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Kari Hemminki

Publications and source records attributed to Kari Hemminki.

At least 163 records · Page 9Linked to original sources
PubMed2004

Cytogenetic markers, DNA single-strand breaks, urinary metabolites, and DNA repair rates in styrene-exposed lamination workers.

The effect of occupational exposure to styrene on frequencies of chromosomal aberrations and binucleated cells with micronuclei and on single-strand break levels in peripheral blood lymphocytes was studied in 86 reinforced plastic workers and 42 control individuals (including 16 maintenance workers with intermittent, low-dose exposure). In these individuals, the irradiation-specific DNA repair rates and the repair rates of 8-oxoguanines were investigated. We assessed the exposure by measuring the concentrations of styrene in air and in blood and of mandelic acid, phenylglyoxylic acid, 4-vinyl phenol conjugates and regioisomeric phenyl hydroxyethyl mercapturic acids in urine. All these parameters correlated with one another. No clear relationship was found between the styrene exposure and the frequencies of chromosomal aberrations. Binucleated cells with micronuclei were moderately related to the parameters of styrene exposure. We found a negative correlation between all exposure parameters and single-strand breaks. The positive correlation between exposure parameters and DNA repair rates suggests that particular DNA repair pathways may be induced by styrene exposure.

Adult↗
PubMed2004

Single nucleotide polymorphisms in breast cancer.

A limited number of genes have been identified that explain heritable risks of breast cancer (BC). We searched for low-penetrant genes in an association study using two populations: 223 Finnish unselected patients and 172 Polish familial cases, both with locally collected healthy controls. Candidate genes included DNA repair genes, methylenetetrahydrofolate reductase (MTHFR) and cyclin D1 genes. The frequencies for single nucleotide polymorphisms (SNPs) were measured in the following genes: NBS1, XPC, XPD, XRCC1, XRCC3, MTHFR, and cyclin D1. Odds ratios (ORs) were calculated to the wild-type genotype. The positive findings in the Finnish series were repeated in the Polish series. Significant findings among Finns were associations to XPC exon 15, XPD exon 10 and XRCC3 exon 7, the latter of borderline significance. None of these results could be repeated in the Polish series. The XPC result among Finns was probably an artifact of the control group deviating from the Hardy-Weinberg Equilibrium (HWE). The attempt to repeat the result for the XPD polymorphism among Poles was probably not valid because the control group deviated from the HWE. We conclude that within statistical power of the present study, none of the tested polymorphisms associated with BC, with the probable exception of XPD.

Breast Neoplasms↗
PubMed2004

Implications of results of molecular epidemiology on DNA adducts, their repair and mutations for mechanisms of human cancer.

This review covers human data on DNA adducts, their repair and induced mutations. The new data on human studies in vivo challenge some widely held notions relating to cancer and ageing. These data collected from humans of different ages show no age-dependent change in levels of diverse DNA adducts in peripheral lymphocytes, no deterioration of global DNA excision repair in skin in situ and no change in mutation rate, because the HPRT mutant fraction increases linearly by age. These molecular epidemiological results argue against earlier animal and in-vitro data, but are in line with multistage models for cancer. A further application of DNA adducts as an intermediary tool for genotyping studies, for both metabolic enzyme and DNA repair system genotypes, is recommended. As the common polymorphisms are likely to cause at most moderate increases in the risk of cancer, the intermediary adduct end-point is a necessary proof of causal relationships. The mechanistic data on the mutational spectra induced by important human DNA adducts may be helpful in the characterization, not only of carcinogenic exposures, but also of protective factors, such as dietary ingredients. Examples are shown of the application of mutational spectra on the von Hippel Lindau (VHL) gene in kidney cancer in relation to dietary intake. Some fruit and vegetables provide protection against mutations and the effect is stronger among smokers who have both endogenous and exogenous mutagenic exposures.

Aging↗
PubMed2004

Multiple primary cancers as clues to environmental and heritable causes of cancer and mechanisms of carcinogenesis.

