DNA photodamage induced by UV phototherapy lamps and sunlamps in human skin in situ and its potential importance for skin cancer.
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DNA↗
Biomedical subjects
K Hemminki
Publications and source records attributed to K Hemminki.
Cyclobutane thymidine dimers are present in human urine following sun exposure: quantitation using 32P-postlabeling and high-performance liquid chromatography.
Cyclobutane thymidine dimer (T=T) is the major DNA photoproduct formed in human skin after solar radiation. We have developed a 32P-postlabeling method suitable for quantitating T=T in human urine with a detection limit of about 0.5 fmol per 10 microl urine. The method was used in the present study to measure the daily T=T urinary level of two volunteers over a 15 d period, including frequent sun exposures ranging from 0 to 5 h daily. T=T was not detected before or immediately (4 h) after the initial sun exposure but was first observed in urine samples collected 18 h after the initial exposure. Thereafter, urinary T=T levels gradually increased up to a peak reached about 3 d after the maximum sun exposure. The levels decreased during the following days but were still detectable 8 d after the last sun exposure. About 70-75% decrease in excreted T=T was observed after 8 d. The T=T levels measured in urine were lower but in the same order of magnitude as the levels expected after a theoretical calculation based on previous published results and reasonable assumptions. This study shows the occurrence of cyclobutane thymidine dimers in human urine after skin exposure to solar radiation.
Adult↗
The nation-wide Swedish family-cancer database--updated structure and familial rates.
The Swedish Family-Cancer Database was expanded to include all Swedes born in 1932 and later (offspring) with their parents, totaling 10.2 million individuals. Cancer cases were retrieved from the Swedish Cancer Registry from the years 1958 to 1998, including over 1 million primary cancers and in situ tumors. Some 10%, of offspring diagnosed with cancer lack any parental information. Incidence rates of cancers were similar in the database and in the Cancer Registry to age 70, but at higher ages the rates in the Database were lower, probably because of selection. The familial risk for all types of cancer in offspring was 1.73 when a parent had the same type of cancer. The familial rates were increased for all main cancer sites, except for the upper aerodigestive tract, stomach, liver, pancreas and bone marrow (leukemia). The rates were 7.47 for thyroid, 4.69 for testis, and over 2.00 for melanoma, ovary, prostate, skin, endocrine glands and endometrium.
Adolescent↗
Genetic Epidemiology--science and ethics on familial cancers.
Genetic epidemiology provides data on cancer etiology, familial risks and genotype-specific risks. These data are useful for clinical counselling and gene identification. The studies require large, unbiased sample sizes and collaboration between research teams, nationally and internationally. A recent study on Nordic twins suggests that in colorectal, breast and prostate cancer, the inherited component ranges between 27 and 42%, far in excess of the known susceptibility genes. The data from the Swedish Family-Cancer Database, particularly on second cancers, also suggest that a main genetic component in cancer is polygenic. The results have implications for design of genetic studies and for clinical counselling.
Case-Control Studies↗
Allelic imbalance on chromosomes 13 and 17 and mutation analysis of BRCA1 and BRCA2 genes in monozygotic twins concordant for breast cancer.
To study genetic changes associated with the development of breast cancer and the extent of its hereditary predisposition, paraffin-embedded tissue samples were obtained from monozygotic twin pairs concordant for breast cancer through the linked Swedish Twin and Cancer Registries. DNA samples extracted from the matched tumour and normal tissues of nine twin pairs were analysed for allelic imbalance using a series of microsatellite markers on chromosomes 13 and 17, containing loci with known tumour suppressor genes. Multiple losses of constitutional heterozygosity (LOH), consistent with a loss of large genomic region, the whole chromosome or chromosome arm, was found in at least three pairs of twins. One double mitotic crossover was identified in one tumour sample in a pair concordant for LOH at multiple loci on both chromosomes. Recombination breakpoints were mapped to regions delineated by D13S218 and D13S263, and D13S155 and D13S279, respectively. In general, no genetic effect of losing the same allele within a twin pair was found. However, for one marker at chromosome 13 (D13S328, between the BRCA2 and the RB-1 loci) and two markers on chromosome 17 (D17S786, distal to the p53 locus, and D17S855, an intragenic BRCA1 marker) the proportion of twin pairs with the same LOH was significantly higher than expected. These regions may reflect hereditary genomic changes in our sample set. In addition, tumour DNA samples from a subset of 12 twin pairs were analysed for BRCA1 and BRCA2 mutations using exon-by-exon single-strand conformation polymorphism analysis. Two unclassified BRCA2 variants, with a putative pathogenic effect, were identified, but no pathogenic alterations were found in the BRCA1 gene.
