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Biomedical subjects

K Hemminki

Publications and source records attributed to K Hemminki.

At least 163 records · Page 9Linked to original sources
PubMed1999

Familial risks in cervical cancer: is there a hereditary component?

The Swedish Family-Cancer Database was used to analyze familial relationships in mothers and daughters in invasive and in situ cervical cancers from years 1958-1994, including a total of 125,000 in situ and 14,000 invasive cancers. In situ cancers were diagnosed on average 10 years earlier than invasive cancers. Familial relative risks (FRRs) were calculated separately for mothers and daughters, and were between 1.8 and 2.3 for the 2 forms. The risks were only slightly modified by age of onset, except at higher ages where there was no familial risk; in mothers, the risks increased if more than one daughter was affected. Aggregation of in situ cases among sisters was observed in families. Heritability estimates were between 0.11 and 0.15 for in situ and 0.22 and 0.34 for invasive cervical cancer. A comparison of cancers in mothers and daughters showed an association between cervical cancer and many cancer types observed in immunosuppressed patients, suggesting a role for a mild form of immunosuppression, in addition to sexual behavior leading to human-papilloma-virus infections, in familial cervical cancer.

Adolescent↗
PubMed1999

Biomonitoring of occupational exposure to styrene in a plastics lamination plant.

A comprehensive approach to biological monitoring of 44 workers occupationally exposed to styrene in a hand lamination plant was performed by using several end-points: styrene in workplace air, styrene in exhaled air, styrene in blood, DNA strand breaks (SBs) and oxidised bases in mononuclear leukocytes, chromosomal aberrations in lymphocytes, immune parameters and genotyping of polymorphic genes of some xenobiotic-metabolizing enzymes (CYP 1A1, EPHX, GSTM1 and GSTP1). We found a significantly higher number of DNA SBs, measured by a modified comet assay, in mononuclear leukocytes of the styrene-exposed workers compared with results from 19 unexposed controls (P<0.001). A fairly strong correlation was observed between SBs and years of exposure (P<0.001, r=0.545). The styrene-exposed workers also showed a significantly increased frequency of chromosomal aberrations (P<0.0001 for highly exposed group, P<0.004 for medium-exposed group, and P=0.0001 for low-exposed group). The proliferative response of T-lymphocytes stimulated with concanavalin A was significantly suppressed in people exposed to styrene (P<0.05). We recorded a significant increase of the percentage of monocytes in differential white blood cell counts in the exposed group (P<0.05). Using flow cytometry, we found an increased expression of adhesion molecules CD62L, CD18, CD11a, CD11b, CD49d and CD54 in the exposed workers as compared with the control group (P<0.05).

Adult↗
PubMed1999

DNA copy number losses at 1p32-pter in monozygotic twins concordant for breast cancer.

To find similarities that may possibly indicate novel mutations, we performed comparative genomic hybridization (CGH) analysis following degenerate oligonucleotide primed polymerase chain reaction (PCR) for DNA obtained from unique material of breast cancer that developed in monozygotic twin-pairs. Polymerase chain reaction amplification was successful in 12 samples for 11 patients, including 3 pairs. Six samples exhibited DNA copy number changes. Gains (76%) were more frequent than losses (24%). Gains or high-level amplifications in 8q were present in all but 1 of the abnormal cases. Frequent gains were detected with a minimal common overlapping region at 5p (4 cases), at 1q25-qter (3 cases), and at 20q12-qter (2 cases). The most frequent loss, detected in half of the abnormal cases, was at 1p32-pter. One twin-pair showed similar changes in 4 chromosomal locations involving loss of 1p32-pter and gains in 1q25-qter, 5, and 8q.

Base Sequence↗
PubMed1999

Novel somatic mutations in the VHL gene in Swedish archived sporadic renal cell carcinomas.

