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Kari Hemminki

Publications and source records attributed to Kari Hemminki.

At least 19 recordsLinked to original sources
PubMed2026

GWAS meta-analysis provides new insights into uveal melanoma risk.

OBJECTIVE: The aim of this research is to identify germline genetic variants that predispose to uveal melanoma (UM) using data from nine studies involving 5839 individuals with UM (3853 novel) and 349,863 healthy controls. METHODS: Five novel UM genome-wide association studies (GWAS) were performed and included for meta-analysis with four previously published UM GWAS. A fixed-effects inverse-variance weighted (IVW) meta-analysis was performed by combining data from these nine UM case-control cohorts. A follow-up transcriptome-wide association study (TWAS) was conducted to identify candidate target genes at UM risk loci. Genetic correlations with melanoma-related phenotypes were measured to elucidate UM's genetic architecture. RESULTS: We identify nine linkage disequilibrium (LD)-independent loci (three novel) with an IVW P value of less than 5 × 10-8. TWAS analysis indicates five potential target genes, including MOB3B, RBAK, and MTSS1, which have established links to multiple cancer types. We note a significant genetic correlation (rg = 0.31, P = 0.01) between UM and cutaneous melanoma (CM), and a non-significant but consistent correlation with naevus count (rg = 0.25, P = 0.08). CONCLUSIONS: This meta-analysis offers new insights into the genetic architecture of UM, highlights potential therapeutic targets, and explores the genetic relationship with CM and skin pigmentation.

Humans↗
PubMed2007

Risk of second malignant neoplasms among lymphoma patients with a family history of cancer.

Radiotherapy and chemotherapy are known risk factors for second cancers after lymphoma. The role of genetic influences, however, remains largely unknown. We assessed risk of second cancers associated with family history of any cancer in 41,181 patients with Hodgkin lymphoma (HL) (n = 7,476), non-Hodgkin lymphoma (NHL) (n = 25,941), or chronic lymphocytic leukemia (CLL) (n = 7,764), using a large population-based database. Family history of cancer was based on a diagnosis of any cancer in 110,862 first-degree relatives. We found increased relative risk (RR) (1.81, 95% confidence interval (CI): 1.04-3.16) of breast cancer among HL patient with positive (vs. negative) family history of cancer. Among CLL patients with positive (vs. negative) family history of cancer, we observed elevated risks of bladder (RR = 3.53, 95% CI: 1.31-9.55) and prostate cancer (RR = 2.15, 95% CI: 1.17-3.94). For NHL patients with positive (vs. negative) family history of cancer, we observed non-significantly increased risk of non-melanoma skin cancer (RR = 1.94, 95% CI: 0.86-4.38) and lung cancer (RR = 1.99, 95% CI: 0.73-5.39). Our observations suggest that genetic factors, as measured by positive family history of cancer, may be influential risk-factors for selected second tumors following lymphoproliferative disorders.

Adult↗
PubMed2007

Second malignancies among survivors of germ-cell testicular cancer: a pooled analysis between 13 cancer registries.

We investigated the risk of second malignancies among 29,511 survivors of germ-cell testicular cancer recorded in 13 cancer registries. Standardized incidence ratios (SIRs) were estimated comparing the observed numbers of second malignancies with the expected numbers obtained from sex-, age-, period- and population-specific incidence rates. Seminomas and nonseminomas, the 2 main histological groups of testicular cancer, were analyzed separately. During a median follow-up period of 8.3 years (0-35 years), we observed 1,811 second tumors, with a corresponding SIR of 1.65 (95% confidence interval (CI): 1.57-1.73). Statistically significant increased risks were found for fifteen cancer types, including SIRs of 2.0 or higher for cancers of the stomach, gallbladder and bile ducts, pancreas, bladder, kidney, thyroid, and for soft-tissue sarcoma, nonmelanoma skin cancer and myeloid leukemia. The SIR for myeloid leukemia was 2.39 (95% CI: 1.41-3.77) after seminomas, and 6.77 (95% CI: 4.14-10.5) after nonseminomas. It increased to 37.9 (95% CI: 18.9-67.8; based on 11 observed cases of leukemia) among nonseminoma patients diagnosed since 1990. SIRs for most solid cancers increased with follow-up duration, whereas they did not change with year of testicular cancer diagnosis. Among subjects diagnosed before 1980, 20 year survivors of seminoma had a cumulative risk of solid cancer of 9.6% (95% CI: 8.7-10.5%) vs. 6.5% expected, whereas 20 years survivors of nonseminoma had a risk of 5.0% (95% CI: 4.2-6.0%) vs. 3.1% expected. In conclusion, survivors of testicular cancers have an increased risk of several second primaries, where the effect of the treatment seems to play a major role.