Successes in cancer therapy are leading to an increasing incidence of second cancers, which may be due to the same factors that cause first cancers or to the effect of therapy for the first cancer. There are also a number of specific methodological and sampling problems that have to be controlled before informative studies can be embarked upon. The risk of a second cancer is higher than that for the first one, which may be an indication of a particular exposure, an inherited set of genes, or both. We show clustering of multiple cancers caused by tobacco, alcohol and infections. We discuss familial aggregation of cancer as one of the causes of multiple primary cancers. However, multiple primary cancers may particularly be a manifestation of polygenic susceptibility, which cannot easily be recognized as familial clustering, and multiple cancers may offer a model for understanding the complex etiology of human cancer and for generating and testing hypotheses on mechanisms of carcinogenesis.

Animals↗
PubMed2004

Familial risk for colorectal cancers are mainly due to heritable causes.

A family history is an identified risk factor for colorectal cancer (CRC). However, it is not known to what extent the risk is due to environmental or heritable genetic factors. We wanted to examine this question for familial CRC adenocarcinoma based on the nationwide Swedish Family-Cancer Database on 10.3 million individuals whose invasive cancers were followed up to year 2000. Standardized incidence ratios (SIRs) for offspring, siblings, and spouses were calculated based on 5-year age, sex, period (10-year bands), area (county), and socioeconomic status standardized rates. A significant risk was observed in the parent-offspring comparison among different subsites (left-sided and right-sided colon, rectum, and all CRC), the SIRs ranging from 1.74 to 1.84. When husbands were probands, the SIR in wives was 0.92 for colon cancer (left-sided 0.67 and right-sided 1.07), 0.98 for rectal cancer, and 0.96 for CRC. The risks for husbands when wives were probands were quite similar. None of the SIRs between spouses were significant, indicating lack of concordance between spouses that resided together for a minimum of 30 years. The risks between siblings were also increased particularly for cancer in the right-sided colon (SIR 6.89). The effect of shared childhood environmental effects were probed by analyzing the risks by age difference between the siblings. However, the risks were independent of the age difference. Data among spouses and siblings consistently point to the importance of heritable factors in familial CRC.

Adenocarcinoma↗
PubMed2003

Polymorphisms in DNA repair and metabolic genes in bladder cancer.

We investigated the association of urinary bladder cancer with genetic polymorphisms in the xeroderma pigmentosum complementation group C (XPC), group D (XPD) and group G (XPG), X-ray repair cross-complementing group 1 (XRCC1) and group 3 (XRCC3), Nijmegen breakage syndrome 1 (NBS1), cyclin D1, methylene-tetrahydrofolate reductase (MTHFR), NAD(P)H dehydrogenase quinone 1 (NQO1), H-ras and glutathione S-transferase theta 1 (GSTT1) genes. Bladder cancer patients from the different hospitals in Stockholm County Council area and matching controls were genotyped for different polymorphisms. The frequency of the variant allele for A/C polymorphism in exon 15 of the XPC gene was significantly higher in the bladder cancer cases than in the controls (OR 1.49, 95% CI 1.16-1.92, P = 0.001). The variant allele homozygote genotype for the T/C polymorphism in exon 1 of the H-ras gene was associated with a decreased risk for bladder cancer (OR 0.12, 95% CI 0.02-0.67, P = 0.006). The variant allele genotypes for the single nucleotide polymorphisms (SNPs) in DNA repair genes, XPG and NBS1, showed a marginal association with the occurrence of bladder cancer (OR 0.38, 95% CI 0.15-0.94, P = 0.03 and OR 1.64, 95% CI 0.92-2.90, P = 0.09, respectively). We also report a positive correlation between the null homozygote of GSTT1 with the risk of bladder cancer (OR 2.54, 95% CI 1.32-4.98, P = 0.003). For other polymorphisms included in this study, NBS1 Glu185Gln, XPD Lys751Gln, XPG Asp1104His, XRCC1 Arg399Gln, XRCC3 Thr241Met, cyclin D1 Pro242Pro, MTHFR Ala222Val and Glu429Ala, NQO1 Arg139Trp and Pro187Ser, no significant differences for genotype distributions and allele frequencies between the bladder cancer cases and the controls were observed in the present study.

