The laboratory is studying molecular, cellular and clinical abnormalities in human cancer-prone genetic diseases with defective DNA repair. Current studies are focusing on xeroderma pigmentosum (XP), a cancer-prone genetic disease with cellular hypersensitivity to ultraviolet radiation (UV) and other environmental agents, and trichothiodystrophy (TTD), a genetic disease with similar cellular hypersensitivity but no increase in cancer risk. Both disorders have defects in DNA nucleotide excision repair (NER) despite markedly different clinical features. We identified several unusual XP complementation group C (XPC) patients: a. We found that mutations in the splice lariat branch point sequence of the XPC gene result in either severe or mild clinical symptoms, depending on the amount of normal XPC mRNA produced. b. Two XP patients had the same XPC initiation codon mutation. While both had many skin cancers at an early age, one had neurological symptoms while the other had no neurological abnormalities. c. We treated two dark-skinned African brothers with XP and cancers of the skin, eye and tip of the tongue in association with mutations in the XPC gene. Thus normally functioning DNA repair provides more protection from UV-induced skin cancer than does dark skin pigmentation. We identified new patients with mutations in the XPB helicase, a protein that is essential for life and is involved in transcription and DNA repair. These patients had severe or mild disease, depending on their mutations. We ascertained 16 XP variant families from America, Europe and Asia and identified different mutations in an error-prone DNA polymerase (pol) eta in each kindred. Using locaized UV irradiation, immunostaining and confocal microscopy, we were able to demonstrate that persistence of DNA repair proteins at sites of unrepaired DNA damage distinguish XP cells from TTD cells with mutations in the same ERCC2 (XPD) gene. A systematic literature review revealed 112 case reports of TTD. There was a 20-fold increased mortality in patients under 10 years of age, primarily from infections. There were many reports of abnormal pregnancies in mothers of the TTD patients. We found that normal appearing parents of XPC patients have markedly reduced levels of XPC mRNA. In a collaborative study we found that the frequency of an XPA founder mutation approaches 1% of the general population in Japan. Thus there are about 1 million normal appearing carriers of this mutation in Japan. We have begun a collaborative molecular epidemiology study to examine the cancer risk in carriers of mutations in XP DNA repair genes. Chemoprevention of skin cancer in XP with oral 13-cis retinoic acid was found to be effective in preventing skin cancers but very toxic. The lowest effective dose varied in different patients.
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