Adult↗
PubMed2007

Associations between ocular melanoma and other primary cancers: an international population-based study.

Ocular melanoma is a rare neoplasm with a poorly understood etiology, especially concerning its link with ultraviolet-light exposure. Studying the risk of second primary cancers may help to formulate causal hypotheses. We used data from 13 cancer registries, including 10,396 first occurring ocular melanoma cases, and 404 second occurring cases. To compare the second cancer incidence in ocular melanoma patients to that in noncancer population, we calculated standardized incidence ratios (SIRs) of 32 types of cancer. We also calculated SIRs of second ocular melanoma after other primaries. Ocular melanoma patients had significantly increased risk of cutaneous melanoma (SIR = 2.38, 95% CI 1.77-3.14), multiple myeloma (SIR = 2.00, 1.29-2.95), and of liver (SIR = 3.89, 2.66-5.49), kidney (SIR = 1.70, 1.22-2.31), pancreas (SIR = 1.58, 1.16-2.11), prostate (SIR = 1.31, 1.11-1.54), and stomach (SIR = 1.33, 1.03-1.68) cancers. Risks of cutaneous melanoma were highly variable between registries and were mainly increased in females, in younger patients, in first years following diagnosis, and for patients diagnosed after 1980. The risk of ocular melanoma was significantly increased only after prostate cancer (SIR = 1.41, 1.08-1.82). Risk of cutaneous melanoma after ocular melanoma had epidemiological patterns, similar to cutaneous melanoma screening in the general population. The increased risk of cutaneous melanoma would be largely due to greater skin cancer surveillance in ocular melanoma patients, and not to common etiological factors. The high SIR found for liver cancer may be explained by misclassification bias. Common etiological factors may be involved in ocular and prostate cancers.

Adolescent↗
PubMed2007

Familial risks for nerve, nerve root and plexus disorders in siblings based on hospitalisations in Sweden.

BACKGROUND: Nerve, nerve root and plexus disorders are common diseases, but little is known about familial clustering in these diseases. This is, to our knowledge, the first systematic family study carried out on these diseases. METHODS: Familial risks for siblings who were hospitalised for nerve, nerve root and plexus disorders in Sweden were defined. A nationwide database for neurological diseases was constructed by linking the Multigeneration Register on 0-69-year-old siblings to the Hospital Discharge Register covering the years 1987-2001. Standardised risk ratios (SIRs) were calculated for affected sibling pairs by comparing them with those whose siblings had no neurological disease. RESULTS: 29,686 patients, 43% men and 57% women, were diagnosed at a mean age of 37.5 years. 191 siblings were hospitalised for these disorders, giving an overall SIR of 2.59 (95% CI 1.58 to 4.22), with no sex difference. Plantar nerve mononeuritis and carpal tunnel syndrome showed the highest familial risks: 4.82 (1.08 to 16.04) and 4.08 (2.07 to 7.84), respectively. Lateral poplitean and plantar nerve neuritis preferentially affected women, with SIRs of >8; disorders of the other cranial nerves affected only men, with an SIR of >10. Concordant trigeminal neuralgia, Bell's palsy and carpal tunnel syndrome showed familial risks, but, with the exception of Bell's palsy, they also showed correlation between spouses, implying environmental sharing of risk factors. CONCLUSIONS: The results cannot distinguish between inheritable or shared environmental factors, or their interactions, but they clearly show familial clustering, suggestive of multifactorial aetiology and inviting for aetiological research.