Frequent loss-of-function somatic mutations of the VHL gene have been detected in sporadic renal cell carcinoma (RCC), indicating that inactivation of the VHL gene plays a critical role in RCC. In this study, we collected 35 archived Swedish sporadic RCCs identified from an epidemiological study on occupational exposure and kidney cancer to test how well stored pathological specimens could be retrieved and analyzed for VHL mutations. Thirty specimens were successfully analyzed with PCR-SSCP and sequencing. Aberrant SSCP bands were detected in 16 out of the 30 samples (53%). Sequencing analysis of the aberrant bands revealed seven deletions, one insertion, one base substitution on a splicing site, six missense mutations, one silent mutation and several base substitutions in the 5' non-coding region and intron 1. Most were novel somatic mutations that have not been reported in sporadic RCC. The mutations were found in three types of non-papillary RCC cases, i.e. 14 clear cells, one granular chromophilic and one sarcomatoid RCC. Interesting multiple mutations were found in three cases (5, 3, 2 mutations, respectively).

Adult↗
PubMed1999

Familial cancer risks in offspring from discordant parental cancers.

Analysis of familial cancer risks between discordant sites provides etiologic understanding on genetic and environmental risks factors of site-specific cancers. We used the Swedish nation-wide Family-Cancer Database to analyze familial risks in discordant cancers of offspring and parents. Familial risk ratios (FRRs) were calculated for cancer in offspring aged 15 to 53 years at 22 sites, discordant from parental sites. We confirmed many reported associations. Consistent novel findings associated parental-offspring sites of pancreas-breast, breast-testis and uterus-nervous system. For these, the FRRs were modest, 1.2 to 1.5 in the whole Database, but the FRRs increased in those whose parents were diagnosed before age 50. Pancreas and liver cancers showed FRRs of 2.5 to 3.3 in offspring of women and of 1.3 in offspring of men. One or both of these cancers was/were associated with cancers of stomach, colon, breast, uterus, ovary and prostate. Melanoma was associated with pancreas, breast, skin and nervous-system cancers and with leukemias. Myeloma showed a concordant FRR of about 4.0 and was associated with prostate cancer and non-thyroid endocrine-gland cancers. Mutations in known cancer-related genes may explain some of these findings, but new susceptibility genes are yet to be found. For melanoma, pancreatic and liver cancer, environmental factors are important etiologic factors and may contribute to the familial effects observed.

Adolescent↗
PubMed1999

Endogenous and background DNA adducts by methylating and 2-hydroxyethylating agents.

Detection of 7-alkylguanine DNA adducts is useful to assess human exposure to and the resulting DNA damage caused by simple alkylating agents. The background 7-methylguanine (7-MG) and 7-hydroxyethylguanine (7-HEG) adduct levels were determined in human and rat tissues, using thin-layer chromatography (TLC) combined with high pressure liquid chromatography (HPLC). In addition, these two adduct levels were also compared in various tissues between smokers and non-smokers. The results demonstrated that the background level of 7-alkylguanine adducts in WBC and lung tissues of non-smokers was 2.9 and 4.0 adducts/107 nucleotides, respectively. In smokers with lung cancers 7-MG adduct level in lung samples (6.3+/-1.9 adducts/107 nucleotides) and in bronchus samples (6.1+/-1.5 adducts/107 nucleotides) was significantly higher than that in WBC samples (3.3+/-0.9 adducts/107 nucleotides). 7-HEG adduct levels obtained from the same individuals were 0.8+/-0.3 in lung, 1.0+/-0.8 in bronchus and 0.6+/-0.2 adducts/107 nucleotides in WBC, respectively. Animal studies showed that background levels of 7-MG (2.1-2.5 adducts/107 nucleotides) in control rats were approximately 2-4-fold higher than 7-HEG levels (0.6-0.9 adducts/107 nucleotides). After a 3-day exposure to 300 ppm ethene, 7-HEG adducts accumulated to a similar extent in different tissues of rats, with the mean adduct level of 5.6-7.0 in liver, 7.4 in lymphocytes and 5.5 adducts/107 nucleotides in kidney.

Animals↗
PubMed1999

Familial risks in second primary breast cancer based on a family cancer database.

