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Biomedical subjects

K Hemminki

Publications and source records attributed to K Hemminki.

At least 127 records · Page 7Linked to original sources
PubMed2000

Adenine N3 is a main alkylation site of styrene oxide in double-stranded DNA.

Styrene 7,8-oxide (SO), a major metabolite of styrene, is classified as a probable human carcinogen. In the present work, salmon testis DNA was reacted with SO and the alkylation products were analysed after sequential depurination in neutral or acidic conditions followed by HPLC separation and UV-detection. A novel finding was that the N-3 position of adenine was the next most reactive alkylation site in double-stranded DNA, comprising 4% of the total alkylation, as compared to alkylation at the N-7 position of guanine, 93% of the total alkylation. Both alpha- and beta-products of SO were formed at these two sites. Other modified sites were N2-guanine (1.5%, alpha-isomer), 1-adenine (0.4%, both isomers) and N6-adenine (0.7%, both isomers) as well as 1-hypoxanthine (0.1%, alpha-isomer), formed by deamination of the corresponding 1-adenine adduct. The results indicated that in double-stranded DNA N-7 of guanine and N-3 of adenine account for 97% of alkylation by SO. However, these abundant adducts are not stable, the half-life of depurination in DNA for 3-substituted adenines being approximately 10 and approximately 20 h, for alpha- and beta-isomers, respectively, and 51 h for both isomers of 7-substituted guanines.

Adenine↗
PubMed2000

Subsequent cancers after in situ and invasive squamous cell carcinoma of the skin.

OBJECTIVES: To compare cancer risks after in situ and invasive squamous cell carcinoma (SCC) of the skin and to determine whether these 2 forms of cancer differ in prognostic significance. PATIENTS: Subsequent events after in situ and invasive SCC were studied in the Swedish Family-Cancer Database, in which cancer data were obtained from the Swedish Cancer Registry from 1958 to 1996. Among 22293 patients with in situ SCC, 3940 had first invasive cancer; among 17637 patients with invasive SCC, 3624 had a second occurrence of cancer. MAIN OUTCOME MEASURE: Standardized incidence ratios (SIRs), ratios of the observed to expected number of cases, served as a measure of relative risk. For overall risks, cases diagnosed within the first year of follow-up were omitted. RESULTS: The median age of onset was 72 to 73 years for in situ and invasive SCC, respectively. Standardized incidence ratios of all cancers were increased after in situ SCC (men-women, 1.5:1.3) and invasive SCC (men-women, 1.9:1.5). The subsequent occurrences of cancer and their SIRs were similar after in situ and invasive SCC, with skin cancer showing the highest SIR of 6.4:10.0. Among discordant cancers, increased SIRs were recorded for melanoma and a group of malignant neoplasms observed in patients with immunosuppression, including lymphoma and oral cancers. Subsequent cancers in the salivary glands and nasal cavity also showed increased SIRs, particularly after invasive SCC. CONCLUSION: Risks of subsequent cancers, including skin cancer, melanoma, and internal cancers, showed similar patterns in patients with in situ and invasive SCC, suggesting that the 2 groups have a similar susceptibility to cancer.

Aged↗
PubMed2000

Analysis of G(1)/S checkpoint regulators in metastatic melanoma.