Adult↗
PubMed2003

Activating BRAF and N-Ras mutations in sporadic primary melanomas: an inverse association with allelic loss on chromosome 9.

We searched and report mutations in the BRAF and N-ras genes in 22 out of 35 (63 percent) primary sporadic melanomas. In three melanomas, mutations were concomitantly present in both genes. In all, 10 out of 12 mutations in the BRAF gene involved the 'hot spot' codon 600 (In all communications on mutations in the BRAF gene, the nucleotide and codon numbers have been based on the NCBI gene bank nucleotide sequence NM_004333. However, according to NCBI gene bank sequence with accession number NT_007914, there is a discrepancy of one codon (three nucleotides) in exon 1 in the sequence with accession number NM_004333. The sequence analysis of exon 1 of the BRAF gene in our laboratory has shown that the sequence derived from NT_007914 is correct (Kumar et al., 2003). Due to the correctness of the latter, sequence numbering of codons and nucleotides after exon 1 are changed by +1 and +3, respectively.), one tandem CT1789-90TC base change represented a novel mutation and another mutation caused a G466R amino-acid change within the glycine-rich loop in the kinase domain. Mutations in the N-ras gene in 11 melanomas were at codon 61 whereas two melanomas carried mutations in codon 12 including a tandem mutation GG>AA. We observed an inverse association between BRAF/N-ras mutations and the frequency of loss of heterozygosity (LOH) on chromosome 9 at 10 different loci. Melanomas with BRAF/N-ras mutations showed a statistically significant decreased frequency of LOH on chromosome 9 compared with cases without mutations (mean fractional allelic loss (FAL)=0.29+/-0.23 vs 0.72+/-0.33; t-test, P=0.0001). Difference in the FAL value between tumours with and without BRAF/N-ras mutations on 33 loci on five other chromosomes was not statistically significant (mean FAL 0.17+/-0.19 vs 0.25+/-0.22; t-test, P=0.24). Melanoma cases with BRAF/N-ras mutations were also associated with lower age at diagnosis than cases without mutations (mean age 80.38+/-7.24 vs 65.77+/-19.79 years; t-test, P=0.02). Our data suggest that the occurrence of BRAF/N-ras mutations compensate the requirement for the allelic loss at chromosome 9, which is one of the key events in melanoma.

Alleles↗
PubMed2003

Familial risk of urological cancers: data for clinical counseling.

Familial risks for cancer are important for clinical counseling and understanding cancer etiology. The nationwide Swedish Family-Cancer Database includes all Swedes born in 1932 and later (0 to 68-year-old offspring) with their parents, totaling over 10.2 million individuals. Urological cancer cases were retrieved from the Swedish Cancer Registry up to year 2000. Standardized incidence ratios (SIR) and 95% confidence limits (CI) were calculated for age-specific familial risk in offspring by an exact proband status. The familial risks for offspring cancer were increased at all urological sites from concordant cancer in the parent and in a sibling proband. The highest SIRs by parent were for testicular and prostate cancer (4.26 and 2.45). When a sibling was affected, even kidney cancer (4.74) showed a high SIR. For kidney cancers, and also for prostate and testicular cancers, the SIRs were higher among siblings than among offspring and parents, which may indicate the involvement of recessive effects. Family members of patients with prostate cancer or von Hippel Lindau disease can expect organized clinical counseling, but family members of patients with other urological cancers are probably not counseled. Guidelines for clinical counseling or action level should be developed for all urological cancers because of the established familial risks. Urological cancers also offer a challenge to molecular geneticists attempting to identify the susceptibility genes underlying the familial clustering.

Adolescent↗
PubMed2003

BRAF mutations in metastatic melanoma: a possible association with clinical outcome.

