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Biomedical subjects

K Hemminki

Publications and source records attributed to K Hemminki.

At least 181 records · Page 10Linked to original sources
PubMed1999

Parental age as a risk factor of childhood leukemia and brain cancer in offspring.

We use here the Swedish Family-Cancer Database to analyze the time trends in childhood leukemia and brain cancer between 1960 and 1994 and the effect of parental age on childhood leukemia and brain cancer of some 1500 cases each. The database includes all persons born in Sweden after 1940 with their biological parents, over 6 million individuals, whose cancers were retrieved from the Swedish Cancer Registry from years 1958-1994. Incidence in cancer increased from 1960 to 1994; low grade astrocytoma accounted for most of the increase, whereas high grade astrocytoma has not increased in incidence. There has been a moderate increase in leukemia to about 1980. We found a parental age effect for both leukemia and brain cancer, with the former (of about 50% excess in those over 35 years) being mediated by maternal age and the latter (of about 25% excess) by paternal age. Accumulation of chromosomal aberrations and mutations during the maturation of germ cells is a likely mechanism for these findings. They can help to explain partially the secular trends of these malignancies and the excess risks in offspring of the well educated.

Adolescent↗
PubMed1999

Parental age and risk of sporadic and familial cancer in offspring: implications for germ cell mutagenesis.

We used the nationwide Swedish Family-Cancer Database to analyze the effect of parental age on cancer in offspring at ages 15-53 years. We studied 13 cancer sites, including 37,877 people. Data on familial and sporadic cancers were analyzed separately. We adjusted for age of spouse, year of diagnosis, and birth order. Rate ratios (RRs) were calculated by Poisson regression. Maternal age was associated with sporadic melanoma and leukemia, causing a 30% excess if mothers were more than 40 years vs. less than 20 years of age. A marginal effect of about 10% of both maternal and paternal age was observed for sporadic breast cancer. Paternal age increased the RR of sporadic nervous system cancer by about 15%. Accumulation of chromosomal aberrations and mutations during the maturation of germ cells may be a mechanism for these findings. In familial cancers of colon, melanoma, and thyroid, higher age showed an apparent protective effect, which was also noted for sporadic cervical cancer and melanoma. The results argue against major age-induced mutagenic/carcinogenic effects on germ cells as well as against age-induced adverse cancer-related hormonal effects during pregnancy. Because two or more mutations are required for adult cancers, however, these cancers may be an insensitive indicator of germ cell mutagenesis.

Adolescent↗
PubMed1999

Environmental pollution and human exposure to polycyclic aromatic hydrocarbons in the east Baltic region.

Environmental contamination by polycyclic aromatic hydrocarbons (PAH) and human exposure were surveyed in the east Baltic region. Polluted and heavily industrialized areas are upper Silesia in Poland, northern Bohemia in the Czech Republic, and the northeast part of Estonia. In Estonia the pollution is in a defined geographic area, where lung cancer incidence is higher than elsewhere. In Silesia, exposure of some 5 million people appears to be elevated; DNA (deoxyribonucleic acid) adduct levels in white blood cells are increased in groups of residents with apparently only environmental exposure. By extrapolation, some 150 annual lung cancer cases could be predicted due to PAH in Silesia. Air levels of benzo[a]pyrene were increased in northern Bohemia, and domestic heating and power plants using brown coal appeared to be major contributors to particulate air pollution in winter. Further studies are needed to assess health risks of PAH exposure in central and eastern Europe.

Animals↗
PubMed1999

Endometrial cancer in the family-cancer database.

