Identification of frequent chromosome copy-number polymorphisms by use of high-resolution single-nucleotide-polymorphism arrays.
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Chromosome Aberrations↗
Biomedical subjects
Kari Hemminki
Publications and source records attributed to Kari Hemminki.
Socio-economic and occupational risk factors for gastric cancer: a cohort study in Sweden.
The effects of socio-economic/occupational factors on gastric cancer at various subsites (including corpus, cardia and unspecified cancers) are not well known. To investigate this issue, we carried out a follow-up study on the economically active Swedish population, based on the Swedish Family-Cancer Database. We calculated standardized incidence ratios and 95% confidence intervals for different occupational groups, adjusted for age, period, region and socio-economic status. The reference group was all the economically active population. Manual workers and farmers were at an increased risk of stomach cancer. An increased risk of corpus cancer was observed for male miners and quarry workers, fishermen, construction workers, packers, loaders and warehouse workers, clerical workers and female assistant nurses and postal workers. For cardia cancer, significantly increased standardized incidence ratios were observed for gardeners, transport workers, bricklayers and chemical process workers among men. Only male miner and quarry workers showed significantly increased risk of unspecified cancer. In conclusion, the present study indicates that socio-economic groups differ in risk by almost a factor of two for corpus and unspecified cancers, and less for cardia cancers. Cement and mineral dusts appear as major occupational risk factors.
Cohort Studies↗
Lifestyle and cancer: effect of parental divorce.
According to previous studies, divorced individuals have increased risks of cancers related to alcohol and tobacco consumption and sexual habits, but the increases are balanced with decreased risks of many common cancers. In the present study, cancer risks were analyzed for 0-70-year-old offspring of divorced parents, on the basis the Swedish Family-Cancer Database with cancer data from the years 1958 to 2002. We calculated standardized incidence ratios for cancer among offspring of divorced parents (19,000 cancer patients) and compared them with offspring of stably married parents (121,000 cancer patients). Standardized incidence ratios were adjusted for many factors, including socio-economic status. Offspring of divorced parents were divided into groups depending on whether their mothers, fathers or both had had children with different partners. Offspring of divorced parents had an increased risk of upper aerodigestive tract, esophageal, anal, pancreatic, lung and cervical cancers. Decreased risks were noted for Hodgkin's disease and bone cancer. For Hodgkin's disease, the data suggest protective effects through early exposure to childhood pathogens but for bone cancer mechanisms remain to be established. The overall cancer risk for offspring of divorced parents was at or above unity. The results show that offspring of divorced parents have increased cancer risks at tobacco-related, alcohol-related and sex-related sites, in analogy to their parent, but they lack decreased risks at common sites, experienced by their parents. Divorce is becoming increasingly common in many countries and any deviant cancer patterns among offspring of divorced parents will have an impact on the population risk.
Adolescent↗
Familial risks for eye melanoma and retinoblastoma: results from the Swedish Family-Cancer Database.
No systematic population-based studies have been conducted on familial eye cancers. Reliable data on familial risks are important for clinical counselling and cancer genetics. The current analysis was based on the nation-wide Swedish Family-Cancer Database on 10.5 million individuals, containing families with parents and offspring. Cancer data were retrieved from the Swedish Cancer Registry from the years 1958 to 2002, including 3636 patients with any type of eye cancer. Familial risk for offspring was defined using the standardized incidence ratio (SIR), adjusted for many variables. Ocular melanoma was detected in two parent-offspring pairs, but the SIR of 3.90 was not significant. Parental upper aerodigestive tract (2.05), left-sided colon (1.83) and male non-medullary thyroid (6.98) cancers showed an association with ocular melanoma, albeit some with a borderline significance. The SIR for leukaemia was increased when parents were diagnosed with eye melanoma. There was no evidence for the association of ocular melanoma with cutaneous melanoma. The SIR for ocular melanoma was 1.76 when a sister was diagnosed with breast cancer, but there was no increase when a mother was diagnosed with breast cancer. When both a child and the parent presented with retinoblastoma, the SIR was 900. The parents of children with retinoblastoma had an excess of small intestinal and rectal cancers and Hodgkin's disease. The present findings were based on a limited number of cases, but they display a complex and heterogeneous pattern of familial associations in ocular melanoma, including an association with breast cancer through a putative recessive mechanism.
