We found a 10000-fold increased risk of sunlight induced cancers of the skin and eyes in XP patients along with a 50 year reduction in age of onset of these cancers, providing compelling evidence that DNA repair plays an important role in cancer prevention in the general population. We ascertained and intensively examined XP patients and TTD patients at NIH and are collaborating with researchers in Israel, Turkey, Europe and Japan to study additional patients. We completed a follow-up report on all 106 XP patients we examined at the NIH Clinical Center since 1971. There was a 10000-fold increase in non-melanoma skin cancer (NMSC) and a 2000-fold increase in melanoma skin cancer in XP patients under age 20. The 9 year median age of diagnosis of first NMSC was significantly younger than the 22 year median age of melanoma - a relative reversal from the general population suggesting different mechanisms of carcinogenesis between NMSC and melanoma. The median age at death of XP patients with neurodegeneration (29 years) was significantly younger than XP patients without neurodegeneration (37 years). This 39 year study indicates a major role for DNA repair genes in the etiology of skin cancer and neurodegeneration. We are studying clinically normal family members of XP patients to determine if XP heterozygotes have increased cancer risk. We have established several hundred carefully documented cell lines and contributed them to cell banks for use of the general scientific community. Our laboratory has become a major center in the US for basic, clinical and translational expertise concerning DNA repair related disorders. We have developed host cell reactivation assays for measuring DNA repair and mutagenesis at the molecular level in human cells. We have now identified mutations in all 8 DNA nucleotide excision repair (NER) genes (XPA, XPB, XPC, XPD, XPE, XPF, XPG, and TTDA) and in the error-prone polymerase, pol eta in more than 150 XP and TTD families. In a study of 16 XP-C families we found that most of the XP-C patients had mutations leading to premature stop codons. We found low levels of XPC mRNA in XPC patients while their obligate heterozygote parents had an intermediate level of XPC mRNA between the patients and the normal controls. We found two XP-C families from Turkey that had severe or mild disease that correlated with mutations in two different splice lariat branchpoints (LBP). These LBP mutations resulted in no measurable XPC mRNA or a low (3%) level of XPC mRNA, respectively. This indicates that a) low levels of normal XPC mRNA may provide some protection against cancer and b) reduced levels may increase cancer risk (e.g. potential risk to heterozygotes). We identified new mutations in the XPB gene in cells from XP patients with and without the XP/Cockayne syndrome complex. We found a wide spectrum of mutations in pol eta in cells from 10 XP variant families in America, Europe and Asia. We are continuing to compare the genotype to the clinical features of XP patients and to characterize the progressive neurologic degeneration that occurs in some XP patients because it may be a model for more common neurodegenerative disorders. In contrast to the profound environmental influence on XP, TTD is a disease of altered development. We performed a comprehensive literature review and identified reports of 112 TTD cases. We found a wide variety of clinical symptoms in many organ systems including an unsuspected 20-fold increase in mortality in children under age 10 years primarily due to infections. We documented significant increased frequency of complications in pregnancies of TTD affected fetuses compared to pregnancies carrying their unaffected siblings and to the general population. More than 80% of these pregnancies had one or more complications. The TTD affected neonates had high frequency of abnormalities including low birth weight, cataracts and cryptorchidism. This date provides evidence of DNA repair gene function in human fetal growth and pregnancy possibly by altering the development of the placenta. Using localized UV irradiation we were able to show a consistent difference in the pattern of movement of NER proteins in cultured cells from XP or TTD patients with different XPD defects. In XP cells at late times after UV, the NER proteins persisted at sites of unrepaired DNA damage. In contrast, in TTD cells the NER proteins did not persist. These differences suggest a mechanism that may explain the difference between the increased cancer susceptibility in XP patients and the absence of increased cancer in TTD. While skin cancer is the most common cancer occurring in the US, and rates of melanoma, the most dangerous skin cancer are rapidly increasing, there remains controversy as to the role of UV in induction of cutaneous melanomas. Because of their high frequency of melanomas, XP patients are a unique resource to study the pathophysiology of melanoma. We used laser capture micro-dissection to remove melanoma cells from tissue blocks of XP melanomas and sequenced the PTEN tumor suppressor gene. We found a high frequency of UV-type mutations in 59 XP melanomas. These data provide evidence for a direct effect of UV in the development of melanoma. In one of the first controlled studies of effective chemoprevention of skin cancer in humans, we found that, in XP patients, oral 13 cis retinoic acid was very effective in preventing skin cancers, although all patients had toxicity. We are continuing to follow these patients to determine the long term effects of therapy.

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Kuschal, Christiane; Botta, Elena; Orioli, Donata et al. (2016) GTF2E2 Mutations Destabilize the General Transcription Factor Complex TFIIE in Individuals with DNA Repair-Proficient Trichothiodystrophy. Am J Hum Genet 98:627-42
Heller, Elizabeth R; Khan, Sikandar G; Kuschal, Christiane et al. (2015) Mutations in the TTDN1 gene are associated with a distinct trichothiodystrophy phenotype. J Invest Dermatol 135:734-741
Kuschal, Christiane; Khan, Sikandar G; Enk, Benedikt et al. (2015) Readthrough of stop codons by use of aminoglycosides in cells from xeroderma pigmentosum group C patients. Exp Dermatol 24:296-7
Kraemer, Kenneth H; DiGiovanna, John J (2015) Forty years of research on xeroderma pigmentosum at the US National Institutes of Health. Photochem Photobiol 91:452-9
Tamura, Deborah; DiGiovanna, John J; Khan, Sikandar G et al. (2014) Living with xeroderma pigmentosum: comprehensive photoprotection for highly photosensitive patients. Photodermatol Photoimmunol Photomed 30:146-52
Kraemer, Kenneth H; DiGiovanna, John J (2014) Global contributions to the understanding of DNA repair and skin cancer. J Invest Dermatol 134:E8-17
Masaki, Taro; Wang, Yun; DiGiovanna, John J et al. (2014) High frequency of PTEN mutations in nevi and melanomas from xeroderma pigmentosum patients. Pigment Cell Melanoma Res 27:454-64
Atkinson, Emily C; Thiara, Diana; Tamura, Deborah et al. (2014) Growth and nutrition in children with trichothiodystrophy. J Pediatr Gastroenterol Nutr 59:458-64
Kuschal, Christiane; DiGiovanna, John J; Khan, Sikandar G et al. (2013) Repair of UV photolesions in xeroderma pigmentosum group C cells induced by translational readthrough of premature termination codons. Proc Natl Acad Sci U S A 110:19483-8
Kraemer, K H; Tamura, D; Khan, S G et al. (2013) Burning issues in the diagnosis of xeroderma pigmentosum. Br J Dermatol 169:1176

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