We have analyzed the expression of the CDKN1A (p21(CIP1)), CDKN1B (p27(Kip1)), TP53, RB1 and MDM2 proteins and tumor cell proliferation by immunohistochemical staining in 59 cases of metastatic melanoma. The genomic status of the CDKN2A (INK4-ARF, p16/p14(ARF)), CDKN2B (p15) and CDKN2C (p18) genes was determined by PCR-SSCP (single-strand conformation polymorphism) in 46 of these cases. These results were correlated with various clinico-pathological parameters, including the outcome of combined chemoimmunotherapy. We found positive correlations between the expression of CDKN1A and MDM2 (r = 0.5063, P = 0.001), between the expression of CDKN1B and RB1 (r = 0.5026, P = 0.001), and between RB1 expression and tumor cell proliferation (0.5564, P<0.001). Two mutations in the CDKN2A (p16) gene were detected, including a novel base change AAC-->ATC (Asn to Ile) at codon 71, that also changes the codon 85 of the alternative reading frame gene p14(ARF) from CAA to CAT (Gln to His). Homozygous deletion at exon 2 of the CDKN2A (INK4-ARF) gene was detected in six cases. In seven cases, the 540C-->G polymorphism in the 3'UTR of the CDKN2A (p16) gene was found in linkage disequilibrium with the 74C-->A polymorphism in intron 1 of the CDKN2B gene (P < 0.0001). These cases had significantly lower expression of the TP53 protein (P = 0.0032). Both 540C-->G and 580C-->T polymorphisms in the 3'UTR of the CDKN2A (p16) gene were associated with significantly shorter progression time from primary to metastatic disease (P = 0.0071). We conclude, that although none of the analyzed cell cycle regulators could be singled out as a major prognostic factor, G(1)/S checkpoint abnormalities remain one of the most significant factors in the development of malignant melanoma.

Adolescent↗
PubMed2000

Familial cancer risks in affected sibships: results from the Swedish family-cancer database.

We used the nationwide Swedish Family-Cancer Database to assess familial risks to sibs in sibsibs where at least two sibs had concordant cancer and their parents either concordant or discordant cancer. Familial relative risks (FRRs) were calculated by comparing to concordant sib-pairs whose parents had no cancer. Cancer sites were included if at least ten such concordant sib-pairs were found. In situ cancers were included in order to increase the numbers of cases. Concordant triads, one parent and the sib-pair affected, had an FRR over 100 for thyroid (FRR 399), colon, all bowel, and ovarian cancer. In these cancers, some 40% or more of the concordant sib-pairs belonged to this group. Melanoma and cancer of the nervous system showed FRRs of about 20, and invasive breast cancer of only 2. 9; in these cancers no more than 10% of the concordant sib-pairs belonged to the concordant triads. Discordant family sets, one or two parents presenting with a cancer discordant from that of the sib-pair, showed an FRR of about 3.0 and breast cancer about 2.0, suggesting the involvement of familial effects shared by many forms of cancer.

Family Health↗
PubMed2000

A rapid fluorescence based multiplex polymerase chain reaction--single-strand conformation polymorphism method for p53 mutation detection.

We have developed a fast single-strand conformation polymorphism (SSCP) technique to screen for mutations and polymorphisms in exons 5-8 of the human tumor suppressor gene p53. We use multiplex polymerase chain reaction (PCR) to amplify the four exons in one single PCR reaction and then fluorescent SSCP for screening. p53 fragments are labeled with three different colors and a fourth color is used for an internal size marker calibrating the gel. The method was evaluated in two ways: (i) 16 different cell lines with known mutations were tested blindly for band-shifts with SSCP, and (ii) 32 human urinary bladder cancer samples were screened for mutations using the present technique. After screening for mutations all exons from all samples were sequenced, both sense as well as antisense strands. Evaluating the method with four different gels shows that 21/23 mutations and polymorphism were detected in the cell lines and that 10/10 mutations and polymorphisms were detected in the patient samples. Sensitivity, specificity, positive and negative predictive values were 91/100%, 88/ 97%. 78/77% and 96/100% for cell lines / patient samples, respectively. Sensitivity, using one SSCP gel only, was 87% (20/23) for cell lines and 90% (9/10) for patient samples. We conclude that our modified SSCP technique is efficient and has a sensitivity close to 100% in detecting mutations.

DNA Mutational Analysis↗
PubMed2000

Dna adducts, mutations, and cancer 2000.

