PubMed Health⌕ Search

Biomedical subjects

Kari Hemminki

Publications and source records attributed to Kari Hemminki.

At least 217 records · Page 12Linked to original sources
PubMed2002

In situ repair of cyclobutane pyrimidine dimers in skin and melanocytic nevi of cutaneous melanoma patients.

The development of cutaneous malignant melanoma (CMM) and its precursor lesions, melanocytic nevi, has been linked to sun exposure. Cyclobutane pyrimidine dimers (CPDs) are the majority of DNA lesions induced by sun exposure. In our study, we investigated if CMM patients have impaired ability to repair CPDs in skin as well as in melanocytic nevi. The repair kinetics were followed up to 3 weeks after exposure to 40 mJ/cm(2) of solar simulating radiation. Altogether 12 CMM patients and 10 healthy controls were included in our study. Buttock skin biopsies were taken at 0 hr, 48 hr and 3 weeks after UV exposure, whereas melanocytic nevi and surrounding skin biopsies were taken only at 0 hr and 3 weeks. The CPD levels were measured by a (32)P-postlabeling method. The results showed that the repair rate of CPDs in neither the skin nor the nevi was significantly different between the CMM patients and the control group. For both groups, the repair rate of TT = C was faster than that for TT = T. The important finding is that about 10% of the initial TT = T damage remained unrepaired after 3 weeks, and was detectable in normal epidermis as well as in nevi of all subjects. We also found that the amount of TT = C and TT = T at 0 hr in nevi was significantly lower than that in surrounding skin (Wilcoxon rank sum test, p < 0.05).

Adult↗
PubMed2002

CDH1 mutations are present in both ductal and lobular breast cancer, but promoter allelic variants show no detectable breast cancer risk.

Mutations and diminished expression of the E-cadherin gene (CDH1) have been identified in a number of epithelial malignancies. Although somatic CDH1 mutations were detected in lobular breast cancer with a frequency ranging from 10-56%, CDH1 alterations in more frequent ductal tumors appear to be rare. Here we have analyzed the coding region of CDH1 for mutations using denaturing high performance liquid chromatography and found 4 mutations in 83 ductal carcinomas (5%) and 3 mutations in 25 lobular carcinomas (12%). The germline of 13 patients with familial lobular tumors was also analyzed for mutations, but none were detected. In a case-control study, we also tested whether a variant adenine allele in the promoter polymorphism -161C-->A with a putative influence on the transcriptional activity of CDH1 in vitro confers any detectable risk of breast cancer. No significant difference in the allelic frequency between patients with breast cancer (326/1,152, 28.3%) and controls (190/696, 27.3%, p > 0.05; relative risk 1.05, 95% confidence interval 0.85-1.30) was found. A novel promoter polymorphism was identified at position -152, but the frequency of the variant cytosine allele was also similar in patients with breast cancer and controls (0.71% vs. 0.21%, p = 0.23). Transient transfection experiments using reporter constructs containing the nucleotide substitutions -161C/-152C and -161A/-152T showed only a slight decrease in the transcription activity compared to the wild-type construct. These results do not support CDH1 as a prominent low-penetrance cancer susceptibility gene, but indicate that CDH1 mutations contribute to the progression of both lobular and ductal tumors.

Adenine Nucleotides↗
PubMed2002

Familial and second esophageal cancers: a nation-wide epidemiologic study from Sweden.

A few case-control studies have been published on familial risks in esophageal cancer. Reliable data on familial risks are needed for prevention and clinical decisions. We used the nation-wide Swedish Family-Cancer Database on 10.1 million individuals and close to 6000 esophageal cancers to calculate standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) for esophageal cancer in 0-66-year-old offspring by cancers in family members. Additionally, SIRs for second esophageal cancers were analyzed. The SIR for esophageal cancer was 3.91 (95% CI 1.55-7.35) when a parent presented with esophageal cancer and 4.91 (95% CI 1.77-9.62) when a parent presented with squamous cell carcinoma. The sibling risk for esophageal cancer was increased but was based on 1 pair only. The population-attributable proportion of familial esophageal cancer was 0.70%. Risks for second esophageal cancers were increased after upper aerodigestive tract, esophageal, stomach, larynx, and lung cancers. The data on second cancers suggest that environmental factors are important for esophageal cancer and probably contribute to the familial clustering. However, the high familial risk of 3.91 is unlikely without the involvement of heritable factors. The population-attributable proportion of familial esophageal cancer is small.

