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Biomedical subjects

Kari Hemminki

Publications and source records attributed to Kari Hemminki.

At least 37 records · Page 2Linked to original sources
PubMed2006

Familial risks of hospitalization for Parkinson's disease in first-degree relatives: a nationwide follow-up study from Sweden.

The aim of this study was to estimate familial risks of Parkinson's disease (PD) in first-degree relatives of probands with PD compared with first-degree relatives of control probands. Standardized incidence ratios (SIRs) of PD were estimated in the total Swedish population for the period January 1, 1987 to December 31, 2001. SIRs were calculated by age, sex, occupation, geographic region, family size, and type of related proband on the basis of first hospital diagnoses of PD during the study period. Results showed that during the study period, there were 65 cases of first-degree relatives who were hospitalized for PD out of the total 13,276 events (first hospital diagnoses of PD) between 1987 and 2001. Age-specific analyses of familial PD revealed that there was no apparent difference in SIRs by age category. Overall, significant SIRs for PD in first-degree relatives were 3.1 (95% CI 2.1-4.3) for men and 4.0 (95% CI 2.8-5.7) for women. When the related PD proband was a sibling, the SIR was significantly higher (8.7) than when the related proband was a parent (SIR=2.9, p=0.01) or a child (SIR=3.6, p=0.04). For spouses, no increased risks were found. In conclusion, the findings of the present study suggest that genetic factors are important in early- (age < or =50 years) and later (age >50 years) onset PD, and that shared environmental factors during childhood or recessive effects may partly be important for familial aggregation of the disease.

Age Distribution↗
PubMed2006

Second primary malignancies among patients with soft tissue tumors in Sweden.

Survival from soft tissue tumors (STTs) has been improved because of the successful treatment. One of the late sequelae in STT survivors is the development of a second malignancy. The present study aimed at quantifying risks for second malignancies in patients with STTs, and risks for second STTs after other primary malignancies. Adjusted standardized incidence ratios (SIRs), calculated from the Swedish Family-Cancer Database, were used as a measure of risk. Among 6,671 primary STT patients, a total of 650 second malignancies occurred. Besides second STTs, other cancer sites with an increased SIR were the nervous system, endocrine glands, skin (melanoma and squamous cell carcinoma) and prostate; the risk for non-Hodgkin lymphoma (NHL) was also increased. The overall risk of second malignancies decreased in the following order: fibrosarocma (1.63) > myxosarcoma (1.48) > leiomyosarcoma (1.44) > liposarcoma (1.21). An increased risk of second STTs after primary cancers of the bone, ovary, nervous system, cervix, thyroid gland, skin, endometrium, breast, upper aerodigestive tract, and after Hodgkin disease, NHL and leukemia was also noted. This study showed that the incidence of second primary malignancies in patients with STTs was increased, but the SIRs varied among specific cancer sites. Besides therapeutic effects, the associations between STTs and bone and nervous system tumors suggested that cancer syndromes, such as neurofibromatosis type 1 and Li-Fraumeni syndrome, may partly explain the excesses. The associations of STTs with cancers of the skin (squamous cell carcinoma and melanoma) and with NHL may be related to immunodeficiency.

Adult↗
PubMed2006

Familial risks for epilepsy among siblings based on hospitalizations in Sweden.

PURPOSE: Epilepsy is a common disabling condition, with high heritability according to twin studies. Characterization of familial risks for common subtypes of epilepsy will advance the search for the heritable causes of these conditions and their underlying mechanisms. We aim at defining familial risks for siblings to be hospitalized because of epilepsy. METHODS: A nationwide ad hoc epilepsy database was constructed by linking the Multigeneration Register on 0- to 69-year-old siblings to the Hospital Discharge Register for data on epilepsies covering the years 1987-2001. Standardized risk ratios (SIRs) were calculated for affected sibling pairs by comparing them to those whose siblings had no epilepsy. RESULTS: Among a total of 26,799 hospitalized cases, 598 affected siblings were identified with a familial SIR of 2.35; the SIR was highest at ages 0-4 years (6.82). Infantile spasms showed the highest risk for any subtype (10.45), when a co-sibling was diagnosed with any epilepsy. When both siblings were diagnosed with a concordant (same) subtype of epilepsy, the SIRs were high, i.e. 8.43 for generalized idiopathic epilepsy, 2.56 for partial epilepsy, 24.72 for status epilepticus and 24.39 for other epilepsies. Generalized idiopathic epilepsy was also associated with grand mal (4.06) and other epilepsies (7.61). The numbers of cases were small but concordant diagnoses always showing higher SIRs compared with discordant diagnoses. CONCLUSIONS: Within the limits of the present sample size, our results suggest high familial aggregation for certain subtypes of epilepsy for which distinct genetic mechanisms may underlie.