Adolescent↗
PubMed2006

Association between number of siblings and nervous system tumors suggests an infectious etiology.

OBJECTIVE: To estimate the effect of the number of siblings on the risk of histopathologic subtypes of tumors of the nervous system using large population-based data. METHODS: The Swedish Family-Cancer Database comprises 13,613 diagnoses of nervous system tumors with histopathologic information. We analyzed the data using Poisson regression models taking into account potential confounding effects of age, birth cohort, socioeconomic status, and family history of cancer. RESULTS: The rate ratios (RR) for having four or more siblings vs none were significantly increased for hemangioblastoma (RR = 1.68), childhood neuroblastoma (RR = 2.01), and ependymoma (RR = 1.83, p trend < 0.01). For age at diagnosis < or =15 years, the RRs for individuals with three or more younger siblings compared to none were 1.34 for astrocytoma, 2.30 for medulloblastoma, 2.61 for ependymoma, 3.71 for meningioma, and 2.13 for neuroblastoma, with significant trends in risk. Non-significant decreased risks were found between the number of older siblings and nervous system tumors. CONCLUSIONS: We provide the first reliable quantification of the effects of number of siblings on the risk of nervous system tumors. Sibship size and number of younger siblings correlate with the incidence of childhood nervous system tumors, suggesting a role of infectious agents in the etiology of the disease.

Adolescent↗
PubMed2006

Heritable and environmental components in cervical tumors.

The familial risk of 18,199 women with invasive and/or in situ cervix cancers when compared with that of 72,796 women free of cervical tumors was analyzed. The risk of cervical tumors was significantly higher for women with a mother and/or sister(s) with cervical tumors (odds ratio (OR) = 1.79, 95% CI: 1.71-1.88) than with an affected grandmother and/or aunt(s) (OR = 1.28, 1.22-1.35). This risk did not differ according to the family side of the affected relative. Taking the familial risk of 1.28 for second-degree relatives as the best estimate of a true heritable effect for 25% of gene sharing, the calculated heritable effect for full siblings, sharing 50% of their genes, would correspond to an OR of 1.56. This model suggests, as a best estimate, a heritable component of 71% and an environmental component of 29% in young familial cervical tumors. The data imply that familial risks for cervical tumors are best explained by complex multifactorial mechanisms.

Adult↗
PubMed2006

Risk for contralateral breast cancers in a population covered by mammography: effects of family history, age at diagnosis and histology.

BACKGROUND: Improved survival for breast cancer is increasing the likelihood of contralateral tumors. Mammographic screening is partially contributing to the survival advantage, while changing many aspects of breast cancer presentation, including age at diagnosis, histology and familial risk. As mammography has become widely used, it is important to quantify the risks for contralateral breast cancer in a population with a national access to mammographic screening service. METHODS: The nation-wide Swedish Family-Cancer Database was used to calculate risks for contralateral breast cancer between years 1990 (1993) and 2002. The standardized incidence ratio (SIR) measured the risk for contralateral breast compared to first breast cancer. RESULTS: The risks for contralateral breast cancer ranged between 1.85 and 3.79, and they tended to be higher when in situ cancer was diagnosed. Family history and early diagnosis of first cancer increased the risks for contralateral breast cancer, approximately equally for invasive and in situ cancers. The risk for contralateral in situ cancer was 9.01 following two independent invasive cancers. The risk for the same, concordant histology between the first and the contralateral cancer was higher than that for discordant histologies. The risks for concordant histologies were particularly high for mucinous (12.16), comedo (11.74) and lobular (5.06) tumors. When the first lobular cancer was diagnosed before age 45 years, the risk for contralateral lobular cancer was 32.20. CONCLUSION: In situ breast cancer poses an approximately equally high risk as invasive cancer. Family history and earlier age of onset are associated with high risks needing clinical attention.

