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Biomedical subjects

K Hemminki

Publications and source records attributed to K Hemminki.

At least 199 records · Page 11Linked to original sources
PubMed1998

National database of familial cancer in Sweden.

A family cancer database was constructed from the nationwide Swedish registries and includes approximately 6 million persons and >30,000 cancers in offspring diagnosed at ages 15-51 years and their parents. A particular advantage of the database is that the contribution of both parental lineages on cancer risk can be examined. Cancer risk in the offspring was increased approximately 1.1 times when the father had cancer, and no increase was noted when the mother had cancer. If both parents had cancer, the risk for sons was 1.4 and for daughters 1.3. The sites of increased cancer risk in the offspring were colorectum, breast, cervix, corpus uteri, ovary, testis, melanoma, eye, other endocrine glands, and multiple myeloma. The results among young and middle-age adults suggest that cancer in both parents increases the cancer risk in the offspring at many sites. The molecular genetic explanation may be that rare dominant single genes increase susceptibility at many sites, or that overlapping sets of genes control susceptibility at multiple sites.

Adolescent↗
PubMed1998

Cancer incidence among Finnish workers exposed to aromatic hydrocarbons.

OBJECTIVES: To assess whether occupational exposure to aromatic hydrocarbons increases carcinogenic risk. METHODS: We followed cancer incidence among 3,922 male and 1,379 female workers monitored for exposure to styrene, toluene, or xylene. The follow-up after the first personal measurement comprised 66,500 person-years at risk over the period 1973-1992. We computed the indirectly standardized incidence ratios (SIR) with 95% confidence interval (CI) with regard to age-, gender-, and period-specific incidence rates of cancer in the Finnish general population. RESULTS: The overall rate of cancer incidence for the total cohort was fairly similar to that of the general population. The risk for nervous system tumors was increased at 10 years after the first personal measurement (SIR 2.80, CI 1.03-6.08). For styrene there was an excess risk for rectal cancer (SIR 3.11, CI 1.14-6.77), and risks for pancreatic and nervous system tumors were increased nonsignificantly. For toluene and xylene, no clear increase in cancer risk was found. CONCLUSIONS: The data are not supportive of an overall increase in the cancer risk for these solvents, even though we cannot rule out site-specific associations with the rectum, pancreas, and nervous system. There is supporting evidence in the epidemiology literature for pancreatic cancer risk and heavy exposure to styrene. More studies are warranted on solvents, with detailed information on lifetime exposures and habits being collected whenever possible.

Adult↗
PubMed1998

Time to pregnancy among the wives of men exposed to organic solvents.

OBJECTIVES: To assess whether paternal exposure to organic solvents is associated with decreased fertility. METHODS: A retrospective time to pregnancy study was conducted among men biologically monitored for organic solvents. The workers were classified into exposure categories on the basis of work description and the use of solvents as reported in the questionnaires, and on biological exposure measurements. The relative fecundability density ratios (FDR--an analogue of incidence density ratio of clinically recognised pregnancies) were calculated with discrete proportional hazards regression. RESULTS: After three mailings 316 (72.1%) wives of the monitored men participated. The final study population consisted of 282 couples who did not use contraception at the beginning of pregnancy. The FDRs, adjusted for potential confounders, were 0.80 (95% confidence interval (95% CI) 0.57 to 1.11) and 0.74 (95% CI 0.51 to 1.06) for high or frequent and low or intermediate exposure, respectively. High or frequent and low or intermediate exposure were related to decreased fecundability among primigravida (FDRs 0.36; 95% CI 0.19 to 0.66 and 0.53; 95% CI 0.27 to 1.04) but not among couples with at least one previous pregnancy (FDRs 0.96; 95% CI 0.62 to 1.49 and 0.77; 95% CI 0.47 to 1.24). CONCLUSIONS: The findings of the study provide limited support for the hypothesis that paternal exposure to organic solvents might be associated with decreased fertility. Further studies with careful design are warranted.

Adolescent↗
PubMed1998

High levels of dipyrimidine dimers are induced in human skin by solar-simulating UV radiation.

UV light is considered an important contributor to skin cancer, but methods have been lacking to quantify specific UV-induced lesions in human skin in situ. We applied a newly developed 32P-postlabeling technique to measure specific UV-induced cyclobutane dimers and 6-4 dipyrimidine lesions in the skin of healthy volunteers. At a dose of 400 J/m2, solar-simulated radiation caused at least 20 cyclobutane dimers/10(6) nucleotides, which is much higher than any known DNA adducts induced by specific external chemical exposure in human target tissues. This may explain why patients with DNA repair syndromes, such as xeroderma pigmentosum, preferentially develop skin cancer. We applied the 32P-postlabeling technique to study rates of DNA repair in healthy individuals. The obtained data indicated a base sequence dependence of the repair process. The applied method has potential for the study of DNA repair as a determinant of individual susceptibility to skin cancer.