Adolescent↗
PubMed2006

Trisomy 8q and partial trisomy 22 in a 43-year-old man with moderate intellectual disability, epilepsy and large cell non-Hodgkin lymphoma.

Partial trisomies are chromosome abnormalities resulting in a broad range of malformations depending on the size and location of the chromosomal rearrangement. Whereas diagnosis of these syndromes is usually made in early childhood, few descriptions exist about the clinical picture in adulthood. We report on a patient diagnosed at the age of 43 years with a 47,XY,+der(22)t(8;22)(q24.13;q11.21) karyotype and predominant clinical features of trisomy 8q. To our knowledge, this is the oldest patient described with a partial trisomy 8. The patient presented with moderate intellectual disability, a past history of epilepsy and facial anomalies. In addition, a large cell non-Hodgkin lymphoma was diagnosed in adulthood. Detailed breakpoint mapping by single nucleotide polymorphism (SNP) arrays showed that the derivative chromosome contains a full-length copy of the C-MYC oncogene. Given that trisomy 8q is the most frequent secondary chromosomal abnormality in hematological diseases, the possibility of a genetic predisposition for these disorders in patients with 8q duplication is raised.

Adult↗
PubMed2006

Familial risk for histology-specific bone cancers: an updated study in Sweden.

We used the nation-wide Swedish Family-Cancer Database to examine the familial risks of histology-specific bone cancers in offspring by parental or sibling probands. Adjusted standardised incidence ratios (SIRs) were used to measure the risk. Among the 1327 offspring bone cancers, only two parent-offspring pairs and one sibling pair were noted with concordant bone cancer but the SIRs were not significant. Significant associations were observed in specific histological types or specific age groups, some of which may be chance findings arising from multiple comparisons. However, the risk of early-onset (< 25 years) osteosarcoma in offspring was significantly increased when mothers presented with breast cancer (1.7) and melanoma (2.9), suggesting that Li-Fraumeni syndrome could partly explain this familial aggregation. Other associations, such as childhood osteosarcoma with parental liver cancer, Ewing's sarcoma with kidney cancer and giant cell sarcoma with maternal breast cancer, were novel findings and may be related to other familial diseases.

Adolescent↗
PubMed2006

Polymorphisms in the KDR and POSTN genes: association with breast cancer susceptibility and prognosis.

Angiogenesis is an important step in the development of cancer. Vascular endothelial growth factor is a major regulator of breast cancer angiogenesis, the effects of which are transmitted through the kinase domain receptor (KDR). Up-regulation of KDR by periostin (POSTN) induces angiogenesis. We screened the KDR and the POSTN genes for published single nucleotide polymorphisms (SNPs) and chose two SNPs in each gene for further analyses. We carried out a case-control study consisting of 412 familial and 912 unselected breast cancer cases together with ethnically and geographically selected controls. Genotype, haplotype and genotype combination analyses were carried out to evaluate their effect on susceptibility to and prognosis of breast cancer. A haplotype in the POSTN gene was associated with an increased risk even after correction for multiple comparisons. Nominal associations between the SNPs and prognostic indicators were also observed. Tumors of the KDR 472His allele carriers were less often progesterone receptor negative according to both genotype and haplotype analyses (OR 0.61, 95%CI 0.40-0.92 and OR 0.60, 95%CI 0.40-0.91, respectively). The POSTN -33G allele carriers had more often high grade and estrogen receptor negative tumors (OR 1.75, 95%CI 1.02-3.01 and OR 1.70, 95%CI 1.04-2.78, respectively). The overall and cancer specific survival after 15 years of follow-up was more than 75%, and it did not depend on the genotype. Although a major effect of the SNPs in the KDR and the POSTN genes on breast cancer susceptibility and prognosis was excluded, the effect of the POSTN C-33G SNP on prognosis needs further characterization.