Endometrial cancer was studied in the Swedish Family-Cancer Database, updated in 1999 to cover individuals born after 1934 with their biological parents, totaling 9.6 million persons. Cancer data were obtained from the Swedish Cancer Registry from 1958 to 1996 and included over 20,000 cases of endometrial cancer. Seventy-six families were identified in which both the mother and the daughter had endometrial cancer, giving a familial standardized incidence ratio (SIR) of 3.19 for daughters and 2.78 for mothers. The risk depended inversely on the age at diagnosis, and the risk was almost 10 in daughters who were diagnosed before age 50 when their mothers were also diagnosed before that age. The discordant cancer site that associated with endometrial cancer between the two generations was colon, with a SIR of 1.44-1.68. However, when the maternal endometrial cancer was diagnosed before age 50, increased SIRs were observed in daughters or sons for rectal, pancreatic, nervous system, breast, and ovarian cancers. Second cancers were followed in females diagnosed with endometrial cancer, and the highest overall risks were observed for ovarian and connective tissue cancers; colorectal cancers were also clearly in excess. Among the other family members of the 76 families in which both mother and daughter were affected with endometrial cancer, there were 11 cases of colorectal cancer. When a sister was affected in such families, the SIR of endometrial cancer was 31.40, and the median diagnostic age was several years lower than in endometrial cancer families in which no colorectal cancers were found. Many of these families may have hereditary nonpolyposis colorectal carcinoma syndrome. However, the risk of endometrial cancer was increased even in families presenting no colorectal cancers.

Adolescent↗
PubMed1999

32P-postlabelling with high-performance liquid chromatography for analysis of abundant DNA adducts in human tissues.

Abundant complex DNA adducts can be detected in human tissues by a combined 32P-postlabelling and high-performance liquid chromatography (HPLC) method. The HPLC profiles reveal a panorama of nuclease P1-resistant human adducts, which are not among the known human DNA adducts and are suspected of being endogenous. Lipid peroxidation-induced DNA adducts and I-compounds are two possible candidates for these adducts. Therefore, we performed two experiments: one was to identify chromatographically the lipid peroxidation-induced adducts among other human adducts with two acrolein- and crotonaldehyde-derived propano adduct standards (Acr-dG3 and Cro-dG1&2) and a structurally unknown adduct (Cro-DNA) derived from crotonaldehyde-treated DNA; and the other was to analyse the adducts in breast tissue from patients with breast cancer and from controls and to compare their behaviour with that of I-compounds in cancerous tissues. In the first experiment, Acr-dG3 and Cro-dG1 were detected in three human lung tissues, at levels ranging from 3.4 to 8.9 (x 10(-8)) and from not detectable to 2.9 (x 10(-8)), respectively. Acr-dG3 and Cro-DNA were detected in three human colon tissues, at levels of 0.2-0.4 (x 10(-8)) and 1.2-3.4 (x 10(-8)), respectively. In the second experiment, adjacent and tumorous breast tissues from 15 patients with breast cancer (of an average age of 33.4 years) and normal breast tissue from 18 controls (of an average age of 57.3) were analysed for the abundant complex adducts. The total adduct levels in the adjacent and tumorous tissues were lower than in the normal tissues (with medians of 8.0, 11.8 and 13.3 (x 10(-7)), respectively). Significant differences in the adduct levels between adjacent or tumorous tissues and normal tissues were observed in three HPLC peaks, and age was significantly associated with three peaks. These results are consistent with our speculation that the abundant adducts are comprised of lipid peroxidation-induced adducts and human homologues of I-compounds.

Acrolein↗
PubMed1998

32P-postlabelling of N6-adenine adducts of epoxybutanediol in vivo after 1,3-butadiene exposure.

Epoxybutanediol is one of the epoxide metabolites of butadiene (BD). A pair of diastereomeric N-1-adenine adducts were formed by reacting epoxybutanediol with deoxyadenosine 5'-monophosphate (5'-dAMP). These two N-1-adenine adducts rearranged in a base-catalysed reaction to an N6-trihydroxybutyl-adenine adduct, which was characterized by UV and mass spectroscopy. Using the 32P-postlabelling/HPLC assay the same adducts were detected in diepoxybutane (DEB)-treated DNA in vitro and in liver DNA samples from rats exposed to BD by inhalation. Adenine adducts of epoxybutanediol are probably suitable for monitoring BD exposure.

Animals↗
PubMed1998

DNA binding of tamoxifen and its analogues: identification of the tamoxifen-DNA adducts in rat liver.