PURPOSE: The RAS-RAF-mitogen-activated protein kinase pathways mediate the cellular response to growth signals. In melanocytes, BRAF is involved in cAMP-dependent growth signals. Recently, activating mutations in the BRAF gene, were reported in a large proportion of melanomas. We have studied mutations in the BRAF gene and their association with clinical parameters. EXPERIMENTAL DESIGN: We analyzed exons 1, 11, and 15 of the BRAF gene and exons 1 and 2 of the N-ras gene for mutations in 38 metastatic melanomas by PCR-single-strand conformation polymorphism and direct sequencing. Kaplan-Meier survival and multivariate analyses were used to correlate mutations with various clinical parameters. RESULTS: Mutations in exon 15 of the BRAF gene were detected in 26 (68%) melanomas. In 25 cases, mutation involved the "hot spot" codon 600(2)of the BRAF gene. Three melanomas without a BRAF mutation carried amino acid substituting base changes at codon 61 of the N-ras gene. In a multivariate proportional hazard (Cox) model, BRAF mutation, along with the stage of metastatic melanomas, showed a statistically significant hazard ratio of 2.16 (95% confidence interval 1.02-4.59; chi(2) for the model 6.94, degrees of freedom 2, P = 0.03) for diminished duration of response to the treatment. In a Kaplan-Meier survival model, cases with BRAF mutation showed longer disease-free survival (median of 12 months) than cases without mutation (median of 5 months), although this association was not statistically significant (Log-rank test P = 0.13). CONCLUSIONS: Our results, besides confirming the high frequency of BRAF mutations in metastatic melanomas, also underline the potential importance of these mutations in disease outcome.

Adult↗
PubMed2003

Socioeconomic factors in cancer in Sweden.

It is well known that certain cancers have shown clustering in socioeconomic groups, but limited data are available on recent results and time trends in such clustering. We determined standardized incidence ratios (SIR) for cancer, adjusted for age, period, region, parity and age at first childbirth among men and women in 6 socioeconomic groups based on the Swedish Family-Cancer Database. Persons had to be identified with the same socioeconomic status in the census of years 1960 and 1970, or of years 1960, 1970 and 1980; the comparison group was all people according to the same censuses. Cancers were followed from years 1970 to 1998 or from 1980 to 1998. Both increased and decreased SIRs were found, and a consistent pattern emerged, although the overall SIRs for cancer did not differ much, the lowest being for farmers (0.85) and the highest for professional men (1.07) and women (1.11). At individual sites, manual workers were at risk of tobacco-, alcohol- and occupation- and human papilloma virus-related cancers and at a decreased risk at most other cancers. Manual workers and farmers showed an excess of stomach cancer; professionals had an excess of melanoma and squamous cell skin cancer. Male and female SIRs correlated highly for manual and blue-collar workers and for professionals. The overall population-attributable fraction for selected sites was 16.7% for men and 10.9% for women and it was highest, over 50%, for lung cancer in both genders.

Agricultural Workers' Diseases↗
PubMed2003

Familial invasive and borderline ovarian tumors by proband status, age and histology.

Age-specific familial risks in ovarian cancer have not been assessed by histologic types of medically verified cancers. We used the nationwide Swedish Family-Cancer Database on 10.2 million individuals and 19,175 invasive and 3,436 borderline ovarian cancers to calculate, by affected family members, standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) for familial ovarian cancer in 0-66 year old daughters. SIRs for all invasive ovarian cancer were 2.68 (95% CI 2.22-3.21) by ovarian cancer in mother, 2.94 (1.40-5.94) by an affected sister and 24.03 (6.12-74.46) by both an affected mother and sister. The population-attributable fraction from mothers was 2.52%. Seropapillary cystadenocarcinoma showed the highest familial risk, but the effect of histopathol subtype could not be fully assessed because of lack of data in probands. Age-specific data showed some early-onset components and an unusual maximal incidence in the 40s. A comparison to an earlier study on BRCA1/2 mutation analysis and relative risks of ovarian and breast cancer suggests that these mutations could account for 26% of the familial aggregation of ovarian cancer. Histopathology and age of onset appear to be important attributes of familial ovarian cancer, suggesting that further gene identification efforts should target a specific histopathology in early-onset patients.