The main achievements in the DNA adduct field in the 1990s have been technical innovations of methods for specific adducts reaching sensitivities required for low levels encountered in humans. Over 20 specific adducts or closely related groups of adducts have been determined in humans. The sources of the DNA-binding agents are endogenous and exogenous or both. In some of these studies adduct levels have been correlated to metabolic or DNA repair genotypes. An example of DNA adduct studies in human target tissue is taken on UV photoproducts in skin in situ. Adduct-induced mutations, specific mutation spectra, and their relationship to cancer are discussed. The quantitative adduct techniques will enable comparisons of endogenous and exogenous adduct levels and will give important clues to the etiology of human cancer. Furthermore, adducts will provide an intermediary tool for genotyping studies, both for metabolic enzyme and for DNA repair system genotypes. As the common polymorphisms are likely to cause at most moderate increases in the risk of cancer, the intermediary adduct endpoint is a necessary proof of causal relationships. The present and future biomonitoring studies will cover many endpoints to link the mechanistic steps from DNA adducts to cancer via mutations and modulating host susceptibility factors.

Animals↗
PubMed2000

A genetic study of Hodgkin's lymphoma: an estimate of heritability and anticipation based on the familial cancer database in Sweden.

Hodgkin's lymphoma (HL) is a heterogeneous hemopoietic malignancy. Previous studies have implicated a genetic etiology responsible for familial HL. We have estimated the heritability of HL and tested the hypothesis of genetic anticipation by using a high quality cancer database of the Swedish population. Heritability was estimated by employing a threshold-liability model. To test the hypothesis of anticipation, the usual T-test procedure was used to test whether there was a difference in cancer age-of-onset between parents and children who were affected with HL. A randomization test was carried out to test the validity of the P-values. Additional analyses were performed after stratifying the data based on birth cohorts. This data set revealed that there was a difference between the age-of-onset of parents and of offspring who were affected with HL. We also estimated the heritability of HL in the Swedish population to be approximately 28.4%. Both findings provide further evidence for a genetic basis for HL.

Adult↗
PubMed2000

Initiation-development modelling of allelic losses on chromosome 9 in multifocal bladder cancer.

Multiple low-grade, low-stage superficial tumours were analysed for loss of heterozygosity (LOH) on chromosome 9 with 29 markers. Three consensus regions were found, one at 9p (9p21-22) and two at 9q (9q21-31 and 9q32-34). Phylogenetic trees were calculated for each patient using both designated chromosome 9 regions and, separately, using individual microsatellite data. Regional analysis suggested that multiple, equally important regions for bladder tumour initiation exist on chromosome 9. During the development of tumours all regions were eventually affected. The phylogenetic analyses with individual markers were used as molecular clocks to trace the ordering of tumours. The results were compared with the physical locations of the tumours and a hypothetical development model was built. These are novel approaches which, to our knowledge, have not been used before.

Chromosome Mapping↗
PubMed2000

Familial prostate cancer from the family-cancer database.

The aim of this study was to calculate the familial risk for prostate cancer (PC) for different family relationships. PC was studied in the Swedish Family-Cancer Database, updated in 1999 to cover individuals born after 1934 with their biological parents, totalling 9.6 million persons. Cancer data were obtained from the Swedish Cancer Registry from 1958 to 1996 and included 1035 PC cases amongst offspring. 188 families were identified where a father and a son had PC, giving a familial standardised incidence ratio (SIR) of 2.44 (2.10-2.80). The proportion of familial cancers was 18.2% amongst all PC amongst all PC amongst sons. There were only 5 pairs of affected brothers, of which 3 had an affected father. Age of onset modified familial risks modestly; the highest SIR of 4.43 (1.40-9.17) was for sons diagnosed before 50 years of age when the father was diagnosed before 65 years of age. When analysed across sites, an association of PC in one generation and stomach, liver and skin cancer and myeloma in another generation was observed. The link was most consistent for skin cancer. No maternal site was associated with a son's PC, although the SIR of breast cancer was 1.22 (0.95-1.53). No increased risk of malignancy was observed in wives of affected men excluding any shared environmental effect for PC and female cancers.

Age Distribution↗
PubMed2000

IPCS guidelines for the monitoring of genotoxic effects of carcinogens in humans. International Programme on Chemical Safety.