Adult↗
PubMed2006

Transcription factor 7-like 2 (TCF7L2) variant is associated with familial breast cancer risk: a case-control study.

BACKGROUND: The transcription factor 7-like 2 (TCF7L2) is a critical component of the Wnt/beta-catenin pathway. Aberrant TCF7L2 expression modifies Wnt signaling and mediates oncogenic effects through the upregulation of c-MYC and cyclin D. Genetic alterations in TCF7L2 may therefore affect cancer risk. Recently, TCF7L2 variants, including the microsatellite marker DG10S478 and the nearly perfectly linked SNP rs12233372, were identified to associate with type 2 diabetes. METHODS: We investigated the effect of the TCF7L2 rs12255372 variant on familial breast cancer (BC) risk by means of TaqMan allelic discrimination, analyzing BRCA1/2 mutation-negative index patients of 592 German BC families and 735 control individuals. RESULTS: The T allele of rs12255372 showed an association with borderline significance (OR = 1.19, 95% C.I. = 1.01-1.42, P = 0.04), and the Cochran-Armitage test for trend revealed an allele dose-dependent association of rs12255372 with BC risk (Ptrend = 0.04). CONCLUSION: Our results suggest a possible influence of TCF7L2 rs12255372 on the risk of familial BC.

Adult↗
PubMed2006

The GH1/IGF-1 axis polymorphisms and their impact on breast cancer development.

The growth hormone 1/insulin-like growth factor-1 (GH1/IGF-1) axis plays an essential role in the development of the breast by regulating cell proliferation, differentiation and apoptosis. Imbalances within this axis lead to an aberrant signalling and recent research has focussed on the overexpression of these growth factors and their involvement in breast cancer development. The increased understanding of the molecular mechanisms and signalling pathways connected to the GH1/IGF-1 axis has provided important insights into aetiology, prevention and therapy for breast cancer. However, to identify the contribution of the GH1/IGF-1 signalling pathway to cancer risk still remains a challenge since the results of various studies are controversial. Here, we discuss the influence of low-penetrance polymorphisms in the genes along the GH1/IGF-1 axis and their impact on hormone levels and cancer risk, especially breast cancer. We point out what is known about the effects of the variants and show how the interaction of genetic variants affects breast cancer risk.

Breast Neoplasms↗
PubMed2006

Promoter polymorphisms in matrix metalloproteinases and their inhibitors: few associations with breast cancer susceptibility and progression.

The importance of matrix metalloproteinases and their inhibitors in tumor progression is well documented. We wanted to investigate if single nucleotide polymorphisms (SNPs) in the promoter regions of these genes are associated with susceptibility to or progression of breast cancer. In this, so far largest case-control study, we genotyped eight SNPs in the MMP1, MMP2, MMP3, MMP9, MMP13, RECK and TIMP3 genes in a well-characterized breast cancer series of 959 cases and 952 controls from Sweden. Even though we did not correct for multiple comparisons, only a few associations were noted. We observed a moderately increased risk for the TT homozygotes of the MMP9-1562 C/T SNP (OR 1.88, 95% CI 0.97-3.63) and for the C allele carriers of the TIMP3-1296 T/C SNP (OR 1.25, 95% CI 1.05-1.50). In the survival analysis, only the TC heterozygotes of the RECK-420 T/C SNP showed a better survival compared to the TT homozygotes (P = 0.02 in all cases and P = 0.03 in lymph node negative cases). None of the other SNPs conferred an increased breast cancer risk, nor did they correlate with survival. A combination of the -585 TT homozygosity in the RECK gene and the -1296 TT homozygosity in the TIMP3 gene correlated with estrogen and progesterone receptor status (OR 1.81, 95% CI 1.03-3.21 and OR 2.10, 95% CI 1.18-3.86, respectively), and a combination of the -1306 TT homozygosity in the MMP2 gene and the -1562 CC homozygosity in the MMP9 gene with progesterone receptor status (OR 2.34, 95% CI 1.08-5.08). Although our study suggests some correlations between the studied SNPs and the progression of breast cancer, the rarity of the risk genotypes limits their usefulness in the clinic.