DNA binding of tamoxifen and some structurally-related drugs (toremifene, clomiphene, triparanol and raloxifene) in rat liver was studied using the 32P-postlabelling method. As only tamoxifen was shown to form high levels of DNA adducts, the identity of these adducts was studied. Recently, we have identified by mass spectroscopy the two main tamoxifen adducts in rat liver DNA as the N-desmethyltamoxifen and tamoxifen adducts of N2-deoxyguanosine in which the linkage is through alpha-carbon in the tamoxifen structure. Minor adducts were identical to different diastereomers of alpha-(N2-deoxyguanosinyl)tamoxifen and of alpha-(N6-deoxyadenosinyl)tamoxifen. Altogether these adducts accounted for at least 95% of adducts formed in vivo, implicating that the alpha-hydroxylation of the ethyl group is the major activation pathway for DNA adducts.

Animals↗
PubMed1998

Abundant lipophilic DNA adducts in human tissues.

Lipophilic DNA adducts are a complex group of structurally unidentified DNA adducts present in human DNA which can be extracted to 1-butanol and are well retained in C-18 columns during HPLC analysis. Levels of these lipophilic adducts when determined by 32H-HPLC are high. Their abundance highlights the importance of further study. In this study, the lipophilic adducts were analysed by 32H-HPLC in human lung, lymphocyte, breast, skin, colon and endometrial tissues. Tissue-specific patterns of the adducts were shown and the adduct levels in these tissues were 9.7, 13.8, 8.9, 17. 0, 1.8 and 2.3x10-7, respectively. In order to find the possible sources of the lipophilic DNA adducts, effects of cigarette smoking, occupational exposure to PAHs, and age on adduct levels in lymphocytes were examined by analyzing samples collected from 20 Swedish elderly volunteers with a mean age of 55 (10 smokers and 10 non-smokers) and 20 Swedish younger aluminium and control workers with a mean age of 39. Exposures to cigarette smoke and PAHs did not increase total adduct levels nor the levels of major, individual adducts. The total adduct levels in the elderly volunteers and the younger workers were (13.7+/-4.7)/107 and (13.8+/-8.0)/107, respectively, not influenced by age. But the levels of two major HPLC fractions in the elderly volunteers differed significantly from those in the younger workers (25.1/108 vs. 8.7/108 (P<0.0001), and 15.4/108 vs. 28.5/108 (P<0.01), respectively). These results suggested a possible endogenous origin of some of the lipophilic DNA adducts. In further support of this speculation, by comparing migration properties in HPLC and TLC of human adducts with a standard, we found an adduct in human lung tissue that was putatively induced by 2,3-epoxy-4-hydroxynonenal which is an epoxidation product of 4-hydroxynonenal, a major product of lipid peroxidation.

Adult↗
PubMed1998

Age-specific familial risks in common cancers of the offspring.

Quantitative data on familial cancer risks are important for clinical, psychological and scientific reasons. The available estimates carry many uncertainties due to sample size and possible bias in data collection and often refer to first-degree relatives of unspecified age and sex. We calculated sex- and age-specific familial hazard ratios (FHRs) of cancer in offspring aged 15-53 years of cancer probands at 16 male and 17 female cancer sites, based on registered nation-wide data, free from bias. The familial risks in offspring were high, > 5 for thyroid (FHR 10.7 in all offspring, CI 95% 6.9-16.6), and testicular cancer (FHR 5.4, CI 95% 2.6-11.3), or intermediate, FHR 2-5, for colon, rectal, lung, breast, cervical, uterine, ovarian, skin (melanoma and squamous cell) and other endocrine gland cancers. FHRs < 2.0 were observed for stomach, renal and nervous system cancers, lymphomas and leukemias. Some sex differences were observed: FHRs for male breast (only 2 cases) and thyroid cancers were over 2 times higher than the respective female ones. When parents were diagnosed before age 50 years, offspring were at an increased risk of familial breast, renal, skin (melanoma), nervous system, thyroid and non-thyroid endocrine gland cancers, particularly affecting young (< 40 years) individuals. The parental diagnostic age also affected offspring's risk of colon, rectal, uterine and ovarian cancers, but young individuals were not at a particular risk. No effect of age was noted for cervical cancer and lymphoma.

Adult↗
PubMed1998

Familial breast cancer in the family-cancer database.

