congenitaDKC1,TERC,TINF2,NHP2/NOLA2,NOP10/NOLA3,TERT,WRAP53,C16orf57DKC1, TERC, TINF2, NHP2, NOP10, TERTTelomere maintenance and trafficking
Rothmund-Thomson syndromeRECQL4,C16orf57RECQL4Chromosomal stability
Bloom syndromeBLM/RECQL3Sister chromatid exchange,BLMChromosomal stability
Werner syndromeWRN/RECQL2NoChromosomal stability

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