Adult↗
Differences in global gene expression in melanoma cell lines with and without homozygous deletion of the CDKN2A locus genes.
We studied differential global gene expression in four melanoma cell lines with three cell lines without homozygous deletion of the CDKN2A locus using HG-U133A microarrays with 22 277 transcripts. None of the cell lines carried mutations in the B-RAF and N-RAS genes. Data analysis using stringent criteria showed specific upregulation of 70 genes and downregulation of 86 genes in cell lines with homozygous deletion of the CDKN2A gene. A comparison with previous expression data showed overlapping of upregulation and downregulation of seven and 23 genes, respectively, in melanoma cell lines with homozygous deletion of the CDKN2A locus or mutations in the B-RAF and N-RAS genes. Microarray data for eight selected genes were validated with an extended number of cell lines using quantitative real-time polymerase chain reaction. The upregulated genes in cell lines with the deletion besides others included MAGE A2 [fold change 128, 95% confidence interval (CI) 82.8-172.2; t-test P=0.004], MAGE A6 (fold change 623, 95% CI 473.4-772.1; t-test P=0.001), MAGE A12 (fold change 90, 95% CI 65.1-115.5; t-test P=0.001) and dopachrome tautomerase (fold change 42, 95% CI 32.5-51.8; t-test P=0.001). Downregulated genes included interleukin 18 (fold change 489, 95% CI 146.4-831.2; t-test P=0.04), ID2 (fold change 3, 95% CI 2.2-4.9; t-test P=0.001), KLF4 (fold change 9, 95% CI 4.3-14.7; P=0.01) and CD24 antigen (fold change 1308, 95% CI 766.0-1850.8; t-test P=0.01). The upregulated genes common to cell lines with homozygous deletion of the CDKN2A gene and mutations in B-RAF and N-RAS gene included those that are involved in RAS/RAF/MEK/ERK pathways. Our results highlight effects of homozygous deletion of the CDKN2A locus on global gene expression.
Biomarkers, Tumor↗
Familial risks of aortic aneurysms among siblings in a nationwide Swedish study.
PURPOSE: Aortic aneurysms have a high fatality rate that could be reduced with control of risk factors and use of available screening methods for detection of early changes in aortic walls. The available data on familial risks, a potential indication for screening, are mainly limited to abdominal aortic aneurysms. METHODS: A nationwide Swedish cohort was constructed by linking the Multigeneration Register on 0- to 69-year-old siblings to the Hospital Discharge Register and the Cause of Death Register for data on aortic aneurysms from years 1987 to 2001. Standardized incidence ratios (SIRs) were calculated for affected siblings by comparing with those whose siblings had no aneurysm. RESULTS: A total of 71 affected siblings were identified with a familial SIR of 8.71; when one sibling was diagnosed before age 50 years, the SIR was 19.69. For concordant thoracic or concordant abdominal aneurysms, the SIRs were 21.68 and 13.06, respectively. For brothers, the risk of abdominal aneurysms was 14.63, and 49.50 for diagnosis before age 50 years. Familial risks and the effects of early diagnostic age were shared by the anatomic subtypes of aneurysms. Within limits of the sample size, no gender differences could be observed. Affected siblings constituted 2.2% of all diagnosed patients. CONCLUSIONS: A family history of any aortic aneurysms and age groups younger than 50 years should be considered in recommendations for screening. The high familial risks are likely to be the result of heritable genes, the identification of which would allow gene testing and preventive counseling.
Adult↗
Socioeconomic and occupational risk factors for pancreatic cancer: a cohort study in Sweden.
OBJECTIVE: The objective of this study was to examine the associations between socioeconomic/occupational factors and pancreatic cancer. METHODS: The Swedish Family-Cancer Database was used to calculate standardized incidence ratios for different social classes and occupational groups. Lung cancer risks were also determined. The reference group was all the economically active population. RESULTS: Farmers were at a decreased risk of pancreatic cancer. A slightly increased risk of pancreatic cancer, independent of lung cancer, was observed for male professionals and administrators and managers. For women, increased risks were observed for cooks and stewards, and glass, ceramic, and tile workers. CONCLUSIONS: The results show that socioeconomic/occupational factors play a small role in the etiology of pancreatic cancer. In addition to smoking, physical inactivity and obesity may contribute to the observed differences.