The purpose of these guidelines is to provide concise guidance on the planning, performing and interpretation of studies to monitor groups or individuals exposed to genotoxic agents. Most human carcinogens are genotoxic but not all genotoxic agents have been shown to be carcinogenic in humans. Although the main interest in these studies is due to the association of genotoxicity with carcinogenicity, there is also an inherent interest in monitoring human genotoxicity independently of cancer as an endpoint. The most often studied genotoxicity endpoints have been selected for inclusion in this document and they are structural and numerical chromosomal aberrations assessed using cytogenetic methods (classical chromosomal aberration analysis (CA), fluorescence in situ hybridisation (FISH), micronuclei (MN)); DNA damage (adducts, strand breaks, crosslinking, alkali-labile sites) assessed using bio-chemical/electrophoretic assays or sister chromatid exchanges (SCE); protein adducts; and hypoxanthine-guanine phosphoribosyltransferase (HPRT) mutations. The document does not consider germ cells or gene mutation assays other than HPRT or markers of oxidative stress, which have been applied on a more limited scale.

Carcinogens↗
PubMed2000

Levels and repair of cyclobutane pyrimidine dimers and 6-4 photoproducts in skin of sporadic basal cell carcinoma patients.

The 32P-postlabeling method was applied to measure directly the levels and repair rates of specific cyclobutane pyrimidine dimers and 6-4 photoproducts in 10 basal cell carcinoma patients and 10 controls matched on age, skin type, and gender after exposure to 400 J per m2 of solar simulating radiation on previously unexposed buttock skin. The results showed an identical level of photoproducts at 0 h after solar simulating radiation in the basal cell carcinoma group and the control group. Erythemal response correlated with the repair of cyclobutane pyrimidine dimers within 24 h in both groups, i.e., repair was faster in those with a strong erythemal reaction. The basal cell carcinoma patients showed a somewhat slower repair of photoproducts in skin compared with the controls, but the result was not significant. Photoproducts formed at the TTC sites were repaired faster than those at the TTT sites for both cyclobutane pyrimidine dimers and 6-4 photoproducts in the basal cell carcinoma group and in the controls.

Aged↗
PubMed2000

Effect of constitutional pigmentation on ultraviolet B-induced DNA damage in fair-skinned people.

Ultraviolet light has been implicated as a dominant factor in skin cancer development. Skin pigmentation is traditionally regarded as an important protection against skin cancer. Yet, little is known about how skin pigmentation is modulating induction of DNA damage, which is the primary event in carcinogenesis. We applied a recently developed 32P-postlabeling technique to measure the effect of constitutional pigmentation on the formation of major ultraviolet-induced DNA damage in human skin in vivo. The induction of photoproducts showed a statistically significant negative correlation with erythemal response and skin pigmentation. Our results demonstrated that the constitutional pigmentation is efficiently guarding DNA against the formation of photoproducts. The difference in melanin content is likely to be one of the reasons for the observed interindividual variation in levels of DNA damage after the uniform exposure to ultraviolet B.

Adult↗
PubMed2000

Cutaneous melanoma patients have normal repair kinetics of ultraviolet-induced DNA repair in skin in situ.

The DNA lesions induced by ultraviolet radiation include cyclobutane pyrimidine dimers and 6-4 photoproducts. We investigated whether cutaneous melanoma patients have an impaired ability to repair their ultraviolet-induced photolesions. Seventeen patients with melanoma and 13 healthy controls took part in this study. Both groups received a dose of 40 mJ per cm2 Commission Internationale de l'Eclairage of solar simulating radiation on previously unexposed buttock skin. Skin biopsies were taken at 0 h, 24 h, and 48 h after ultraviolet exposure. A 32P-postlabeling method was used to measure both cyclobutane pyrimidine dimers and 6-4 photoproducts in skin. Cyclobutane pyrimidine dimers and 6-4 photoproduct levels did not differ in the melanoma patients from those in the control group at any time point post-ultraviolet radiation. The repair rate of cyclobutane dimer TT=C was faster than that for TT=T both at 24 h and 48 h postirradiation in both groups, providing evidence of site-specific repair (p < 0.05). We conclude that patients with melanoma have a normal ultraviolet-induced DNA repair capacity in skin in situ.