Adolescent↗
PubMed2002

Familial and second gastric carcinomas: a nationwide epidemiologic study from Sweden.

BACKGROUND: Familial risks in gastric carcinoma have been assessed mainly through case-control studies based on reported but not medically verified carcinomas in family members. Reliable data on familial risks are needed for prevention and clinical decisions. METHODS: The authors used the nationwide Swedish Family-Cancer Database on 10.2 million individuals and more than 34,000 gastric carcinomas to calculate standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) for gastric carcinoma in offspring, from birth to 66 years old, by carcinomas in family members. In addition, SIRs for second gastric carcinomas were analyzed. RESULTS: Standardized incidence ratios for gastric carcinoma were 1.31 (95% CI, 0.97-1.70) and 1.47 (95% CI, 1.08-1.92) when a parent presented with gastric carcinoma or gastric adenocarcinoma, respectively. The risk was 1.59 (95% CI, 1.10-2.16) in offspring whose diagnosis was at ages older than 50 years. Offspring risk from parental corpus carcinoma was of borderline significance whereas that from cardia carcinoma was below unity. The sibling risk for gastric carcinoma was 3.16 (95% CI, 1.35-5.72) and 5.75 (95% CI, 2.07-11.26) when diagnosed before age 50. The population attributable proportion of familial gastric carcinoma was 0.45%. Risks for second gastric carcinomas were increased in men and women after esophageal and skin carcinomas, and after non-Hodgkin lymphoma. CONCLUSIONS: The data suggest that environmental factors, perhaps Helicobacter pylori infections are the main reason for familial clustering of gastric carcinoma. The population attributable proportion of familial gastric carcinoma is much lower than that cited in the literature. The patterns of multiple carcinomas suggest that immunologic factors modulate susceptibility to gastric carcinoma.

Adult↗
PubMed2002

Time trends in the incidence of cervical and other genital squamous cell carcinomas and adenocarcinomas in Sweden, 1958-1996.

OBJECTIVES: We wanted to examine reasons for the different incidence trends for cervical squamous cell carcinoma (SCC, declining) and adenocarcinoma (increasing). METHODS: The Swedish Family-Cancer Database on 9.6 million individuals was used to derive incidence trends between 1958 and 1996. Cervical cancers were compared to vaginal and vulvar cancers. RESULTS: A total of 15405 invasive cervical SCCs and 1920 adenocarcinomas were identified. The incidence of SCCs decreased and that of adenocarcinoma increased during the study period, with similar trends among the in situ forms. The incidence of in situ vaginal and vulvar SCC increase 22-fold, whereas, invasive SCC and adenocarcinoma remained unchanged. The age-incidence curves for adenocarcinoma resembled those for SCC before screening, suggesting similar clinical course. CONCLUSIONS: The data suggest that the increase in the incidence of adenocarcinoma is related to an increasing prevalence of human papilloma virus (HPV) infection in female genitals, perhaps in addition to other factors. The increase is not seen in SCC because of effective screening.

Adenocarcinoma↗
PubMed2002

Significant impact of promoter hypermethylation and the 540 C>T polymorphism of CDKN2A in cutaneous melanoma of the vertical growth phase.