The nationwide Swedish Family Cancer Database was used to analyse the risk of breast cancer in daughters of mothers presenting second, bilateral breast cancer. The database contained information on family relationships and cancers of mothers and daughters when the daughter was born after 1940, totalling 55,411 maternal and 9966 daughters' primary breast cancers. Some 95% of the second breast cancers were diagnosed in the contralateral breast. Familial risk of breast cancer in daughters was 1.70 when the mothers had first breast cancer and 3.28 when the mothers had bilateral breast cancer. Thus, the increased familial effect of the second breast cancer was 1.93. The risk was highest in daughters diagnosed at a young age when the mother was diagnosed before 50 years of age. If the mothers had breast cancer following any other type of cancer, the familial effect was as for the first breast cancer (1.03). The age of onset for breast cancer in daughters was 0.7 years younger for those whose mother had bilateral as compared with unilateral breast cancer, although the difference was not statistically significant. The mothers with bilateral breast cancer whose daughters also had breast cancer were diagnosed with the first breast cancer 3.8 years younger than mothers whose daughters did not have breast cancer. The present results apply to a relatively young population of daughters (< 54 years of age).

Adolescent↗
PubMed1999

Familial cancers in a nationwide family cancer database: age distribution and prevalence.

We calculated sex- and age-specific familial relative risks (FRRs) of cancer in offspring of cancer probands at 19 male and 20 female cancer sites, based on the nationwide Family Cancer Database from Sweden. The proportion of familial cancers among all cancers was also determined. The database contained 550,000 primary cancers. The familial risk at known sites: colon, breast, ovary, testis, skin (melanoma), nervous system, thyroid and other endocrine glands were confirmed. The FRR of thyroid cancer exceeded any other cancer and was over twice as high for male as for female offspring, and appeared to constitute an early- and late-onset component. Novel register-based findings were familial risks in cervical and uterine cancer, and in male offspring of male probands kidney and skin (mainly squamous cell) cancer. Familial risks were noted also for lung cancer, lymphoma and leukaemia but they may have largely environmental causes. The proportion of familial cancers depended on the site, ranging from 11% in prostate to 8.7% in female breast and to well below 1% at many sites.

Adult↗
PubMed1999

Comparison of (32)P-postlabeling and high-resolution GC/MS in quantifying N7-(2-Hydroxyethyl)guanine adducts.

This study compares (32)P-postlabeling and high-resolution gas chromatography/mass spectrometry (GC/MS) in the quantification of N7-(2-hydroxyethyl)guanine adducts (7-HEG) in DNA obtained from the same tissue samples of control rats and rats exposed to ethene. The samples were obtained from two independent studies. In one study, male Sprague-Dawley rats were exposed to 300 ppm ethene for 12 h/day for 3 days ("Euro samples"). In the other study, male F-344 rats were exposed to 3000 ppm ethene for 6 h/day for 5 days ("U.S. samples"). DNA from liver and kidney from the European study was isolated in the European laboratory, and DNA from liver and spleen from the U.S. study was isolated in the U.S. laboratory. The DNA samples were coded, divided into two portions, and exchanged between the two laboratories. All DNA samples from both laboratories were analyzed with respect to 7-HEG adducts by (32)P-postlabeling and high-resolution GC/MS in the European and U.S. laboratories, respectively. However, the U.S. samples were repurified in the European laboratory before the postlabeling analysis. The data from the Euro and the U.S. samples were therefore treated separately in the regression analysis of the (32)P-postlabeling versus GC/MS data. The slope of the regression line for the Euro samples was 1.19 (r = 0.97), implying that the GC/MS data were slightly lower than the postlabeling data (one possible outlier was excluded). The slope of the regression line for the U.S. samples was 0.61 (r = 0.94), implying that the GC/MS data were somewhat higher than the postlabeling data. The main conclusion from this study is that there is very good agreement between the (32)P-postlabeling and high-resolution GC/MS methods in quantifying 7-HEG adducts to DNA, particularly when identical DNA samples are analyzed and the RNA content is <2%. The paper also discusses the background levels of adducts, the interorgan distribution, comparison between different strains, and exposure conditions.

Animals↗
PubMed1999

Modification of cancer risk in offspring by parental cancer (Sweden).

