Genetics of Skin Cancer (PDQ®): Genetics - Health Professional Information [NCI] - Squamous Cell Carcinoma
Table 3. Hereditary Syndromes Associated with Squamous Cell Carcinoma of the Skin continued...
Work on genotype-phenotype correlations among the XP complementation groups continues. The main distinguishing features appear to be the presence or absence of burning on minimal sun exposure, skin cancer, and progressive neurologic abnormalities. All complementation groups are characterized by the presence of cutaneous neoplasia. There is clinical variation within each complementation group. Mild to severe neurologic impairment has been described in individuals with XPA mutations. Individuals with XPA mutations in the DNA binding region (amino acids 98-219) may have a more severe presentation that includes neurological findings. A very small number of people in the XPB, XPD, and XPG complementation groups have been identified as having xeroderma pigmentosum-Cockayne syndrome (XP-CS) complex. These individuals have characteristics of both disorders, including an increased predisposition to cutaneous neoplasms and developmental delay, visual and hearing impairment, and central and peripheral nervous system dysfunction. It should be noted that people with Cockayne syndrome without XP do not appear to have an increased cancer risk. Similarly, trichothiodystrophy (TTD) is another genetic disorder that can occur in combination with XP. Individuals affected solely with TTD do not appear to have an increased cancer incidence, but some affected with XP/TTD have an increased risk of cutaneous neoplasia. The complementation groups connected with XP/TTD (XPD and XPB) and XP-CS (XPB, XPD, and XPG) are associated with defects in both transcription-coupled nucleotide excision repair and global genomic nucleotide excision repair. In contrast, XP complementation groups C and E have defects only in global genomic nucleotide excision repair. In addition, individuals in the XPA, XPD and XPG groups may exhibit severe neurologic abnormalities without symptoms of Cockayne syndrome or TTD. Cerebro-oculo-facio-skeletal syndrome, which has been described with some ERCC2 (XPD) or XP-CS mutations, does not appear to confer an increased risk of skin cancer.[75,76,77,78]
The diagnosis of XP is made on the basis of clinical findings and family history. Functional assays to assess DNA repair capabilities after exposure to radiation have been developed, but these tests are currently not clinically available in the United States. Sequence analysis testing may be done to confirm mutations in XPA and XPC previously identified in an affected family; however, molecular testing for mutations associated with other complementation groups is currently done only in research laboratories.