Adenocarcinoma↗
PubMed2003

Cancer risks in hairdressers: assessment of carcinogenicity of hair dyes and gels.

More than a decade ago, an increased risk for bladder cancer among male hairdressers was established. Frequent changes of hair dye formulations together with their widespread use call for safety guarantees. We carried out a follow-up study of a cohort of 38866 female and 6824 male hairdressers from Sweden and analyzed all of their malignancies over a period of 39 years. Standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) for 28 cancer sites were calculated using the economically active population as a reference. During the years 1960-1998 a total of 1043 cancer cases were recorded in male hairdressers. Excess risks for cancers of the upper aerodigestive tract and lung and colorectal adenocarcinoma were observed. Additionally, male hairdressers working in 1960 had an increased risk for urinary bladder cancer, which was highest in the 1960s with an SIR of 2.56 (95% CI 1.36-4.39) and decreased with the follow-up time. A total of 2858 cancers were recorded in female hairdressers. An increased risk was observed for cancers of the pancreas, lung and cervix and in situ cancer of the skin. The increased risk for in situ skin cancer specifically affected the scalp and neck, sites of contact for hair dyes, with an SIR of 2.43 (95% CI 1.14-4.44). The increase in lung cancer, the only site for which cancer was increased in either sex, may depend on confounding from smoking. Bladder cancer was not increased among hairdressers in the recent decades and is therefore not likely to be associated with modern hair dyes.

Adolescent↗
PubMed2003

Subsequent primary malignancies after endometrial carcinoma and ovarian carcinoma.

BACKGROUND: Population-based data on subsequent neoplasms after women are diagnosed with endometrial and ovarian carcinomas are limited, particularly regarding specific histologic tumor types. METHODS: The nationwide Swedish Family-Cancer Database of 10.2 million individuals, which includes 19,128 invasive endometrial carcinomas and 19,440 ovarian carcinomas, was used to calculate standardized incidence ratios (SIRs) and 95% confidence intervals (95% CIs) for second primary carcinomas. SIRs were calculated for specific follow-up periods. Data on histopathologic types also were used. RESULTS: An excess of subsequent malignancies after women were diagnosed with endometrial carcinoma was noted at 11 sites. The highest SIRs were recorded for synchronous or metasynchronous ovarian carcinomas (SIR, 55.77; 95% CI, 48.82-63.43) and carcinomas of the small intestines (SIR, 14.71; 95% CI, 4.64-34.59). Primary ovarian carcinoma was followed by an increased risk of developing endometrial carcinoma, and the risks of developing many other malignancies also were increased after women were diagnosed with endometrial carcinoma, including intestinal malignancies, renal cell carcinoma, bladder carcinoma, squamous cell skin carcinoma, connective tissue malignancies, and leukemia. When ovarian endometrioid histology was diagnosed synchronously with primary endometrial carcinoma, the SIR was 140; when endometrial carcinoma was the subsequent neoplasm, the SIR was 87. A small familial component was found in the cooccurrence of endometrial carcinoma and ovarian carcinoma. CONCLUSIONS: The current data show a strong clustering of endometrial carcinomas and ovarian carcinomas, particularly involving tumors of endometrioid morphology. The patterns of second neoplasms also suggest that hereditary nonpolyposis colorectal carcinoma may contribute to the association between endometrial and ovarian malignancies. Increased risks for connective tissue tumors and leukemia may signal a response to treatment, and an increased risk for squamous cell skin carcinoma may signal a depressed immune function.

Carcinoma, Endometrioid↗
PubMed2003

Incidence trends and familial risks in invasive and in situ cutaneous melanoma by sun-exposed body sites.