Adolescent↗
PubMed1998

Familial risks in in situ cancers from the Family-Cancer Database.

The Swedish Family-Cancer Database was used to analyze relationships between parents and offspring with in situ cancers and between in situ cancers in one generation and invasive cancer in the other generation. A total of 130,000 in situ cancers and close to 400,000 invasive cancers were included from 1959 to 1994. The data on family relationships and cancers came from registered sources and should be free from bias. The offsprings' familial relative risks (FRRs) were calculated for concordant and discordant parental cancer sites. The most common male in situ site was skin (both melanoma and precancerous epithelial lesion), whereas cervix, breast, and skin were common female sites. Increased FRRs were observed for concordant sites: colon, breast, cervix, skin (melanoma), and, in males, precancerous epithelial lesions. The findings were consistent when in situ cancer-in situ cancer and in situ cancer-invasive cancer relationships were explored. FRRs were higher for in situ colon cancer and melanoma than the respective estimates in invasive cancers, and for the remaining sites, they were equal or somewhat lower. At discordant sites, increased FRRs of in situ cancers were observed for female breast and melanoma and, at many sites, implicated in tobacco and human papilloma virus carcinogenesis, together with cervix. Family histories of in situ cancers deserve clinical attention.

Bias↗
PubMed1998

Glutathione S-transferase mu1 and N-acetyltransferase 2 genetic polymorphisms and exposure to tobacco smoke in nonsmoking and smoking lung cancer patients and population controls.

We conducted a case-control study to assess the risk of lung cancer in relation to genetic polymorphisms of the detoxifying enzymes glutathione-S-transferase mu1 (GSTM1) and N-acetyl transferase 2 (NAT2), focusing on never-smokers, women, and older people. The study base consisted of persons > or =30 years of age in Stockholm County from 1992 to 1995. We recruited never-smoking lung cancer cases and a sex- and age-matched sample of ever-smoking cases at the three county hospitals mainly responsible for diagnosing and treating lung cancer. A total of 185 cases (25.4% men; 47.6% never-smokers) and 164 frequency-matched population controls (28.7% men; 48.2% never-smokers) supplied blood for genotyping. Detailed information was collected by interview on active and passive smoking, occupations, residences, and diet. The overall odds ratio (OR) for lung cancer associated with the GSTM1 null (GSTM1-) versus GSTM1+ genotype was 0.8 [95% confidence interval (CI), 0.5-1.2], with an OR close to unity among smokers, and lower ORs suggested among never-smokers. For NAT2 slow versus rapid acetylator genotypes, the OR was 1.0 (95% CI, 0.6-1.5) overall, which broke down into an increased risk for slow acetylators among never-smokers but an increased risk for rapid acetylators among smokers. Among never-smokers, a gene interaction was suggested, with combined slow acetylator and GSTM1+ genotype conferring particularly high risk (OR = 3.1; 95% CI, 1.1-8.6), but no clear pattern emerged among smokers. A detailed analysis among smokers showed no interaction between pack-years of smoking and the GSTM1 genotype but suggested a steeper increase in risk with increasing pack-years of smoking exposure for rapid than for slow acetylators. Our results do not support a major role for the GSTM1 genetic polymorphism as a risk factor for lung cancer among smokers or nonsmokers. There was, however, some suggestion that the slow acetylator genotype may confer an increased risk among never-smokers and that the rapid acetylator genotype interacts with pack-year dose to produce a steeper risk gradient among smokers.

Acetylation↗
PubMed1997

Molecular analysis of occupational cancer: infrequent p53 and ras mutations in renal-cell cancer in workers exposed to gasoline.

