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Biomedical subjects

K Hemminki

Publications and source records attributed to K Hemminki.

At least 55 records · Page 3Linked to original sources
PubMed2001

Kinetics of formation of specific styrene oxide adducts in double-stranded DNA.

The possible carcinogenicity of styrene is believed to be related to the DNA-binding properties of styrene 7,8-oxide (SO). In order to compare the intrinsic reactivity of the different nucleophilic sites in DNA towards SO and to evaluate the candidates for human biomonitoring we have determined the second-order rate constants and stabilities of several SO-adducts in double-stranded DNA. These include alpha- and beta-isomers of N7-substituted and alphaN(2)-substituted guanines, alpha- and betaN3-substituted and alphaN(6)-substituted adenines as well as betaN3- and alphaN(4)-substituted cytosines. The highest rate constants were found for the spontaneously depurinating N7-guanines being ca. 3-15-fold higher than those for the stable adducts. When the relative proportions of different alkylation products were determined in course of time, after a single addition of SO, the labile N7-guanines and N3-adenines were the major products at early time points. After 144 h of incubation at 37 degrees C, alphaN(6)-SO-adenine and alphaN(2)-SO-guanine as well as betaN3-SO-uracil were the major adducts. Regarding human biomonitoring, the N7-substituted guanines should be one of the main targets because of the high reactivity of the N7-atom of guanine. However, in the case of chronic styrene exposures the chemically more stable DNA adducts may become important.

Alkylation↗
PubMed2001

A single nucleotide polymorphism in the 3'untranslated region of the CDKN2A gene is common in sporadic primary melanomas but mutations in the CDKN2B, CDKN2C, CDK4 and p53 genes are rare.

In this report we present the results of mutational analysis of the CDKN2B, CDKN2C, CDK4, p53 genes and 5'UTR of the CDKN2A gene in a set of 44 sporadic primary melanomas, which had been earlier analysed for mutations in the CDKN2A (p16/p14(ARF)) gene. No tumour-associated mutations were detected except in 1 melanoma where we found a CC>T* deletion-mutation in the codon 151-152 (exon 5) of the p53 gene. On the basis of our preliminary results, we did extended genotyping of the 500 C>G and 540 C>T polymorphisms in the 3'UTR of the CDKN2A gene in 229 melanoma cases and 235 controls. The T-allele frequency (for 540 C>T polymorphism) in melanomas was significantly higher than in controls (0.14 vs. 0.08; chi(2) = 5.95, p = 0.01; OR = 1.71, 95%CI = 1.11-2.66). The heterozygote frequency for this polymorphism was 0.26 (59/229) in melanomas compared to 0.13 (30/235) in healthy controls (chi(2) = 11.4; p = 0.0007; OR = 2.34, 95% CI = 1.40-3.92). The frequency of the 500 C>G polymorphism in the 3'UTR in the CDKN2A gene was not significantly higher in melanomas compared to healthy controls. The 500 C>G polymorphism, however, was in linkage disequilibrium with approximately 50 kb apart the C>A intronic polymorphism in the CDKN2B gene (determined in 44 melanomas and 90 controls; Fisher exact test, p<0.0001). Finally, the sequence analysis of genomic DNA isolated from T cell lymphocytes of healthy individuals exhibited that the codon reported as last of exon 2 of the CDKN2C gene is rather the first codon of exon 3.

3' Untranslated Regions↗
PubMed2001

Familial carcinoid tumors and subsequent cancers: a nation-wide epidemiologic study from Sweden.

Carcinoids are rare neuroendocrine tumors, mainly located in the bowel, stomach and lung. Familial risks in carcinoid tumours are not well known apart from multiple endocrine neoplasia 1 (MEN1). We used the nation-wide Swedish Family-Cancer Database on 10.1 million individuals for assessment. Carcinoid tumors were retrieved from the Cancer Registry covering the years 1958-1998. The offspring generation, aged 0-66 years, accumulated 190 million person-years at risk. The age-adjusted incidence rates were 0.76 for men and 1.29/100,000 for women. Standardized incidence ratios (SIRs) were calculated for offspring when their parents had a carcinoid or any other cancer. When parents presented with carcinoids, SIRs for offspring were 4.35 (n = 8, 95% CI 1.86-7.89) for small intestinal and 4.65 (n = 4, 95% CI 1.21-10.32) for colon carcinoids. If both offspring and parents presented with small intestinal carcinoids, the SIR was 12.31 (n = 4, 95% CI 3.20-27.34). Offspring carcinoids were also increased if parents presented with bladder and endocrine gland tumors, the latter association probably partially due to MEN1. Risks for second cancers were increased, particularly at sites where familial risks were found, including carcinoids in the small intestine.