Adult↗
PubMed2006

Micronuclei, DNA single-strand breaks and DNA-repair activity in mice exposed to 1,3-butadiene by inhalation.

We investigated single-strand breaks and endonuclease III-sensitive sites in DNA along with gamma-irradiation-specific DNA-repair activity in hepatocytes and frequencies of micronuclei in polychromatic bone-marrow erythrocytes of male NMRI mice (2 months old, weight 30-35 g) during sub-acute inhalation exposure to 1,3-butadiene (28 days, 500 mg/m3) and up to 28 days after the exposure. Concentrations of 1,3-butadiene in blood, an indicator of internal exposure, moderately increased during the exposure period. The most interesting finding was that gamma-irradiation-specific DNA-repair activity gradually increased during exposure, being significantly higher compared with control levels on days 7 and 28 of exposure (P = 0.005 and 0.035, respectively), reaching a maximum on day 1 after the termination of exposure (P = 0.003) and then returning to control levels. A significant correlation between gamma-irradiation-specific DNA-repair activity and the concentration of 1,3-butadiene in blood (R = 0.866, P = 0.050) supports a possible induction of DNA-repair activity by the exposure to 1,3-butadiene and formation of its metabolites. The initial increase in micronucleus frequency (micronuclei per 1000 cells) in the exposed mice continuously decreased from 20.4 +/- 5.1 (day 3) to 15.1 +/- 3.2 (day 28) within the exposure period, and subsequently from 12.4 +/- 5.1 to 4.6 +/- 1.6 in the period following termination of the 1,3-butadiene exposure, while micronucleus frequencies in control animals were significantly lower (from 1.7 +/- 1.5 to 4.2 +/- 0.8).

Administration, Inhalation↗
PubMed2006

Familial characteristics of autoimmune and hematologic disorders in 8,406 multiple myeloma patients: a population-based case-control study.

A population-based case-control study was conducted to evaluate risk of developing multiple myeloma (MM) associated with personal history of autoimmune diseases and occurrence of autoimmune and selected hematologic disorders in first-degree relatives. Data were obtained for all (n = 8,406) MM cases diagnosed in Sweden (1958-1998), with linkable relatives, 16,543 matched controls and first-degree relatives of cases (n = 22,490) and controls (n = 44,436). Odds ratios (ORs) were calculated to quantify the risk of MM in relation to personal/family history of 32 autoimmune disorders. Familial aggregation of malignancies was evaluated in a marginal survival model using relatives as the cohort. The risk for MM was significantly elevated among subjects with a personal history of pernicious anemia (OR = 3.27; 2.22-4.83) and individuals with a family history of systemic lupus erythematosus (OR = 2.66; 1.12-6.32). Compared with controls, relative risk (RR) of MM was significantly increased (RR = 1.67; 1.02-2.73) in relatives of cases, particularly relatives of probands aged > or =65 at diagnosis (RR = 2.50; 1.19-5.27). Risks were nearly 4-fold elevated among female relatives (RR = 3.97; 1.54-10.2) and among relatives of female probands (RR = 3.74; 1.58-8.83). MM cases had more cases of monoclonal gammopathy of undetermined significance (MGUS) among their relatives than controls, but the numbers were too small to be conclusive. There was generally no increase in risk of MM in probands whose relatives had hematologic malignancies other than MM. These findings do not support a strong association between personal/familial autoimmune diseases and MM. However, MM itself shows significant familial aggregation, implicating the etiologic importance of this type of hematological neoplasm and perhaps MGUS in germ line genes.

Adult↗
PubMed2006

Aurora kinases A and B and familial breast cancer risk.