Occupational exposure to gasoline has been identified in several studies as a risk factor for renal-cell cancer. Cases of renal-cell cancer with and without work-related exposure to gasoline or gasoline and diesel fuel were studied for the presence of mutations in the tumour-suppressor gene p53 (n = 23 exposed and 30 non-exposed cases studied) and ras oncogene (n = 30 exposed and 36 non-exposed cases studied). An average cumulative exposure was estimated at 10 ppm-years benzene among the exposed. Three p53 mutations were detected by denaturing-gradient gel electrophoresis (DGGE) among the 23 exposed cases (3/23, 13%). Of the non-exposed referent cases, 4 had a mutation (4/30, 13%). All but one of the cases with a p53 mutation had smoked. A ras gene (K-ras or N-ras) mutation was found in 3 (3/66, 4.5%) cases, all of whom were smoker referents. We conclude that p53 and ras mutations are infrequent in renal-cell cancer associated with occupational exposure to gasoline. However, the majority of the mutations (6/7 for p53, and 3/3 for ras genes) were seen in smokers.

Adult↗
PubMed1997

Analysis of tamoxifen-induced DNA adducts by 32P-postlabelling assay using different chromatographic techniques.

DNA isolated from livers of rats receiving tamoxifen was analysed by the 32P-postlabelling method. The postlabelled DNA hydrolysis mixture was analysed both by reversed-phase HPLC with 32P on-line detection and by TLC on polyethyleneimine plates followed by autoradiography. Using the HPLC method, five well separated adduct peaks could be detected, while by the TLC method, two groups of adduct spots were observed. The detection limit of the TLC assay was lower (0.5 adducts/10(10) nucleotides) than that of the HPLC assay (3 adducts/10(10) nucleotides). Thus, the TLC assay is more sensitive but also more laborious. The advantages of the HPLC assay were, in addition to better resolution, the ease of quantification and operation.

Animals↗
PubMed1997

Cancer in twins: genetic and nongenetic familial risk factors.

BACKGROUND: Familial clustering has been observed for cancers that occur at specific sites. Most findings, which leave little doubt about the involvement of a heritable (i.e., genetic) component in the development of some cancers, are based on data from "cancer-prone" families or interviews with subjects who have cancer. The study of twins should be of value in cancer epidemiology because twins either are genetically identical or share half of their segregating genes. PURPOSE: We linked the Swedish Twin Registry to the Swedish Cancer Registry, thereby identifying cases of cancer diagnosed from 1959 through 1992 in twins born in the period from 1886 through 1958, to assess the importance of both genetic and nongenetic (i.e., environmental) familial factors in determining cancer risk. METHODS: Same-sex twin pairs with both individuals alive and living in Sweden in 1959-1961 or 1970-1972 were identified in the old cohort (born from 1886 through 1925) or the young cohort (born from 1926 through 1958), respectively, of the Swedish Twin Registry; pairs for whom zygosity (i.e., the number of eggs that gave rise to the twins) could be determined were considered further. The association of cancer with combined genetic and nongenetic familial factors was tested by comparing all twin pairs (regardless of zygosity) in which at least one member of the pair had been diagnosed with cancer at one of several specific sites with pairs in which neither twin had that cancer. Heritable effects alone were tested by comparing monozygotic (one egg) and dizygotic (two eggs) twin pairs. Statistical methods used in quantitative genetics and standard methods for epidemiologic research were used in parallel to analyze the data. RESULTS AND CONCLUSIONS: In the 10503 twin pairs from the old cohort, 361.7 cases of malignant cancer were identified; 918 malignant cancers were identified in the 12883 twin pairs from the young cohort. When cancer sites with a total number of at least 200 cases and at least one twin pair concordant (i.e., both twins affected) for the site were evaluated, namely, cancers of the stomach, colon and rectum, lung, female breast, and prostate, as well as total cancer, profound genetic and/or nongenetic familial effects were identified in twins from the old cohort. Similar findings were obtained for twins in the young cohort for cancers of the prostate and female breast, as well as for total cancer. Genetic and nongenetic familial effects were also identified in twins from both cohorts for in situ cancer of the cervix. The increase in risk of colon and rectum, breast, cervical, and especially prostate cancer, but not stomach or lung cancer, tended to be greater if a monozygotic rather than a dizygotic twin were affected. IMPLICATIONS: The identification of familial effects for total cancer in this study is consistent with the idea that individuals may possess a genetic susceptibility to cancer in general.

Adult↗
PubMed1997

Use of twins in search for tumor suppressor genes.