We use the population-based Family-Cancer Database from Sweden to study familial breast cancer. The size of the population and the nation-wide registration of cancer offer unique possibilities for epidemiological studies of familial cancer, including complete and unbiased identification of cases in the probands and in their relatives, and complete and unbiased identification of the family relationships. Using the Database, we wanted to answer the following questions: (i) proportion of familial breast cancer among all breast cancers; (ii) familial relative risks in breast cancer alone or in combination with another cancer, defined either through the mother or the daughter; (iii) modification of familial risk by age; and (iv) effects of paternal breast cancer alone or in combination with maternal breast cancer. The proportion of familial female breast cancer among all breast cancers before 54 years of age in Sweden was 8.7%. The familial relative risk was about 1.8, but is likely to decrease to about 1.5 in the ageing population. The higher familial relative risks were evident in young women, being 4.0 when both the mothers and their daughters were diagnosed at ages <40 years. Paternal breast cancer, in combination with maternal breast cancer, caused a large (but not statistically significant) risk in the daughters. In mothers and daughters, ovarian but not colon cancer was increased in combination with breast cancer.

Adult↗
PubMed1998

Ultraviolet B-induced DNA damage in human skin and its modulation by a sunscreen.

The UVB component of solar radiation is a risk factor for skin cancer, the most common cancer in the Western world. Yet little is known about the induction of DNA damage in human skin by UVB and its modulation by sunscreens. Here, we apply a novel postlabeling high-performance liquid chromatography technique to quantify UVB-induced photoproducts in skin biopsies with and without sunscreen. The results showed approximately 30-fold interindividual variations in levels of DNA damage in unprotected skin of the 14 subjects, probably relating to skin cancer susceptibility. On average, sunscreen guards against DNA damage as expected by the erythemal response, but some individuals are poorly protected.

Adolescent↗
PubMed1998

Modulation of DNA adduct levels in human mononuclear white blood cells and granulocytes by CYP1A1 CYP2D6 and GSTM1 genetic polymorphisms.

The CYP1A1, CYP2D6 and GSTM1 genes encode biotransforming enzymes involved in activation and detoxification of xenobiotics. Metabolically activated chemical compounds may interact with DNA and form adducts. In this study, the effect of the GSTM1, CYP1A1 exon 7 and CYP2D6 polymorphisms on DNA adduct levels was studied in 170 healthy volunteers. DNA adducts levels were measured by 32P-postlabelling in mononuclear white blood cells (WBC, lymphocytes and monocytes) and granulocytes collected in summer and winter. The influence of the genotype on the level of DNA adducts in both types of WBCs was observed only in summer samples. Individuals with GSTM1 deficient (null) genotype had significantly elevated level of adducts in mononuclear WBCs (p = 0.045) and granulocytes (p = 0.031) compared to GSTM1 positives. Higher adduct levels in carriers of combined GSTM1(null)/CYP1A1-Ile/Val genotype were found in both types of WBCs when compared to GSTM1(+)/CYP1A1-Ile/Ile genotype carriers (p = 0.046 in granulocytes, p = 0.092 in mononuclear WBCs). CYP2D6 wild-type homozygotes (EMs) and heterozygotes (HEMs) were shown to have significantly higher mononuclear WBC DNA adduct levels than mutant homozygotes (PMs) (p = 0.037 and p = 0.014). When confounding factors associated with PAH exposure were taken into account a statistically significant effect of CYP1A1 exon 7 polymorphism on DNA adduct levels was found (p = 0.012 in mononuclear WBCs, p = 0.043 in granulocytes). In a subgroup of current smokers (n = 95) high DNA adduct levels in granulocytes were associated with GSTM1(null) genotype, and increased adduct levels in mononuclear WBCs correlated with CYP2D6 EM and HEM genotypes. In winter samples the association between the genotype and DNA adduct levels was not observed.

Adult↗
PubMed1998

DNA adduct formation by tamoxifen and structurally-related compounds in rat liver.