OBJECTIVES: Familial cancer risks were studied in offspring whose parents had a similar (concordant) or a different (discordant) cancer in order to assess the modification of cancer risks from one generation to another. METHODS: We used the nation-wide Swedish Family-Cancer Database to calculate familial rate ratios (FRRs) to the offspring when their parents had concordant and discordant cancers. Cancer sites were included if there was at least one pair of parents with the same cancer. In situ cancers were included in a separate analysis in order to increase the numbers of cases. RESULTS: The risk of colon, all bowel, lung and breast cancer and melanoma increased 1.1-1.2 times when one parent and 1.3-1.6 times when two parents had any discordant cancer, suggesting involvement of environmental and hereditary effects shared by many forms of cancer. When both parents had colon cancer or melanoma, the respective risks in the offspring were 3.0 and 9.3 but only based on single triplets. For all bowel cancer the risk was 3.4, approximately multiplicative from the familial one parent-offspring risk. For concordant lung and breast cancer triplets the risk in offspring was 11.8 and 29.4, respectively. CONCLUSIONS: Even discordant cancer in parents increased cancer risk in offspring. This may be due to environmental and hereditary causes, and deserves consideration in epidemiological studies. The high risks in families where both parents had the same cancer suggest interactions of hereditary and environmental factors.

Adult↗
PubMed1999

In situ repair of cyclobutane pyrimidine dimers and 6-4 photoproducts in human skin exposed to solar simulating radiation.

DNA repair is crucial to the integrity of the human genome. The ultraviolet radiation portion of solar radiation is responsible for the rising incidence of skin cancer, one of the most common types of cancer in humans. We applied a recently developed 32P-postlabeling technique to measure the in situ DNA repair efficiency of solar-simulated radiation induced cyclobutane pyrimidine dimers and 6-4 photoproducts in the skin of nine healthy volunteers with skin type II. Our results show about 6-fold interindividual variations in the level of DNA damage after exposure to an equal biologic dose - 2 minimal erythema doses. The kinetics of DNA repair indicated a base sequence dependence of the repair process. The DNA repair efficiency showed a 20-fold difference in volunteers. An age-related decrease of DNA repair capacity was observed; however, the data are limited due to a small number of subjects and a narrow age range. The variable response in DNA damage levels and individual differences in DNA repair efficiency suggest a susceptible subgroup of people probably with a higher skin cancer risk.

Adult↗
PubMed1999

Identification of the major tamoxifen-DNA adducts in rat liver by mass spectroscopy.

We present here the first mass spectroscopic (MS) identification of the main tamoxifen-induced DNA adducts in rat liver. The two main adducts were isolated by high-performance liquid chromatography (HPLC) and identified by MS, MS-MS and ultraviolet spectroscopy. Adduct 1 was the N-desmethyltamoxifen-deoxyguanosine adduct in which the alpha-position of the metabolite N-desmethyltamoxifen is linked covalently to the amino group of deoxyguanosine. Adduct 2 was confirmed to be the trans isomer of alpha-(N2-deoxyguanosinyl)tamoxifen, as previously suggested by co-chromatography.

Animals↗
PubMed1999

Hprt mutant frequency and aromatic DNA adduct level in non-smoking and smoking lung cancer patients and population controls.

T cell cloning and 32P-post-labelling methods were used to study the mutant frequency (MF) at the hypoxanthine-guanine phosphoribosyl transferase (hprt) locus and the aromatic DNA adduct level (AL) in peripheral lymphocytes of newly diagnosed lung cancer patients (92 ever-smokers and 87 never-smokers) and matched population controls (82 ever-smokers and 79 never-smokers). Overall, the MF (total mean 20.6 x 10(-6)) and AL (4.1 x 10(-8)) were similar in cases and controls with the same smoking status, indicating that the disease has limited effect on the two endpoints. When cases and controls were combined, the AL was significantly higher in current smokers than in former or never-smokers (P = 0.0003) and the MF was significantly higher in ever-smokers than in never-smokers (P = 0.004). Age affected the MF significantly in ever-smokers (1.6%/year, 95% CI 0.6-2.5, adjusted for pack-years and years since last smoking), especially among cases (2.1%/year, 95% CI 0.5-3.7). An increase of AL with age was observed in currently smoking cases only (2.3%/year, 95% CI 0.3-4.2, adjusted for smoking dose). For currently smoking cases, there was also a more pronounced effect of smoking dose on both endpoints and a significant correlation between AL and MF (r = 0.52, P = 0.04) was observed among those with the highest dose. Our data also provide additional evidence for the different turnover times of smoking-induced DNA adducts and hprt mutations. The stronger increase of MF and AL with age and dose in currently smoking patients compared with controls is consistent with an interaction between smoking and genetic host factors.