Aurora genes play a crucial role in tumourigenesis and are overexpressed in many kinds of cancers. We investigated whether coding variants within the Aurora genes are associated with familial breast cancer risk. While AURKA Phe31Ile (1712T>A) and AURKB Thr298Met (893G>A) showed no association, the synonymous AURKB Ser295Ser (885A>G) polymorphism resulted in an increased breast cancer risk for carriers of the homozygous 885G genotype (OR=1.45, 95% CI=1.05-2.0, P=0.02). Due to the impact of aurora kinases in the loss of chromosomal integrity during carcinogenesis, this variant may also influence the therapy outcome in breast cancer.

Aurora Kinase A↗
PubMed2006

Familial risks and temporal incidence trends of multiple myeloma.

In several cancer registration areas, the trends in the incidence and mortality of multiple myeloma (MM) have been rising over the last few decades. Pedigrees studies on families with multiple affected members have supported the hypothesis of a contributing hereditary etiology of MM due to shared genetic factors. The aim of our study was twofold: 1) to assess incidence trends of MM over the period 1961-2003 using national cancer registry data and; 2) to quantify the familial risk of MM using the 2004 update of the Swedish Family-Cancer Database. For men, the age-standardized rates were 4.33 per 100,000 in 1961-65 and 4.79 in 2001-03. The corresponding rates for women were 2.76 and 3.43. In the elderly, MM rates have risen from 28.7 per 100,000 to 36.2 in men, and from 20.2 to 24.5 in women. MM clustered in families with MM (standardized incidence ratio, SIR=2.45), non-Hodgkin lymphoma (SIR=1.34) and chronic lymphocytic leukaemia (SIR=2.45). No association was found for Hodgkin lymphoma and other leukaemias. Significant associations were found for rectal, stomach, cervical, prostate, bladder, endocrine glands and connective tissue malignancies. Our study adds further evidence that the incidence of MM in Sweden has been constant for several decades. The apparent increase observed in the elderly is, at least in part, attributable to improved diagnostics and certification. MM aggregates in families with MM, chronic lymphocytic leukaemia and, to a lesser extent, with non-Hodgkin lymphoma. If environmental factors can be excluded, the pattern of familial risk of MM is consistent with an autosomal dominant mode of inheritance.

Adult↗
PubMed2006

Polymorphisms in the growth hormone receptor: a case-control study in breast cancer.

The human growth hormone receptor (GHR) mediates the effects of growth hormone (GH1), starting a signalling cascade that is involved in the regulation of proliferation, differentiation and apoptosis. Recently, an isoform of the GHR gene lacking exon 3 (GHRd3) was associated with accelerated responsiveness to growth hormone. In this study, we investigated the association of the GHRd3 polymorphism with breast cancer risk and performed a haplotype analysis with 3 additional single nucleotide polymorphisms (SNPs) (Gly186Gly, Cys440Phe and Ile544Leu) in the GHR coding region in a Polish cohort. We did not observe any effect of the 4 polymorphisms on breast cancer risk. Neither did the 3 most common haplotypes influence breast cancer risk. However, a rare haplotype (dGGC), containing the GHRd3 allele, was associated with a decreased breast cancer risk (OR 0.30, 95% CI 0.11-0.80).

Adult↗
PubMed2006

Familial risk of ischemic and hemorrhagic stroke: a large-scale study of the Swedish population.

BACKGROUND AND PURPOSE: Previous studies of familial risks have often combined ischemic and hemorrhagic stroke even though it seems unlikely that these 2 very different pathological conditions are under the same genetic influence. This study is the first to investigate the concordant (same subtype) and disconcordant (different subtype) association between ischemic and hemorrhagic stroke. METHODS: Data of first hospitalization for stroke were obtained from the Hospital Discharge Register during the study period 1987 to 2001. All individuals born in Sweden from 1932 onwards were included and linked to their siblings. Risks were calculated as standardized incidence ratios and compared with individuals without affected siblings. Results were standardized for age, gender, geographical region and socioeconomic status. RESULTS: Ischemic stroke (n=25,630) was associated only with ischemic stroke (n=7961), which was also the case for hemorrhagic stroke. The statistically significant standardized incidence ratios were 2.14 (95% CI, 1.21 to 3.74) and 1.82 (95% CI, 1.21 to 2.75), respectively. For discordant subtypes of stroke no significant associations were found. CONCLUSIONS: The results suggest that ischemic and hemorrhagic stroke are not under the same genetic influence. However, further studies of the human genome are needed in order to identify the specific genes that play roles in the pathogenesis of common subtypes of stroke.