Binding of diethylstilbestrol and four different triphenylethylene derivatives: tamoxifen, toremifene, clomiphene and triparanol to DNA in rat liver, was studied using the 32P-postlabelling method with HPLC-radioactivity detection. Three different modifications of the 32P-postlabelling technique (a) a bisphosphate method with adduct enrichment by nuclease P1 (NP1)-treatment or (b) by butanol extraction and (c) a monophosphate method, were applied in order to provide an unbiased analysis of adduct formation. When tamoxifen was administered by daily gavage for 4 weeks (80 mumol/kg for 2 weeks and 40 mumol/kg for a further 2 weeks) two major adducts and about six minor adducts were produced in the liver of female Sprague-Dawley rats. Equimolar doses of toremifene produced one apparent adduct. The adduct levels in the tamoxifen and toremifene treated rats were 600 and 2/10(8) nucleotides, respectively. Under conditions used, clomiphene, triparanol and diethylstilbestrol did not produce DNA adducts. The present and previous data suggest that modification (a) is the 32P-postlabelling method of choice for risk assessment in human subjects. Modification (c) with butanol extraction after labelling has the advantage of low background radioactivity and may be preferable if large amounts of DNA are available. The main tamoxifen adducts were suggested to be alpha-(N2-deoxyguanosinyl)tamoxifen and alpha-(N2-deoxyguanosinyl)-N-desmethyltamoxifen.

Animals↗
PubMed1998

Sensitive 32P-HPLC technique shows base sequence dependent differences in photolesion repair in human keratinocytes.

Understanding the basis for individual susceptibility to skin cancer requires an understanding of the factors contributing to tumorigenesis. One such factor is the ability of the cell to repair DNA lesions induced following insult to the genome. Currently, research in this field is hampered by the lack of a suitably sensitive and specific method for the detection of DNA lesions. Developed previously 32P-HPLC in vitro analysis is applied in this study to measure UVB-induced dipyrimidine photolesions in human keratinocyte cultures. The high sensitivity of this method permitted the detection of individual cyclobutane pyrimidine dimers and 6-4 photoproducts in cells irradiated with UVB at doses below one minimal erythema dose. Using this technique one could detect approximately a 2-fold difference in a base sequence repair of photolesions. The rates of repair in the chromosomally unstable HaCaT keratinocyte cell line and in cultured primary human keratinocytes were compared. The presented data indicate the potential of the 32P-HPLC method for the study of DNA repair in cultured cells as well as for biomonitoring studies in humans.

Cells, Cultured↗
PubMed1998

Mutations in the CDKN2A (p16INK4a) gene in microdissected sporadic primary melanomas.

The role of the CDKN2A (p16INK4a) gene in sporadic primary melanomas has remained unclear due to the inadequate number of mutational studies. In the present study, we analyzed the entire coding region of the CDKN2A gene in microdissected sporadic primary melanomas, for the presence of mutations and polymorphisms, using 2 independent methods of mutation detection, SSCP and CMC. We found 11 intragenic mutations in 8 melanomas out of 31 (26%) and the majority of mutations were located in exon 1, with 2 cases harbouring multiple mutations. Of the mutations detected, 6 were C-to-T transitions, 4 involving CC sites; 2 melanomas showed a novel deletion of one of the two 24-bp repeat units located at the 5' end of exon 1. There was also a high frequency of C-to-G and C-to-T polymorphisms at the nucleotides 540 (frequency of G allele: 0.18) and 580 (frequency of T allele: 0.13) in the 3' untranslated region.

Cyclin-Dependent Kinase Inhibitor p16↗
PubMed1998

Selective deletion of exon 1 beta of the p19ARF gene in metastatic melanoma cell lines.

The INK4A locus on 9p21 is deleted or rearranged in a large number of human cancers. The locus encodes two unrelated and independently acting negative cell-cycle regulators, p16 and p19ARF, arising in alternate reading frames from a partly shared sequence. We analyzed five human melanoma cell lines for deletions at the INK4 loci and flanking microsatellite markers on 9p21. All the cell lines displayed deletions of varying sizes. The metastatic cell line IGR-1 showed a large deletion between the markers D9S736 and D9S171. In the cell lines WM-115 and WM-266-4, the deletion included exon 1alpha of p16, exon 1beta of p19ARF, and exon 2 of the INK4B (p15) gene. Two cell lines, SK-MEL-5 and A2058, had deletions confined to exon 1beta and the microsatellite marker D9S942. RT-PCR experiments showed the presence of the p16 and p15 transcripts and absence of p19ARF expression in both SK-MEL-5 and A2058 cell lines. The selective loss of the exon 1beta of p19ARF and retention of the p16 and p15 genes and their expressions in these two cell lines support the putative tumor suppressor role for the alternate reading frame p19ARF gene.

Cell Cycle Proteins↗