Adolescent↗
PubMed2001

Incidence trends and risk factors of carcinoid tumors: a nationwide epidemiologic study from Sweden.

BACKGROUND: Carcinoids are rare indolent neuroendocrine tumors, mainly located in bowel, stomach, and lung. Their etiology is virtually unknown although a family history is a minor cause. METHODS: Site specific incidence trends and several risk factors of carcinoid tumors were studied based on the nationwide Swedish Family-Cancer Database of 10.2 million individuals and their more than 1 million tumors. Data on a total of 5184 carcinoid tumors were retrieved from the Cancer Registry covering years 1958-1998. RESULTS: The overall age-adjusted incidence rates were 2.0 for men and 2.4/100,000 for women in 1983-1998. Appendix was the main site for women whereas small intestine was the main site for men. The incidence of all carcinoids, including those at the main sites increased during the follow-up period but appeared to plateau in the middle of the 1980s. Appendiceal carcinoids showed an unusually early onset with a maximum incidence at age 15-19 years for women and 20-29 years for men. Among women, parity was not related to the age specific incidence of carcinoid tumors. A Poisson regression analysis showed that family history of carcinoids in first-degree relatives (relative risk, 3.6), well educated social background (relative risk for professionals, 2.8), and birth in large cities were risk factors. CONCLUSIONS: The data suggest that the increase in carcinoid tumors may be largely ascribed to the application of advanced medical viewing techniques that detect asymptomatic tumors. However, the difference in incidence between men and women in appendiceal tumor may be real and independent of parity.

Adolescent↗
PubMed2001

Association between genetic polymorphisms and biomarkers in styrene-exposed workers.

A comprehensive approach to evaluate genotoxic effects induced by styrene exposure was employed in 44 hand-lamination workers in comparison with 18 unexposed controls. The acquired data on single-strand breaks in DNA (SSBs), frequency of chromosomal aberrations and HPRT mutant frequency in peripheral blood lymphocytes were compared to the results on genotyping of some of the xenobiotic-metabolising enzymes (CYP1A1, CYP2E1, epoxide hydrolase and GSTM1, GSTP1 and GSTT1). Multifactorial regression analysis indicated that SSB in DNA were significantly associated with styrene exposure and with heterozygosity in CYP2E1 (5'-flanking region and intron 6; r(2)=0.614). The frequency of chromosomal aberrations (CA), as analysed by linear multiple regression analysis, significantly correlated with years of employment (P=0.004) and with combinations of epoxide hydrolase (EPHX) genotypes (exon 3, Tyr/His and exon 4, His/Arg), where individuals with low and medium activity EPHX genotypes exhibited higher frequencies of CA than those with high activity genotypes (P=0.044, r(2)=0.563). Moderately higher HPRT mutant frequencies were detected in styrene-exposed individuals (20.2 +/- 25.8 x 10(-6)) as compared to controls (13.3 +/- 6.3 x 10(-6)), but this difference was not significant. ANOVA (in the whole set of data) revealed that mutant frequencies at the HPRT gene were significantly associated with years of employment (F=6.9, P=0.0001), styrene in blood (F=10.1, P=0.0001), and heterozygosity in CYP2E1 (intron 6; F=13.5, P=0.0008) and GSTP1 (exon 5; F=3.6, P=0.038). In conclusion, our present data suggest that analysed biomarkers of DNA damage may be modulated by polymorphic CYP2E1, EPHX and GSTP1. In our study, styrene-specific DNA and haemoglobin adducts are under investigation. Completing these data with the results of genotyping of metabolising enzymes may provide a useful tool for individual genotoxic risk assessment.

Adult↗
PubMed2001

DNA adducts, strand breaks and micronuclei in mice exposed to styrene by inhalation.