Adolescent↗
PubMed2006

Incidence of multiple primary malignancies among patients with bone cancers in Sweden.

PURPOSE: The present study aimed at quantifying risks for second malignancies in patients with bone cancers, and risks for second bone cancers after other primary tumors. METHODS: Adjusted standardized incidence ratios (SIRs) were used as a measure of risk. RESULTS: Among 2,546 primary bone cancer patients, a total of 171-second malignancies occurred. Besides second bone cancers, other cancer sites with an increased SIR were the soft tissues and endocrine glands. The overall risk of second malignancies following Ewing's sarcoma was 5.63, followed by chordoma (1.99), osteosarcoma (1.54), and chondrosarcoma (1.51). Patients diagnosed before age 20 years showed an increased SIR of 3.11. The increased occurrence of second bone cancers was noted after the cancer sites of upper aerodigestive tract, kidney and nervous system. CONCLUSIONS: The incidence of second primary malignancies in bone cancer patients was moderately increased. Among histological types, Ewing's sarcoma showed the highest risk of developing second cancers. Young age was also associated with an increased risk. Besides therapeutic effects, the observed excesses of a second bone or soft tissue tumor may be related to Li-Fraumeni syndrome. Increases at other sites may be related to unknown factors or spurious findings.

Adult↗
PubMed2006

Association of the ARLTS1 Cys148Arg variant with familial breast cancer risk.

Recently, ARLTS1 (ADP-ribosylation factor-like tumor suppressor gene 1) has been identified as a tumor suppressor gene, playing a major role in apoptotic signaling. The ARLTS1 Trp149Stop mutation has been shown to predispose to general familial cancer and high-risk familial breast cancer (BC), provoking the attenuation of apoptotic function. We studied the impact of the ARLTS1 Pro131Leu and Cys148Arg variants on high-risk familial and familial BC risk, investigating 482 familial BC cases (including 305 high-risk cases) and 530 control individuals. Unlike ARLTS1 Pro131Leu, Cys148Arg revealed a significant association with an increased risk of high-risk familial BC (odds ratio (OR)=1.47, 95% confidence interval (95% CI)=1.04-2.06, p=0.03) in a dose-dependent manner (ptrend=0.007). The genotype distribution of Cys148Arg in familial cases was similar, indicating significance as well (OR=1.48, 95% CI=1.10-1.99, p=0.009; ptrend=0.003). On the basis of the small number of 46 cases, we additionally showed an association between the Trp149Stop mutation and an increased risk of bilateral BC (OR=4.11, 95% CI=1.27-13.31, p=0.011).

ADP-Ribosylation Factors↗
PubMed2006

Associations of genetic variants in the estrogen receptor coactivators PPARGC1A, PPARGC1B and EP300 with familial breast cancer.

The mitogen effect of the ovarian steroid estrogen is a strong risk factor for breast cancer development. This effect is mainly mediated by the estrogen receptor alpha, a hormone inducible transcription factor, which activates gene expression through recruiting multiple coactivators, such as PPARGC1A, PPARGC1B and EP300. We tested the hypothesis that non-conservative, putative functional amino acid exchanges in PPARGC1A, PPARGC1B and EP300 act as low-penetrance familial breast cancer risk factors. The analysis of 816 BRCA1/2 mutation-negative familial breast cancer patients and 1012 controls revealed an association of the PPARGC1A Thr612Met polymorphism with familial breast cancer (OR = 1.35, 95% CI 1.00-1.81, P = 0.049), high-risk familial breast cancer (OR = 1.51, 95% CI 1.08-2.12, P = 0.017) and bilateral familial breast cancer (OR = 2.30, 95% CI 1.24-4.28, P = 0.009). Logistic regression analyses of the PPARGC1B Ala203Pro variant showed an increased familial breast cancer risk of heterozygous and homozygous variant allele carriers (OR = 1.48, 95% CI 1.15-1.91, P = 0.002). The genotype-combination analysis of the associated PPARGC1A Thr612Met variant and the associated PPARGC1B Ala203Pro variant suggests an allele dose-dependent breast cancer risk (P(trend) = 0.0004). Our results indicate for the first time the importance of inherited variants in the estrogen receptor coactivator genes PPARGC1A and PPARGC1B for familial breast cancer susceptibility. Owing to their impact on estrogen signaling, these polymorphisms might also influence adjuvant anti-estrogen therapy, using agents such as tamoxifen and raloxifen, and outcome of breast cancer patients.