Promoter hypermethylation, mutations, and loss of heterozygosity in the CDKN2A gene as well as polymorphisms at the 3'-untranslated region were determined in vertical growth phase melanomas. Methylation-specific polymerase chain reaction in soluti and in situ showed that 19% of the cases were hypermethylated at the CDKN2A promoter region, and some of these cases were heterogeneous with both methylated and unmethylated tumor cells. Methylation was associated with increased tumor cell proliferation by Ki-67 expression (P = 0.01) and decreased patient survival (P = 0.025). Point mutations in CDKN2A were found in 4% of the cases, whereas 90% had loss of heterozygosity at one or more of 4 markers studied. Furthermore, presence of the 540 C>T polymorphism at the 3'-untranslated region of CDKN2A (23%) was associated with improved survival in multivariate analysis (hazard ratio, 2.6; P = 0.02). Our results suggest that promoter methylation of the CDKN2A gene is present in a subgroup of the tumors and associated with increased tumor cell proliferation and reduced survival. Further, the 540 C>T polymorphism might define a distinct subgroup of low-grade vertical growth phase melanomas. These findings support a significant role of the CDKN2A gene in melanoma progression.

Cell Division↗
PubMed2002

Parental cancer as a risk factor for bone cancer: a nation-wide study from Sweden.

We used the nation-wide Swedish Family-Cancer Database to analyze the risk for bone cancer in offspring by parental cancers and in siblings of bone cancer probands. Additionally, the risk of second cancer following childhood bone cancer was investigated. In offspring, 1,190 bone cancers were diagnosed between years 1958 and 1996. Groups of offspring were compared by calculating standardized incidence ratios (SIRs) for bone cancer. Most bone cancer cases occurred sporadically. Parental breast (SIR 1.7) and prostate (SIR 1.7) cancers were associated with early-onset (<25 years) osteosarcoma in offspring, probably due to Li-Fraumeni syndrome. Giant cell sarcoma was increased by parental breast cancer (SIR 2.9), and early-onset chondrosarcoma by parental kidney cancers (SIR 6.8). Bone cancers conveyed a high risk of second bone and connective tissue cancer.

Adolescent↗
PubMed2002

Spectrum of styrene-induced DNA adducts: the relationship to other biomarkers and prospects in human biomonitoring.

Styrene is an important industrial chemical that has shown genotoxicity in many toxicology assays. This is believed to be related to the DNA-binding properties of styrene-7,8-oxide (SO), a major metabolite of styrene. In this review, we have summarized knowledge on various aspects of styrene genotoxicity, especially in order to understand the formation and removal of primary DNA lesions, and the usefulness of biomarkers for risk assessment. Biological significances of specific DNA adducts and their role in the cascade of genotoxic events are discussed. Links between markers of external and internal exposure are evaluated, as well as metabolic aspects leading to the formation of DNA adducts and influencing biomarkers of biological effect. Finally, we suggest a design of a population study, which may contribute to our understanding genotoxic events in the exposure either to single xenobiotic or complex mixture.

Animals↗
PubMed2002

Ultraviolet photoproduct levels in melanocytic nevi and surrounding epidermis in human skin in situ.

Melanocytic nevi are localized benign proliferations of melanocytes. The number of nevi has been shown to be the major risk marker for the development of cutaneous melanoma. This study compares the induction of photoproducts in nevi and in surrounding skin after exposure to solar-simulating radiation. Cyclobutane pyrimidine dimers (TT=T and TT=C) and 6-4 photoproducts (TT-T and TT-C) were measured in 20 nevi and 20 surrounding skin samples obtained from 14 subjects, using a 32P-postlabeling method. The amount of all four types of photoproducts in nevi was found to be 3-5-fold lower than that in surrounding skin, and the difference was statistically significant (paired t test, p < 0.01). In nevi, the photoproduct level was significantly associated with the color of nevi (the lowest level in the darkest color of nevi; r = -0.86, p < 0.01 for TT=T; r = -0.68, p < 0.01 for TT=C). Our findings suggest that the magnitude of the DNA damage is not a sole risk marker for the development of cutaneous melanoma.

Adult↗
PubMed2002

How fast are UV-dimers repaired in human skin DNA in situ?