Genotoxic and clastogenic effects of styrene were studied in mice. Male NMRI mice were exposed by inhalation to styrene in concentrations of 750 and 1500 mg/m3 for 21, 7, 3 and 1 days (6 h/day, 7 days/week). Followed parameters included styrene in blood, specific styrene oxide (SO) induced DNA adducts, DNA strand breaks and micronuclei. The formation of SO induced 7-SO-guanines and 1-SO-adenines in DNA was analysed from lung tissues by two versions of the 32P-postlabeling technique. In lungs after 21 days of exposure to 1500 mg/m3 the level of 7-SO-guanine was 23.0+/-11.9 adducts/10(8) normal nucleotides, while 1-SO-adenine was detected at the levels of 0.6+/-0.2 adducts/10(8) normal nucleotides. Both 7-SO-guanines and 1-SO-adenines strongly correlated with exposure parameters, particularly with styrene concentration in blood (r=0.875, P=0.0002 and r=0.793, P=0.002, respectively). DNA breaks were measured in peripheral lymphocytes, bone marrow cells and liver cells using comet assay. To discern oxidative damage and abasic sites, endonuclease III was used. In bone marrow of exposed mice slight increase of strand breaks can be detected after 7 days of inhalation. A significant increase was revealed in the endonuclease III-sensitive sites after 21 days of inhalation in bone marrow. In the liver cells inhalation exposure to both concentrations of styrene did not virtually affect either levels of DNA single-strand breaks or endonuclease III-sensitive sites. The inhalation of 1500 mg/m3 of styrene induced significant increase of micronuclei after 7 days of exposure (10.4+/-2.5/1000 cells, i.e. twice higher micronuclei frequency than in controls). After 21 days of inhalation no significant difference between the control group and the two exposed groups was observed. Whether the decrease of micronuclei after 21 days of inhalation was due to the inhibition of cell proliferation caused by styrene or due to the natural elimination of chromatide fragments, remains to be clarified. An interesting link has been found between DNA single-strand breaks in bone marrow and frequencies of micronuclei (r=0.721, P=0.028).

Administration, Inhalation↗
PubMed2001

Second primary neoplasms among 53 159 haematolymphoproliferative malignancy patients in Sweden, 1958-1996: a search for common mechanisms.

The Swedish Family-Cancer Database was used to analyse site-specific risk of second primary malignancies following 53 159 haematolymphoproliferative disorders (HLPD) diagnosed between 1958 and 1996. Standardized incidence ratio (SIR) of a second malignancy was calculated as the ratio of observed to expected numbers of second malignancies by applying site-, sex-, age-, period-, residence- and occupation-specific rates in the corresponding population in the Database to the appropriate person-years at risk. Among 18 960 patients with non-Hodgkin's lymphoma (NHL), there was over a 3-fold significant increase in cancer of the tongue, small intestine, nose, kidney and nervous system, squamous cell carcinoma (SCC) of the skin, NHL, Hodgkin's disease (HD) and lymphoid and myeloid leukaemia. Among 5353 patients with HD, there was over a 4-fold significant increase in cancer of the salivary glands, nasopharynx and thyroid, NHL and myeloid leukaemia, and over a 1.6-fold increase in cancer of the stomach, colon, lung, breast, skin (melanoma and SCC), nervous system and soft tissues and lymphoid leukaemia. Among 28 846 patients with myeloma and leukaemia, there was a significant increase in cancer of the skin, nervous system and non-thyroid endocrine glands and all HLPD except for myeloma. Our findings showed some clustering between first and second primaries among Epstein-Barr virus-, ultraviolet radiation- and immunosuppression-related cancers.

Adolescent↗
PubMed2001

VHL gene alterations in renal cell carcinoma patients: novel hotspot or founder mutations and linkage disequilibrium.

Mutations in the von Hippel-Lindau (VHL) gene are frequently detected in human sporadic renal cell carcinoma (RCC). We analysed 102 Swedish RCCs for VHL mutations by PCR-SSCP and sequencing. In 47 patients (46.1%), 70 different mutations were found, and most of them represented novel variations of the VHL gene. Mutations in the VHL gene were found in 54% of clear cell renal cell carcinomas (CCRCC) and in 18% of chromophilic cancers but in no chromophobe cancers or oncocytomas (P=0.016). Three novel hotspot or founder mutations were detected in our study: four CCRCCs carried a missense mutation (glutamic acid to lysine) at codon 160 which is critical in the stabilization of the H1 helix of the alpha domain and the alpha-beta domain interface in the VHL protein. Five CCRCCs and one chromophilic RCC harbored a 15-nucleotide in-frame deletion (codons 41-45) at a duplex tandem repeat sequence site. Moreover, this deletion was in linkage disequilibrium with a C-->T transition in the promoter region. The frequency of linkage was 17 times more common than chance. Five patients with this linked mutation resided in the same hospital district and at least three of them showed the two sequence variants in the tumor-adjacent tissue. In 5/6 patients the wild-type allele was lost in the tumor samples, suggesting a causal role for the mutations in RCC. These linked mutations might be novel polymorphisms maintained in a relative isolated population. Multiple mutations in VHL were found in 17 tumors out of 47 tumors with the VHL mutation. A higher multiple mutation detected rate (33%) was observed in grade 3 CCRCCs than those in grade 1 (22%) and grade 2 (9%) (P=0.04). This is evidence on the association between VHL mutation and extent of nuclear atypia.