Adult↗
PubMed2000

Cancers in the first-degree relatives of children with brain tumours.

We used the nationwide Swedish Family-Cancer Database with 2060 childhood brain tumours diagnosed in the period 1958-1996 to analyse the risk of this tumour by parental cancers and in siblings of childhood brain tumour probands. Groups of patients were compared by calculating standardized incidence ratios (SIRs) for brain tumours in offspring. 1.3% of brain tumour patients had a parent with nervous system cancer; SIRs were 2.4 and 1.88 for diagnostic ages < 5 and < 15 years, respectively. The data showed distinct patterns of familial risks for childhood brain tumours, the SIR was 10.26 for brain astrocytoma given a parent with meningioma. Parental colon cancer was associated with offspring ependymoma (SIR 3.70), and parental salivary gland cancers with offspring medulloblastoma (SIR 13.33, but two cases only). SIR for sibling nervous system cancer from childhood brain tumour probands was 3.55 up to age 61.

Adolescent↗
PubMed2000

Human DNA adducts of 1,3-butadiene, an important environmental carcinogen.

The N-1-(2,3,4-trihydroxybutyl)adenine (N-1-THB-Ade) adducts induced by 1,3-butadiene (BD) were analysed from lymphocytes of 15 workers occupationally exposed to BD and 11 controls by (32)P-post-labelling using HPLC with radioactivity detection. The difference in the adduct levels between the BD-exposed workers (4.5 +/- 7.7 adducts/10(9) nucleotides) and the controls (0.8 +/- 1.2 adducts/10(9) nucleotides) was statistically significant (Wilcoxon rank sum test, P = 0.038). This study shows for the first time BD-induced DNA adducts in humans and suggests that N-1-THB-Ade adducts may be used to biomonitor human exposure to BD.

Adult↗
PubMed2000

p53 intron 7 polymorphisms in urinary bladder cancer patients and controls. Stockholm Bladder Cancer Group.

A C-->T polymorphism in intron 7 of the human tumour suppressor gene p53 was studied in 159 urinary bladder cancer patients and 171 non-cancer controls. The polymorphism was found in 15% of both patients and controls, suggesting that it has no relevance in urinary bladder cancer pathogenesis or aetiology. A second polymorphism, a T-->G change located 20 bp downstream of the C-->T change, was found in all samples with the C-->T change. Our findings indicate that the C-->T and the T-->G changes occur simultaneously and belong to the same allelotype.

Adult↗
PubMed2000

Increased frequency of LOH on chromosome 9 in sporadic primary melanomas is associated with increased patient age at diagnosis.

We carried out statistical analysis of the frequency of loss of heterozygosity (LOH) at 10 microsatellite markers on chromosome 9. In 44 microdissected sporadic primary melanomas a comparison of LOH frequency data with other patient data, like age at diagnosis and tumour thickness, showed an interesting correlation between patient age at diagnosis and frequency of LOH on chromosome 9. The patient group with age >72 years at diagnosis (n = 22, mean age 82.3 +/- 6.0 years, mean LOH 3.4 +/- 2.3) showed significantly increased LOH frequency (OR 3.1, 95% CI 1.8-5.3; chi(2) test, P < 0.0001) compared with age group </=72 years (n = 22, mean age 56.1 +/- 14.5 years, mean LOH 1.8 +/- 1.7). A statistically significant increased frequency of LOH (OR 3.5, 95% CI 1.5-7.9; chi(2) test, P = 0.03 after Bonferroni correction) was found only at marker D9S736 on 9p22 (telomeric to the INK4-ARF locus) relative to other markers on six different chromosomes. No other marker, including those located within the INK4-ARF locus, showed a statistically significant increased frequency of LOH. Our results for the first time show a non-random tendency for increased allelic loss in melanomas with increased patient age at diagnosis, besides supporting the existence of an additional tumour suppressor gene(s) on chromosome 9.

Adult↗