Adult↗
PubMed2006

Association of DNA repair polymorphisms with DNA repair functional outcomes in healthy human subjects.

We investigated association between polymorphisms in DNA repair genes and the capacity to repair DNA damage induced by gamma-irradiation and by base oxidation in a healthy population. Irradiation-specific DNA repair rates were significantly decreased in individuals with XRCC1 Arg399Gln homozygous variant genotype (0.45 +/- 0.47 SSB/10(9) Da) than in those with wild-type genotype (1.10 +/- 0.70 SSB/10(9) Da, P=0.0006, Mann-Witney U-test). The capacity to repair oxidative DNA damage was significantly decreased among individuals with hOGG1 Ser326Cys homozygous variant genotype (0.37 +/- 0.28 SSB/10(9) Da) compared to those with wild-type genotype (0.83 +/- 0.79 SSB/10(9) Da, P=0.008, Mann-Witney U-test). Investigation of genotype combinations showed that the increasing number of variant alleles for both XRCC1 Arg399Gln and APE1 Asn148Glu polymorphisms resulted in a significant decrease of irradiation-specific repair rates (P=0.008, Kruskal-Wallis test). Irradiation-specific DNA repair rates also decreased with increasing number of variant alleles in XRCC1 Arg399Gln in combination with variant alleles for two other XRCC1 polymorphisms, Arg194Trp and Arg280His (P=0.002 and P=0.005, respectively; Kruskal-Wallis test). In a binary combination variant alleles of hOGG1 Ser326Cys and APE1 Asn148Glu polymorphisms were associated with a significant decrease in the capacity to repair DNA oxidative damage (P=0.018, Kruskal-Wallis test). In summary, XRCC1 Arg399Gln and hOGG1 Ser326Cys polymorphisms seem to exert the predominant modulating effect on irradiation-specific DNA repair capacity and the capacity to repair DNA oxidative damage, respectively.

Adult↗
PubMed2006

ARLTS1 variants and melanoma risk.

Variants in the tumor suppressor gene ARLTS1 (ADP-ribosylation factor-like tumor-suppressor gene 1) have been shown to influence familial cancer risk. Both Cys148Arg and Trp149Stop were associated with an increased risk of familial or high-risk familial breast cancer, respectively. We studied the impact of these gene variants on melanoma risk, investigating 351 melanoma patients and 804 control subjects. While ARLTS1 Trp149Stop did not influence melanoma risk (OR = 0.83, 95% CI = 0.37-1.88, p = 0.65), Cys148Arg revealed a statistically significant association with an increased risk for heterozygous carriers (OR = 1.43, 95% CI = 1.05-1.95, p = 0.02). An additional risk enhancement, though statistically non-significant, was observed in individuals with multiple melanomas (OR = 2.33, 95% CI = 0.87-6.26, p = 0.08).

ADP-Ribosylation Factors↗
PubMed2006

Constraints for genetic association studies imposed by attributable fraction and familial risk.

Candidate gene studies have become very popular but some of their implicit constraints, such as the familial risk and the population attributable fraction (PAF) conferred by the gene under study, are poorly understood. We model here these parameters for susceptibility genes in terms of genotype relative risk (GRR), allele frequency and statistical power in simulated genetic association studies, assuming 500 or 2000 case-control pairs and different modes of inheritance. The results show that the common association studies on genes with minor allele frequency >10% have sufficient power to detect disease-causing variants conferring PAFs >10%, which can be compared to known genes, such as BRCA1 with a PAF of 1.8%. Yet, common low-risk variants confer low familial relative risks (FRRs), typically <1.1. The models show that candidate gene studies may be able to identify genes conferring close to 100% of the PAF, but they may not explain the empirical FRRs. In order to explain FRRs, rare, high-penetrant genes or interacting combinations of common variants need to be uncovered. However, the candidate gene studies for common alleles do not target this class of genes. The results may challenge the common disease-common variant hypothesis, which posits common variants with low GRRs and large PAFs, however failing to accommodate the empirical FRRs.