Adult↗
XPD exon 10 and 23 polymorphisms and DNA repair in human skin in situ.
Forty-four Finnish volunteers who were previously studied with regard to the repair rate of UV-specific cyclobutane pyrimidine dimers in the skin were genotyped for XPD polymorphisms at codons 312 (exon 10 G-->A, Asp-->Asn) and 751 (exon 23 A-->C, Lys-->Gln). The repair rate was measured at 24 h for two different cyclobutane dimers. The data did not show consistent XPD genotype-specific differences in DNA repair rates among all subjects. The combined exon 10 AA and exon 23 CC genotype was associated with an approximately 50% depression of repair rate but this was of borderline statistical significance. However, the exon 23 C allele was associated with depressed repair among subjects aged 50 years or older and the result was consistent with both dimers.
Base Sequence↗
Studies of dose distribution, premutagenic events and mutation frequencies for benzo[a]pyrene aiming at low dose cancer risk estimation.
Cancer risk assessment of polycyclic aromatic hydrocarbons (PAH) is complicated by several of these compounds exerting a promoter action leading to high tumour incidences at high doses. Cancer risks at low doses corresponding to the uptake from air and food in the general environment would best be estimated on the basis of measurement of in vivo target doses of genotoxic (mutagenic) intermediates and a determination of mutation frequency per unit of dose. In experiments ultimately aiming at a risk assessment of environmental PAH from in vivo doses benzo[a]pyrene (BaP) was chosen as a model. gamma-Radiation has earlier been used as a reference standard in cancer risk estimation of genotoxic chemicals where dose equivalents (rad-equivalents) have been shown to give reliable risk estimates for several alkylating agents. Variation in dose of BaP diolepoxide between organs was studied by measurement of deoxyguanosine-N(2) adducts in DNA after administration of BaP by gavage to mice of a strain with reduced DNA repair (Xpa(-/-)). The adduct levels in spleen, forestomach, stomach and small intestine were approximately the same; with the adduct level in spleen as reference it was twice as high in liver and lung and about half as high in colon tissue. A chemical or radiation dose is proportional to the cumulative frequency of putatively premutagenic changes (premutagenic hits) in DNA. The mutation frequency per premutagenic hit (genotoxic chemicals) and per unit of dose (gamma-radiation) were calculated from acutely exposed V79 cells in order to determine the mutagenic effectiveness of each agent. Based on the mutagenic effectiveness determined in this study 10(-4) Gy can be regarded equally effective in causing phenotypically expressed HPRT mutations as the dose of BaP which causes the formation of one deoxyguanosine-N(2) adduct per cell.
Animals↗
Ethnic variation in genotype frequencies of a p53 intron 7 polymorphism.
Using a PCR-restriction enzyme-based method we found large ethnic variations when a C-->T polymorphism in the human p53 gene at position 14181 in intron 7 was studied in Finnish, Polish, Hungarian, Italian, Japanese, Indian and Chinese populations. The largest variations were found between Caucasian and Asian, genotype frequencies varied from C 0.95 and T 0.05 in the Finnish population to C 0.67 and T 0.33 in the Chinese population, the relative risk (RR) for T being 6.5 (95% CI 3.4-12.3, P < 0.001). Variations were also found between Finnish and Italian and between Italian and Chinese (RR for T 2.4, 95% CI 1.2-4.9 and 2.7, 95% CI 1.7-4.2, respectively).