Adenocarcinoma↗
PubMed1999

Loss of heterozygosity at chromosome 9p21 (INK4-p14ARF locus): homozygous deletions and mutations in the p16 and p14ARF genes in sporadic primary melanomas.

Loss of heterozygosity (LOH) was determined in 45 sporadic primary melanomas at six polymorphic microsatellite markers that flank the INK4a (p16-p14ARF) locus on chromosome 9p21. We also determined allelic loss at two markers on chromosome 9q and two markers at the Rb locus on chromosome 13. Homozygous deletion of the p16 and p14ARF genes was determined by a fluorescent-based quantitative multiplex polymerase chain reaction method. LOH at one or more polymorphic microsatellite markers on locus 9p21 was found in 32 of the melanomas (71%). The highest proportion of LOH was found at markers D9S736 and D9S104, which are telomeric and centromeric to the INK4 locus, respectively. Five melanomas showed LOH at all the analysed markers located on chromosome 9p21. LOH at markers D9S942 and D9S974, which are located close to the p16 and p14ARF genes, was found in 39% and 46% of melanomas, respectively. Analysis of the marker D9S257 on 9q22.1 showed LOH in 13 melanomas (44% of the informative cases). A subset of melanomas with LOH at the INK4 locus also carried inactivating mutations within the p16 coding sequence. Four melanomas carried homozygous deletions at the p16-p14ARF locus. Our results suggest, besides the involvement of the INK4 locus in sporadic melanomas, the possibility of the existence of additional tumour suppressor loci on chromosome 9.

Alleles↗
PubMed1999

Detection of methylation damage in DNA of gastric cancer tissues using 32P postlabelling assay.

Gastric cancer is the most common cancer in Korea. The causes are still unknown but it has been speculated that gastric cancer is associated with consumption of foods rich in nitrates/nitrites or a high dietary intake of salt or pickled food. In the present study, we studied the level of alkylated DNA adducts formed in gastric cancer tissues in comparison with that in normal gastric mucosa. DNA was extracted from surgically removed gastric cancer tissues and patient-matched normal gastric mucosa. The level of N7-methyldeoxyguanosine was measured by 32P-postlabelling assay after high performance liquid chromatography (HPLC) enrichment. We found that the level of N7-methyldeoxyguanosine of gastric cancerous tissues was significantly higher than that of normal gastric mucosa (P=0.01685).

Adenocarcinoma↗
PubMed1999

Genotoxic exposures of potroom workers.

OBJECTIVES: Potroom workers in aluminum reduction plants have increased risks for bladder and lung cancer due to exposure from polycyclic aromatic hydrocarbons (PAH). In this study correlations between measures of the external, internal, and biological effective dose have been studied for PAH. METHODS: Venous blood samples were obtained from 98 male potroom workers and 55 unexposed male blue-collar workers, for the analysis of aromatic adducts to DNA (deoxyribonucleic acid) in lymphocytes, using the 32P-postlabeling technique. 1-Hydroxypyrene in urine was analyzed with high-pressure liquid chromatography. Personal sampling of both particulate and gas phase PAH was performed during a full workday for the potroom workers and for 5 referents. Individual PAH congeners were determined with liquid chromatographic-mass spectrometric and gas chromatographic-mass spectrometric techniques. RESULTS: The respiratory-zone airborne level of the sum of 22 particulate (median 13.2 micro/m3) and the 7 gas phase PAH-congeners (median 16.3 microg/m3) among the potroom workers was a hundred times higher than among the referents. The urinary concentration of 1-hydroxypyrene before work was 30 times higher for the potroom workers (median 3.43 micromol/mol creatinine) than for the referents. Most airborne PAH congeners correlated with the excretion of 1-hydroxypyrene in urine. The frequency of aromatic DNA adducts did not, however, differ between the potroom workers and the referents, and no correlation was found for 1-hydroxypyrene in urine. CONCLUSIONS: Despite an obvious occupational exposure to PAH, no increase in aromatic DNA adducts in lymphocytes was found among the potroom workers.

Adult↗