Case-Control Studies↗
PubMed2006

Autoimmunity and susceptibility to Hodgkin lymphoma: a population-based case-control study in Scandinavia.

BACKGROUND: Personal history of autoimmune diseases is consistently associated with increased risk of non-Hodgkin lymphoma. In contrast, there are limited data on risk of Hodgkin lymphoma following autoimmune diseases and almost no data addressing whether there is a familial association between the conditions. METHODS: Using population-based linked registry data from Sweden and Denmark, 32 separate autoimmune and related conditions were identified from hospital diagnoses in 7476 case subjects with Hodgkin lymphoma, 18,573 matched control subjects, and more than 86,000 first-degree relatives of case and control subjects. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) as measures of relative risks for each condition using logistic regression and also applied multivariable hierarchical regression models. All P values are two-sided. RESULTS: We found statistically significantly increased risks of Hodgkin lymphoma associated with personal histories of several autoimmune conditions, including rheumatoid arthritis (OR = 2.7, 95% CI = 1.9 to 4.0), systemic lupus erythematosus (OR = 5.8, 95% CI = 2.2 to 15.1), sarcoidosis (OR = 14.1, 95% CI = 5.4 to 36.8), and immune thrombocytopenic purpura (OR = infinity, P = .002). A statistically significant increase in risk of Hodgkin lymphoma was associated with family histories of sarcoidosis (OR = 1.8, 95% CI = 1.01 to 3.1) and ulcerative colitis (OR = 1.6, 95% CI = 1.02 to 2.6). CONCLUSIONS: Personal or family history of certain autoimmune conditions was strongly associated with increased risk of Hodgkin lymphoma. The association between both personal and family histories of sarcoidosis and a statistically significantly increased risk of Hodgkin lymphoma suggests shared susceptibility for these conditions.

Adolescent↗
PubMed2006

The functional genetic variant Ile646Val located in the kinase binding domain of the A-kinase anchoring protein 10 is associated with familial breast cancer.

Overexpression of cAMP-dependent protein kinase A (PKA) is a hallmark of the great majority of human cancers including breast cancer. A-kinase anchoring proteins (AKAPs) coordinate the specificity of PKA signalling by localizing the kinase to its subcellular sites. We tested the hypothesis whether the functional amino acid exchange Ile646Val, located in the kinase-binding domain of AKAP10, is a low-penetrance familial breast cancer risk factor. Ile646Val alters the binding of AKAP10 to PKA and is associated with morbidity. The analysis of 787 BRCA1/2 mutation-negative familial breast cancer patients and 993 controls revealed an association of the AKAP10 Ile646Val polymorphism with increased familial breast cancer risk [odds ratio (OR)=1.25, 95% confidence interval (CI) 1.03-1.51, P=0.024]. Our previous study has shown that AKAP13 Lys526Gln is associated with familial breast cancer (OR=1.58). Here, we discovered that carriers of both variants, AKAP10 Ile646Val and AKAP13 Lys526Gln, are at a further enhanced breast cancer risk (OR=2.41, 95% CI 1.30-4.46, P=0.005). PKA is a major target of therapeutic anticancer strategies. Phosphorylation of the estrogen receptor (ER) alpha by PKA induces resistance against the anti-estrogen tamoxifen. Our results indicate for the first time the importance of AKAP10 Ile646Val for familial breast cancer susceptibility. Due to the impact of Ile646Val on the subcellular localization of PKA, it will be interesting to investigate whether this polymorphism influences the effectiveness of PKA and tamoxifen based therapeutic anticancer concepts.

A Kinase Anchor Proteins↗