Asian People↗
Polymorphic insertion of additional repeat within an area of direct 8 bp tandem repeats in the 5'-untranslated region of the p53R2 gene and cancer risk.
p53R2 is a recently cloned gene that functions in p53-induced DNA repair. In the 5'-untranslated region of the p53R2 gene two direct tandem 8 bp repeats are located. Within the region of these 8 bp direct repeats we have detected the insertion of an additional repeat. In order to determine a possible association of this novel polymorphism with any cancer or population, we carried out genotyping of 843 European and Asian controls and patients with various cancer types. In addition, 26 cancer cell lines were included in the study. No significant difference in polymorphic frequency could be demonstrated for any of the cancer types, although the allelic frequency in melanoma patients was lower than in controls (chi(2) = 3.28; P = 0.07; OR = 0.32; 95% CI 0.07-1.26). A significantly higher frequency of the polymorphism was detected in the compiled Caucasian individuals compared with Asians (chi(2) = 9.19; P = 0.002; OR = 3.13; 95% CI 1.39-7.43). In one tumour cell line we observed two extra inserted copies of the 8 bp repeat. The functional effect of the insertion polymorphism on the p53R2 gene transcription remains to be determined.
5' Untranslated Regions↗
Risk of multiple primary cancers in nasal cancer patients.
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Adult↗
A population-based study of familial cutaneous melanoma.
We studied familial risks in cutaneous melanoma by comparing the occurrence of melanoma, or discordant cancer, in two generations, based on the Swedish Family-Cancer Database of 9.6 million individuals. Offspring were from 0 to 61 years of age. Cancers were obtained from the Swedish Cancer Registry for the years 1958 to 1996. The study was based on 30,170 cases of melanoma. Among these, 196 offspring came from families where a parent also presented with melanoma. The overall familial hazard ratio (FHR) was 2.47 when a parent had melanoma; an early age of onset increased the risk. Multiple primary melanomas in parents increased the FHR in offspring, being 2.23 for one, 9.10 for two and up to 83 for more than two melanomas in the parent. The number of affected offspring increased the risk of melanoma in the parents, from 3.05 when one was affected to 5.12 and 151 when two or three offspring were affected, respectively. Melanoma risk to a sibling with an affected proband was 3.56. Melanoma in one generation was associated with an increased occurrence of squamous cell carcinoma of the skin in the other generation. Other weaker associations were found to pancreatic, breast, testicular and nervous system cancers and non-Hodgkin lymphomas.
Adolescent↗
Familial risks in invasive and in situ cervical cancer by histological type.
The Swedish Family-Cancer Database was used to analyse familial relationships in mothers and daughters with invasive and in situ cervical cancers by histological type during the years 1958-1996, including a total of 21,727 and 191,081 cases, respectively. Familial standardized incidence ratios (SIRs) were calculated separately for mothers and daughters and for invasive and in situ squamous cell carcinoma (SCC) and adenocarcinoma. Familial risks were about 2.0 in invasive SCC and less in in situ SCC. Limited analyses could be carried out on adenocarcinoma because the number of cases was small. However, familial risks were not much smaller in families where only SCC was diagnosed compared with those where both SCC and adenocarcinoma were present. A comparison of cancers between mothers and daughters showed an association between cervical cancer and SCC of skin, and between cervical cancer and smoking-related cancers. The familial risks were unaffected in Poisson regression analysis on many possible intervening variables. The data suggest that host factors modulate an individual's response to human papillomavirus infections.
Adenocarcinoma↗
Gender-specific incidence trends in lung cancer by histological type in Sweden, 1958-1996.
We used the Swedish Family-Cancer Database to examine the time trends of lung cancer in Sweden by histological type, with special reference to gender. A total of 45,297 lung cancer cases were analysed. The overall age-adjusted incidence rates of squamous cell carcinoma (SCC) in men peaked in the 1980s and then slightly decreased, while corresponding rates in women increased steadily. The incidence of adenocarcinoma increased in both genders. The male-to-female incidence ratio for SCC was 12.4 in the 1960s and 3.6 in the 1990s. For adenocarcinoma the ratio was close to 1.5 throughout the period. Regression analysis indicated that the birth cohort of the 1940s was at the highest risk for adenocarcinoma in men and for all types of lung cancer in women. Lung cancer in parents was a risk factor for offspring. In conclusion, the data, particularly on women, suggest that modern cigarettes induce lung adenocarcinoma and SCC in a proportion of 1:0.6. This proportion was 1:3.7 among men diagnosed in the 1960s. The incidence ratio of 1.3 for adenocarcinoma between men and women in the 1990s is consistent with the smoking prevalence data a few decades ago, suggesting equal sensitivity of both genders to tobacco-induced lung cancer.
Adenocarcinoma↗
Identification of 1-adenine DNA adducts in workers occupationally exposed to styrene.