Age of Onset↗
PubMed2001

Second primary neoplasms in 633,964 cancer patients in Sweden, 1958-1996.

The Swedish Family-Cancer Database was used to analyze concordant (same site) and discordant (different site) second primary neoplasms in 633,964 cancer patients diagnosed from 1958 to 1996. Cases of second malignant neoplasms were extracted from the Database if the diagnosis date of the first and second cancer differed by at least 1 month. The expected numbers of cancers were obtained by applying site-, sex-, age-, period-, residence- and socioeconomic level-specific rates in the corresponding population in the Database to the appropriate person-years at risk. The standardized incidence ratio (SIRs) of a second cancer was taken to be the ratio of observed to expected numbers of second cancers. Of all cancers, 8.5% were subsequent neoplasms (8.4% for males and 8.7% for females). SIRs for both concordant and discordant subsequent cancer were elevated in patients with cancer of the upper aerodigestive tract, colon, nose, breast, other female genitals, testis, kidney, urinary, bladder, skin, nervous system, endocrine, bone, connective tissue, melanoma, lymphoma and leukemia. The risks at some concordant sites, such as nose, squamous cell skin, bone and connective tissue in both sexes, breast in males and upper aerodigestive tract and leukemia in females, were very high (>10). At discordant sites, SIRs were less than 2 but significantly increased after all but gastric and prostatic cancer. Compared with the general population, cancer patients were at a modestly increased risk for new primary cancer after cancers at many sites, calling for attention in treatment, management and prevention.

Databases, Factual↗
PubMed2001

Second primary cancers after anogenital, skin, oral, esophageal and rectal cancers: etiological links?

The Swedish Family-Cancer Database was used to analyze second cancers after oral, esophageal, rectal, cervical, genital and skin (squamous cell carcinoma) cancers. A strong and consistent association of second cancers was observed at all these sites, in men and women. As a novel finding, an association of rectal cancer with the human papillomavirus (HVP)-related cancers was shown. New evidence on an excess of skin cancer with the HPV-related cancers was also provided. As an epidemiological study, the associations were strong and often supported by a number of comparisons. These could not be explained by bias or long-term treatment related effects. However, whether the findings on rectal and skin cancer are due to HPV or other infections, transient or inherited depressed immune function or other constitutional factors remains to be established.

Esophageal Neoplasms↗
PubMed2001

Multiple primary cancers of the colon, breast and skin (melanoma) as models for polygenic cancers.

To assess the role of family history in the development of multiple primary cancer, the Swedish Family-Cancer Database was used to analyze second primary cancer in patients born in 1935 to 1996 with an initial primary cancer of the colon, breast and skin (melanoma) by familial cancer in first-degree relatives. Standardized incidence ratios (SIRs) were calculated from site-, sex- and age-specific rates for all persons (offspring) born in 1935 to 1996. Familial risk (SIR) was calculated for the first and second primary cancers in offspring. A Poisson regression analysis was also performed to assess the risk factors for occurrence of second primary cancer. The familial proportion of multiple primary cancers was 29.0% (9/31) for colon, 16.3% (122/747) for female breast and 14.5% (17/117) for melanoma. Compared with all offspring, patients with family history were at a much higher and significantly increased risk for subsequent primary cancer at colon (SIR = 59.1), skin (SIR = 48.2) and female breast (SIR = 7.9). The corresponding SIRs in patients without family history were 13.8, 10.5 and 5.2 at the three sites. The ratios for incidence of second primary to first primary were highest when diagnosis age was less than 40 years. A Poisson regression analysis showed that family history was one of the major risk factors for occurrence of multiple primary cancers at colon, breast and skin. The high risk of second cancer, even in the absence of family history, would be consistent with a polygenic model of carcinogenesis.

Age Factors↗
PubMed2001

Birth order, family size, and the risk of cancer in young and middle-aged adults.

We used the Swedish Family-Cancer Database to analyse the effects of birth order and family size on the risk of common cancers among offspring born over the period 1958-96. Some 1.38 million offspring up to age 55 years with 50.6 million person-years were included. Poisson regression analysis included age at diagnosis, birth cohort, socio-economic status and region of residence as other explanatory variables. The only significant associations were an increasing risk for breast cancer by birth order and a decreasing risk for melanoma by birth order and, particularly, by family size. When details of the women's own reproductive history were included in analysis, birth orders 5-17 showed a relative risk of 1.41. The effects on breast cancer may be mediated through increasing birth weight by birth order. For melanoma, socio-economic factors may be involved, such as limited affordability of sun tourism in large families. Testis cancer showed no significant effect and prostate cancer was excluded from analysis because of the small number of cases.