A new approach is applied in the mapping of tumor suppressor genes: analysis of loss of heterozygosity (LOH) in concordant tumors of monozygotic and dizygotic twins. The method relies on recognition of genome locations undergoing loss in both twins in a high proportion of the set of all twin pairs examined. The method effectively pinpoints, and excludes, the loci of potential tumor suppressor genes. With the help of a high density linkage map any such candidates can be placed within a narrow region of a chromosome arm and perhaps matched with known genes. The analysis of the Swedish Twin Registry has shown a clear genetic component for breast cancer. We have identified mono- and dizygotic twins concordant for breast cancer and collected the pathology specimens. Tumor and normal tissue was microdissected and microsatellite analysis carried out to test for allelic loss (LOH) in entirely new and putative chromosomal loci in this cancer. It can be calculated that using only six pairs of informative monozygotic twins, a locus can be incriminated with a high probability. Using increasingly dense markers and search for homozygous deletions, it should be possible to map one or more candidates for breast cancer.

BRCA1 Protein↗
PubMed1997

Alteration of p53 gene structure and function in laryngeal squamous cell cancer.

The p53 gene is known as an anti-oncogene that manifests its function by controlling the cell cycle and is responsible for apoptosis of cells with unrepaired DNA. An accelerated p53 protein synthesis is the first response of a cell following DNA damage. However, mutations of the p53 gene can disturb protein synthesis or may be responsible for synthesis of a changed protein unable to control the cell cycle. Laryngeal tissue specimens from 120 patients were tested by immunohistopathological staining to detect mutated wild-type p53 protein. It was found that p53-positive specimens correlated with TNM staging and histopathological grading. Another indication of entering the cell cycle and undertaking an active proliferation by laryngeal cells was shown by detection of proliferating cell nuclear antigen (PCNA) and Ki67 nuclear antigen, which appeared in proliferating cells (late G1, S-G2 and M phase), but was absent in resting cells. Scoring of the staining for p53 protein, PCNA and Ki67 correlated with each other. DNA from 40 specimens was then isolated, amplified by polymerase chain reaction and analysed by single-strand conformation polymorphism and DNA sequencing for mutation in the p53 gene. Fifteen DNA samples were found to be positive, while mutations were detected in exons 5-8 in 13 samples. The majority of mutations were found in tissue specimens from T3 and T4 tumors. A possible explanation is almost half was attributable to genotoxic effects of tobacco smoking. Changes in the p53 gene and its products may also reflect early changes in laryngeal carcinogenesis and be of prognostic value.

Adult↗
PubMed1997

Organic solvents and cancer.

Epidemiologic evidence on the relationship between organic solvents and cancer is reviewed. In the 1980s, more than a million persons were potentially exposed to some specific solvents in the United States; in Canada, 40 percent of male cancer patients in Montreal had experienced exposure to solvents; in the Finnish population, one percent was regularly exposed. There is evidence for increased risks of cancer following exposure to: trichloroethylene (for the liver and biliary tract and for non-Hodgkin's lymphomas); tetrachloroethylene (for the esophagus and cervix--although confounding by smoking, alcohol, and sexual habits cannot be excluded--and non-Hodgkin's lymphoma); and carbon tetrachloride (lymphohematopoietic malignancies). An excess risk of liver and biliary tract cancers was suggested in the cohort with the high exposure to methylene chloride, but not found in the other cohorts where an excess risk of pancreatic cancer was suggested. 1,1,1-trichloroethane has been used widely, but only a few studies have been done suggesting a risk of multiple myeloma. A causal association between exposure to benzene and an increased risk of leukemia is well-established, as well as a suggested risk of lung and nasopharynx cancer in a Chinese cohort. Increased risks of various gastrointestinal cancers have been suggested following exposure to toluene. Two informative studies indicated an increased risk of lung cancer, not supported by other studies. Increased risks of lymphohematopoietic malignancies have been reported in some studies of persons exposed to toluene or xylene, but not in the two most informative studies on toluene. Occupation as a painter has consistently been associated with a 40 percent increased risk of lung cancer. (With the mixed exposures, however, it is not possible to identify the specific causative agent[s].) A large number of studies of workers exposed to styrene have evidenced no consistent excess risk of all lymphohematopoietic malignancies, although the most sensitive study suggested an excess risk of leukemia among workers with a high exposure.

Alcohol Drinking↗
PubMed1997

Tamoxifen-induced DNA adducts in leucocytes of breast cancer patients.

Tamoxifen-induced DNA adducts were searched in leucocyte DNA from breast cancer patients. Total white blood cell DNA from tamoxifen-treated and control patients was analysed by 32P-postlabelling using HPLC-radioactivity detection. Rat liver DNA was used as a positive standard. In blinded analysis four of the six treated patients showed DNA adducts; none of the five controls were positive. The identity of fraction as a tamoxifen adduct was confirmed by using different chromatographic systems, each with spiked rat liver samples. The level of adducts in the treated patients was 5.5 adducts/10(9) nucleotides as compared to an apparent level of 1.9/10(9) in the controls.