Sheehan et al (2002) published a paper on UV-dimers in human skin and their repair with contradictions in their own data. In one experiment they applied two doses, 0.65 and 2 MED, but the apparent dimer levels, measured by a immunohistochemical technique, only increased in skin of type II (Fig 2a). The authors offered as explanation that the level of DNA damage would saturate. The dimer levels reached are at around 1 dimer per 1 million nucleotides, and there has been no evidence for saturation when a quantitative postlabeling technique has been used (Bykov et al, 1998). There is no reason for saturation until most of the thydmidyl-thymidine positions would be occupied in DNA, which, based on literature with other intrastrand cross-linkers, would require dimer levels 1 : 100 (Försti et al, 1989), or 10,000 times higher levels of dimer than that obtained by an irradiation at a MED dose.

DNA Repair↗
PubMed2002

Kidney cancer in the Swedish Family Cancer Database: familial risks and second primary malignancies.

BACKGROUND: Familial risks in kidney cancer and association with second primary malignancies were studied using the nationwide Swedish Family Cancer Database. METHODS: Cancer data were retrieved from the Swedish Cancer Registry from years 1961 to 1998 and included 23,137 cases of kidney cancer. Standardized incidence ratios (SIRs) were used to measure the cancer risks. RESULTS: Seventy-one families were identified where both a parent and an offspring had kidney cancer, giving a familial risk for offspring of 1.56 (1.22 to 1.95) and population attributable proportion of 0.78%. A risk for kidney cancer from an affected sibling was considerably higher with a SIR of 4.72 (2.28 to 9.20), giving an attributable proportion of 0.77%. The discordant tumor site that was associated with kidney cancer between two generations was hemangioblastoma of central nervous system. Discordant cancer sites that were associated with kidney cancer in siblings were ovaries, endocrine glands and pancreas. There was an over threefold increase of second primary malignancies of the urinary bladder, nervous system and endocrine gland in kidney cancer patients. The risks for second primary hemangioblastoma following kidney cancer or familial kidney cancer was 21.19 (6.69 to 43.83) and 1206 (114 to 3456), respectively. CONCLUSIONS: The high ratio of sibling risk to offspring risk in kidney cancer may reflect a recessive susceptibility. The high risk for second primary cancers in the patients without family history is consistent with a polygenic model and variable degree of environmental modification.

Adolescent↗
PubMed2002

The in vivo levels of DNA alkylation products in human lymphocytes are not age dependent: an assay of 7-methyl- and 7-(2-hydroxyethyl)-guanine DNA adducts.

Endogenous DNA damage is assumed to be a major contributor to aging and cancer. This study compares the steady-state levels of 7-methyl- and 7-(2-hydroxyethyl)-guanine DNA adducts in lymphocytes isolated from the younger (mean age 39.8 years) and the older (mean age 82.8 years) healthy subjects. Using a 32P-post-labelling method, these adducts were measured in lymphocyte DNA from a total of 34 subjects. The results show that the amount of both 7-methyl- and 7-(2-hydroxyethyl)-guanine adducts in the younger age group was similar to that in the older age group. Our findings show that at steady-state the levels of DNA alkylation products are independent of age, suggesting that endogenous DNA damage, through methylation or lipid peroxidation, and the repair of such damage may not be deficient in lymphocytes of older individuals.

Adult↗
PubMed2002

Skilled use of DNA polymorphisms as a tool for polygenic cancers.

Association studies are assumed to be an efficient method of deciding whether a gene or its variant is important for cancer. Sequencing data on 30 000 human genes suggest that an average gene contains one to two single nucleotide polymorphisms (SNP), and high through-put technologies have become available for fast genotyping. Because no functional data are available for most SNPs, the result of the large-scale genotyping effort will be a huge amount of data of unknown biological significance. We discuss here the approaches in study design and reporting that will reduce the spread of false positive data and optimize scientific progress in the genotyping field.

False Positive Reactions↗