Breast Neoplasms↗
PubMed2006

Familial risk for esophageal cancer: an updated epidemiologic study from Sweden.

BACKGROUND AND AIMS: Familial risks for esophageal cancer are not well known, especially for specific histologic types. METHODS: We used the nationwide Swedish Family-Cancer Database to examine familial risks for esophageal cancer in offspring. Standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were used to calculate the risk. Age standardized incidence rates for specific histology types of esophageal cancer were available from Swedish Cancer Registry. RESULTS: The incidence of male squamous cell carcinoma (SCC) reached its peak rate in 1985 and decreased afterwards. The incidence of adenocarcinoma exceeded that of SCC in 2000 among men. The SIR for offspring esophageal cancer was significantly increased when a parent presented with esophageal cancer (SIR, 2.60). The SIRs for adenocarcinoma were 4.05 and 3.52 when a parent was diagnosed with SCC and any esophageal cancer, respectively; from maternal probands the SIRs were 10.47 and 7.74, respectively. The familial SIR was above unity but not significant for SCC. For associations with other cancer sites, SCC showed a significantly increased risk when a sibling had lung cancer (SIR, 2.52). CONCLUSIONS: The present study showed that adenocarcinoma became the major histologic type of esophageal cancer in Swedish men around 2000. For the first time we could show that familial risks of esophageal adenocarcinoma were increased when parents presented with esophageal cancer (particularly SCC). The high risk for adenocarcinoma in such families might be due to heritable effects. However, because of the limited number of familial cases, the results should be interpreted with caution.

Adenocarcinoma↗
PubMed2006

Risk of second cancer among women with breast cancer.

A large number of women survive a diagnosis of breast cancer. Knowledge of their risk of developing a new primary cancer is important not only in relation to potential side effects of their cancer treatment, but also in relation to the possibility of shared etiology with other types of cancer. A cohort of 525,527 women with primary breast cancer was identified from 13 population-based cancer registries in Europe, Canada, Australia and Singapore, and followed for second primary cancers within the period 1943-2000. We used cancer incidence rates of first primary cancer for the calculation of standardized incidence ratios (SIRs) of second primary cancer. Risk of second primary breast cancer after various types of nonbreast cancer was also computed. For all second cancer sites combined, except contralateral breast cancer, we found a SIR of 1.25 (95% CI = 1.24-1.26) on the basis of 31,399 observed cases after first primary breast cancer. The overall risk increased with increasing time since breast cancer diagnosis and decreased by increasing age at breast cancer diagnosis. There were significant excesses of many different cancer sites; among these the excess was larger than 150 cases for stomach (SIR = 1.35), colorectal (SIR = 1.22), lung (SIR = 1.24), soft tissue sarcoma (SIR = 2.25), melanoma (SIR = 1.29), non-melanoma skin (SIR = 1.58), endometrium (SIR = 1.52), ovary (SIR = 1.48), kidney (SIR = 1.27), thyroid gland (SIR = 1.62) and leukaemia (SIR = 1.52). The excess of cancer after a breast cancer diagnosis is likely to be explained by treatment for breast cancer and by shared genetic or environmental risk factors, although the general excess of cancer suggests that there may be additional explanations such as increased surveillance and general cancer susceptibility.

Adult↗