Adult↗
PubMed1997

DNA adducts in human nasal mucosa and white blood cells from smokers and non-smokers.

The goal of the present study was to measure the levels of DNA adducts in human nasal mucosa cells and in total white blood cells in relation to smoking. DNA was isolated from samples of 20 healthy volunteers (six smokers and 14 non-smokers). The levels of DNA adducts were measured by 32P-postlabelling assay. In smokers the mean DNA adduct levels were 3.3 and 17.0 adducts/10(8) nucleotides in total white blood cells and nasal mucosa cells respectively. The corresponding values in non-smokers were 2.0 and 6.8 adducts/10(8) nucleotides. The mean adduct level was significantly higher in nasal mucosa cells than in total white blood cells both in smokers and non-smokers. The mean adduct levels in smokers' nasal mucosa cells were significantly higher than those in non-smokers. Thus the nasal mucosa cells constituted a sensitive tissue for the determination of cigarette smoking induced DNA adducts. Combining the sensitivity of the 32P-postlabelling assay with the specificity of the nasal mucosa to the airborne chemical exposures, the DNA adduct analysis from human nasal mucosa cells represents a method of choice in the assessment of exposure to airborne carcinogens.

Adult↗
PubMed1997

Aromatic DNA adducts in foundry workers in relation to exposure, life style and CYP1A1 and glutathione transferase M1 genotype.

Levels of aromatic DNA adducts in foundry workers and controls were followed at four annual samplings. During this time exposure to polycyclic aromatic hydrocarbons (PAH) decreased and the level of DNA adducts decreased accordingly. In the total group exposure was related to the level of adducts. Adduct levels correlated with urinary 1-hydroxypyrene (LOGU1OH), air benzo[a]pyrene, weekly working hours and daily cigarette consumption. In a multivariate model 1-hydroxypyrene had a consistent effect. Neither glutathione transferase M1 (GSTM1) nor cytochrome P450 1A1 (CYP1A1) genotypes had clear effects. Yet the individuals lacking GSTM1 had a stronger effect of LOGU1OH and some effect by other sources of PAH, such as charcoal broiled food, although all these variables were not significant in the multivariate model. The rare individuals with a CYP1A1 polymorphism MspI containing an amino acid change at isoleucine had an increased level of adducts. The results showed that the postlabelling method used was able to detect an increase in aromatic DNA adducts in leukocytes when exposure to benzo[a]pyrene in air was approximately 5 ng/m3. At such low levels smoking and charcoal broiled food may be important contributors to adducts.

Adult↗
PubMed1997

32P-postlabelling analysis of isomeric 7-alkylguanine adducts of styrene oxide.

Styrene 7,8-oxide, which reacts preferentially at the N-7 position of guanine, yielded two pairs of diastereomers 7-(1'-hydroxy-2'-phenylethyl)-dGMP (the alpha-isomer) and 7-(2-hydroxy-2-phenylethyl)-dGMP (the beta-isomer) on reaction with deoxyguanosine-3'-monophosphate (3'-dGMP). The alpha- and beta-isomers were formed in the ratio 32:68. T4 polynucleotide kinase preferentially mediated labelling of diastereomers corresponding to the beta-isomer. The beta-diastereomers showed a labelling efficiency of 52%, whereas the alpha-isomers showed a labelling efficiency of 4%. Molecular modelling experiments showed intrinsic differences between the two isomers. The torsion angles of C8-N7-2'-Ar and C8-N7-2'-1' for the alpha-isomers were 149.9 degrees and -26.4 degrees, whereas the torsion angles of C-8-N7-1'-2' and N7-1'-2'-Ar for the beta-isomers were 105.3 degrees and 179.4 degrees. The consequent interatomic distance between one of the hydrogens on the alpha-carbon and the 3'-phosphate group on the sugar residue was 5.3 A in the alpha-isomer whereas the closest distance between the hydrogens attached to the alpha-carbon and 3'-phosphate group in the beta-isomer was 6.2 A. This arrangement probably leads to steric overcrowding at the 3'-phosphate group in alpha-isomers and these are less efficiently phosphorylated than beta-isomers. In in vitro styrene oxide-modified salmon testis DNA alpha- and beta-isomers of 7-alkylguanines were formed in the ratio 37:63. The recovery of two diastereomeric beta-isomers in a 32P-postlabelling assay was 14%, but one of the diastereomers was obtained in 3-fold greater yield than the second isomer.

Animals↗