We studied incidence trends, age-incidence relationships and familial risks in invasive and in situ cutaneous melanoma, based on the Swedish Family-Cancer Database of more than 10 million individuals. Offspring were 0-66 years of age. Cancers were obtained from the Swedish Cancer Registry from years 1961-98. The study was based on 9,771 offspring and 22,888 parents with invasive melanoma and 2,446 offspring and 5,017 parents with in situ melanoma. Incidence rates increased markedly for invasive melanoma in the trunk. For in situ melanoma, trunk and head and neck were affected, and, in addition, legs for women. The maximal incidence was around age 80 years, independent of the type or site in men; in women early onset superficially spreading melanoma shifted the age for maximal incidence to about 60 years. For in situ melanoma, lentigo maligna was the main histogenetic type in the head and neck but in the trunk and legs superficially spreading melanoma was somewhat more common. Standardized incidence ratios (SIR) were calculated for familial risk at exposed and covered sites. The combined familial risks for invasive and in situ melanoma were higher at covered (SIR 3.56 from parents) than sun-exposed (1.92 from parents) sites and they agreed when familiality was defined between parents and offspring or between siblings; the sibling SIRs were 3.90 at covered and 2.53 at exposed sites. The data suggest that the higher melanoma density at exposed sites masks familial effects. Furthermore, sun exposure does not appear to reinforce the familial effect.

Adolescent↗
PubMed2003

Clinical course of bladder neoplasms and single nucleotide polymorphisms in the CDKN2A gene.

Point mutations and single nucleotide polymorphisms (SNPs) in the CDKN2A gene in bladder cancer patients have been resolved only to a limited extent. The exact frequency of mutations remains uncertain and reports on SNPs are lacking. In this population-based study we investigated mutations and polymorphisms in the CDKN2A gene in bladder cancer patients from all hospitals within the Stockholm County. Mutations were determined in 4 exons of the CDKN2A gene in tumor-tissues from 172 bladder cancer patients and 2 single nucleotide polymorphisms in the 3' UTR of the CDKN2A gene were studied in 309 cases. Missense mutations were identified in only 4 of 172 (2.3%) cases, including 1 in the germ-line. Frequencies of the 500 C-->G and 540 C-->T polymorphisms in the 3' UTR of the CDKN2A in bladder cancer cases were not statistically significantly different compared to an ethnically matched control population. The tumor-specific survival was significantly shorter in patients with either the 500 C-->G or 540 C-->T polymorphism than those with wild-type CDKN2A gene (P = 0.02). Our results corroborate the earlier findings that single base mutation is not the prime mode of inactivation of the CDKN2A gene in bladder cancer. Further, the results indicate, a role for the 3' UTR polymorphisms in the CDKN2A gene in tumor invasiveness.

3' Untranslated Regions↗
PubMed2003

Single nucleotide polymorphisms in the XPG gene: determination of role in DNA repair and breast cancer risk.

In this study we determined the effect of single nucleotide polymorphisms in the XPG gene on DNA repair and breast cancer susceptibility. Ninety individuals, with previously studied DNA repair rate at 24 hr of 2 types of UV-specific cyclobutane pyrimidines dimers (CPDs) in skin were genotyped for XPG polymorphism at codon 1104 (exon 15 G>C; Asp > His). The repair rate of TT=C dimer was similar in both wild-type GG homozygotes and GC heterozygotes, whereas, for TT=T, dimer repair was non-significantly (Student's t-test, p = 0.34) lower in GC heterozygotes than wild-type GG homozygotes. Genotyping of 220 breast cancer cases and 308 controls for the same single nucleotide polymorphism in exon 15 of the XPG gene exhibited marginally significant increased frequency of the variant allele (chi(2) 3.84, p = 0.05; OR 1.33, 95% CI 1.0-1.8) in cases (C-allele 0.29) compared to controls (C-allele 0.24). Combined heterozygote and variant homozygote genotype frequency was also higher in cases than controls (chi(2) 4.79, p = 0.03; OR 1.50, 95%CI 1.04-2.16).

Adult↗