Adolescent↗
PubMed2001

p53 mutations in urinary bladder cancer.

We have screened for mutations in exons 5-8 of the p53 gene in a series consisting of 189 patients with urinary bladder neoplasms. 82 (44%) neoplasms were lowly malignant (Ta, G1-G2a) and 106 (56%) were highly malignant (G2b-G4 or > or = T1). Only one mutation was in a lowly malignant urinary bladder neoplasm, in total we found p53 mutations in 26 (14%) of the 189 patients. 30% of the samples had loss of heterozygosity (LOH) for one or both of the p53 exogenic (CA)n repeat and the p53 intragenic (AAAAT)n repeat markers. 31 samples (21%) showed LOH but were not mutated, suggesting other mechanisms inactivating p53 than mutations. 4 mutations were found at codon 280 and 2 mutations were found at codon 285, 2 previously reported hot spots for urinary bladder cancer. The study indicate a boundary between G2a and G2b tumours concerning the occurrence of genetic events affecting p53 function; moderately differentiated (G2) urinary bladder neoplasms probably are genetically heterogeneous which supports the suggestion that they should not be grouped together but instead, for example, be categorized as either lowly or highly malignant.

Cell Differentiation↗
PubMed2001

Parental cancer as a risk factor for nine common childhood malignancies.

The nationwide Swedish Family-Cancer Database was used to analyse childhood tumours among 8158 offspring by parental cancers. The results showed 2-fold familial increases for nervous system cancers and lymphomas, a 6.4-fold increase for endocrine tumours, a 60-fold increased risk for retinoblastomas but no excess risk for leukaemia and Wilms tumour.

Adolescent↗
PubMed2001

Familial colorectal adenocarcinoma and hereditary nonpolyposis colorectal cancer: a nationwide epidemiological study from Sweden.

Although estimates are available of the proportion of hereditary nonpolyposis colorectal cancer (HNPCC) among all colorectal cancer (CRC), its proportion among familial CRC is unclear. We estimated these proportions epidemiologically from the nationwide Swedish Family-Cancer Database on 9.6 million individuals. Colorectal adenocarcinomas were retrieved from the Cancer Registry covering years 1958-1996. Standardized incidence ratios (SIRs) were calculated for offspring (aged less than 62 years) when their parent had colorectal adenocarcinoma. In 9.82% of all families, an offspring and a parent were affected, giving a population attributable proportion of 4.91% and a familial SIR of 2.00. When offspring and parents shared the anatomic site, the SIR was 2.32 for proximal and 2.00 for distal CRC. When offspring were diagnosed before age 40 years and parents before age 50 years, the SIR was 25.72 for familial proximal CRC. In older age groups familial risks did not differ between proximal and distal CRC. Familial risks were increased also for endometrial, small intestinal and gastric cancers, manifestations in HNPCC. Depending on which assumptions were made, HNPCC was calculated to account for 20 to 50% of familial CRC, corresponding to 1 or 2.5% of all CRC among 0-61-year-old individuals.

Adenocarcinoma↗
PubMed2001

Modification of cancer risks in offspring by sibling and parental cancers from 2,112,616 nuclear families.

Comparisons of cancer risks in persons by sibling cancers and those by parental cancers are informative of elucidating the potential genetic modes in the etiology of the cancers. The Swedish Family-Cancer Database was used to systematically estimate the effects of parental and sibling cancers on the cancer risks in the individuals born after 1934 (offspring). The study population included 5,520,756 offspring and their parents from 2,112,616 nuclear families. Standardized incidence ratios (SIRs) were calculated to analyze the risks for cancers in offspring by parental cancers (offspring risk) and by sibling cancers (sibling risk). For 20 concordant sites, all offspring and sibling risks were significantly increased except for sibling risks for squamous cell carcinoma of the skin and myeloma. Apart from breast cancer, the SIRs were more than 10 when offspring had both an affected parent and an affected sib at the concordant site. The ratio for the sibling to offspring risk was around 2.0 or more for gastric, renal, non-thyroid endocrine, urinary bladder, colon, testicular and prostate cancers and leukemia. For discordant sites, many reported across-site associations were confirmed and several consistent novel associations (rectum-skin, breast-endocrine and lung-endocrine) were found only among sibs. Our findings suggested that low-penetrance polygenic dominant effects or dominant genes of high penetrance but low mutant allele frequency in the population may be involved in the observed familial cancers at many sites. Recessive or X-linked effects may contribute particularly to gastric, renal, non-thyroid endocrine, bladder, colon, testicular and prostate cancers and leukemia. The search for pleiotropic recessive/X-linked susceptibility genes should be well motivated based on our results.

Adolescent↗