Styrene is an extensively used industrial chemical that has been classified as a possible human carcinogen. The possible carcinogenicity may be related to the covalent DNA binding properties of styrene 7,8-oxide, a major metabolite of styrene. We have developed a sensitive and a highly specific phosphorus-32-postlabeling method for the determination of 1-styrene 7,8-oxide-adenine DNA adducts. These adducts were analyzed in white blood cells from workers exposed to styrene at mean level of 76.2 mg/m3. Three of nine exposed workers showed adducts above the detection limit; the mean was 0.79 +/- 0.14 1-styrene 7,8-oxide-adenine DNA adducts/10(9) nucleotides. None of the 11 control cells showed adducts above the detection limit, which was 0.4 adducts/10(9) nucleotides. The results show a potential of 1-adenine DNA adducts for predicting risks in the workers exposed to styrene.
Adenine↗
Childhood cancer and parental occupation in the Swedish Family-Cancer Database.
We used the nationwide Swedish Family-Cancer Database to analyze the risk for common childhood tumors in offspring in relation to parental occupation recorded in the census of 1960. A total of 8158 cancer cases, diagnosed before age 15 between years 1958 and 1996, were included. Standardized incidence ratios were calculated using 52 different parental occupations. Among the maternal occupations, seven were associated with the risk of cancer in offspring. Assistant nurses had an excess of children with leukemia and connective tissue and colon cancers. Children of female cooks had brain cancers at a rate greater than expected. Fifteen different malignancies were associated with children of male workers. Shoe and leathers workers' children had excesses of many tumors. Among the other paternal occupations associated with childhood tumors, miners, quarrymen, and hairdressers were likely to be exposed to harmful dusts and chemicals.
Adolescent↗
Protective effects of tanning on cutaneous DNA damage in situ.
BACKGROUND: The incidence of skin cancer, the most common type of cancer in the Western world, has been shown to be associated with the degree of exposure to solar radiation. However, little is known on how human skin can be protected against UV-induced DNA damage by constitutive and induced pigmentation. OBJECTIVE: To study the effect of skin pigmentation induced by a sunbed-type of treatment on the formation of UV-induced DNA damage in human skin in situ. METHODS: A photoproduct assay was performed in untanned and tanned skin of healthy volunteers. RESULTS: There is no significant difference in the induction of photoproducts between untanned and tanned skin. CONCLUSION: Our data demonstrate that constitutive skin pigmentation is more efficient than the induced one in protection against formation of photoproducts.
Adult↗
A population-based study of familial central nervous system hemangioblastomas.
We used the nationwide Swedish Family-Cancer Database to analyze the risk for central nervous system hemangioblastoma (HB) in offspring (0-61 years) of parents with cancer. Eighty-three offspring were identified, and the age at onset showed a bimodal distribution. The early-onset component peaked at 25-29 years, was associated with von Hippel-Lindau (VHL) disease and presented with HBs, renal cell carcinomas, pheochromocytomas and insulomas in the proband or other family members. Standardized incidence ratios (SIRs) were 600 for offspring HB by parental HB, and they were even high for the other VHL-related tumors. Second tumors were common in this early-onset group, and the types were as expected in VHL. The late-onset component peaked at 40-44 years, and it was twice as prevalent as the early-onset component. Because there was no evidence of familial risks, this is suggested to be a sporadic form of HB.
Adolescent↗
Use of monozygotic twins in search for breast cancer susceptibility loci.
We have used Swedish monozygotic twins concordant for breast cancer to study genetic changes associated with the development of breast cancer. Because loss of heterozygosity (LOH) at a specific genomic region may reflect the presence of a tumour suppressor gene, loss of the same allele in both of the twins concordant for breast cancer may pinpoint a tumour suppressor gene that confers a strong predisposition to breast cancer. DNA samples extracted from the matched tumour and normal tissues of nine twin pairs were analysed for allelic imbalance using a set of microsatellite markers on chromosomes 1, 13, 16 and 17, containing loci with known tumour suppressor genes. The two main regions, where more twin pairs than expected had lost the same allele, were located at 16qtel', including markers D16S393, D16S305 and D16S413, and at 17p13, distal to the p53 locus. Our results show that the monozygotic twin model can be used to suggest candidate regions of potential tumour suppressor genes, even with a limited number of twin pairs.
Adult↗