Cohort Studies↗
Familial risks in testicular cancer as aetiological clues.
We used the nationwide Swedish Family-Cancer Database to analyse the risk for testicular cancer in offspring through parental and sibling probands. Among 0 to 70-year-old offspring, 4,586 patients had testicular cancer. Standardized incidence ratios for familial risk were 3.8-fold when a father and 7.6-fold when a brother had testicular cancer. Testicular cancer was associated with leukaemia, distal colon and kidney cancer, melanoma, connective tissue tumours and lung cancer in families. Non-seminoma was associated with maternal lung cancer but the risk was highest for the late-onset cases, providing no support to the theory of the in utero effect of maternal smoking on the son's risk of testicular cancer. However, the theory cannot be excluded but should be taken up for study when further data are available on maternal smoking. The high familial risk may be the product of shared childhood environment and heritable causes.
Age Factors↗
A single-nucleotide polymorphism in the XPG gene, and tumour stage, grade, and clinical course in patients with nonmuscle-invasive neoplasms of the urinary bladder.
OBJECTIVE: To evaluate whether the single nucleotide polymorphism (SNP), Asp1104His (G3507C), in the XPG gene affects malignant phenotypes of nonmuscle-invasive urinary bladder neoplasms (NIBN), by investigating associations between the SNP and clinicopathological variables in patients with NIBN. PATIENTS AND METHODS: The 233 patients constituted newly diagnosed cases of primary NIBN in the Stockholm area. The Asp1104His polymorphism in the XPG gene was genotyped using a polymerase chain reaction-restriction fragment length polymorphism technique. RESULTS: The GC + CC genotypes were more frequent in stage pT1 tumours at initial diagnosis than pTa (odds ratio 1.9, 95% confidence interval 1.0-3.5, P = 0.048). The difference was larger in the young group (4.6, 1.9-11.8, P = 0.001). In the young group, the GC + CC genotypes were significantly more frequent in high-grade than in low-grade tumours (3.1, 1.5-6.8, P = 0.004) whereas in the older group the genotypes were less frequent in high-grade tumours (0.3, 0.1-0.7, P = 0.007). The XPG genotypes were not associated with tumour recurrence, stage progression or survival. CONCLUSION: These results suggest that the SNP in the XPG gene might be related to tumour invasiveness in NIBN.
Adult↗
Familial risks for cervical tumors in full and half siblings: etiologic apportioning.
Many studies have shown familial aggregation for cervical cancer, but they have been unable to distinguish between shared environmental and genetic effects. Full and half-siblings were identified from the nationwide Swedish Family-Cancer Database, including invasive and in situ cervical cancers in women up to age 70 years. Half-siblings were defined through a common father or mother. Standardized incidence ratios, adjusted for several variables, were calculated for proband-wise risks between full and half-siblings. The familial risk for full siblings was 1.84, compared with 1.40 for maternal and 1.27 for paternal half-siblings. These data were used to apportion familial risk for cervical tumors in full siblings into a heritable component, accounting for 64%, and an environmental component, accounting for 36% of the total risk. No evidence for gene-environment interactions was found. The intractable difficulty in separating cervical cancer causation will be an obstacle for a successful identification of susceptibility genes.
Adolescent↗
Death receptor 4 variants and colorectal cancer risk.
The tumor necrosis factor-related apoptosis-inducing ligand receptor modulates apoptotic response by binding to the proapoptotic death receptor 4 (DR4). Perturbed apoptosis due to missense alterations in the candidate tumor suppressor gene DR4 leads to deregulated cell proliferation and cancer predisposition. Recent studies have discussed the association of DR4 variants with cancer risk. We evaluated, for the first time, the role of the Thr(209)Arg (626C>G) and Glu(228)Ala (683A>C) polymorphisms on colorectal cancer risk by genotyping 659 incident cases and 607 healthy controls drawn from the German population-based Darmkrebs: Chancen der Verhütung durch Screening (DACHS) study. Whereas DR4 Glu(228)Ala was not associated with colorectal cancer, Thr(209)Arg heterozygotes were at a significantly decreased colorectal cancer risk [odds ratio (OR), 0.73; 95% confidence interval (95% CI), 0.54-0.97]. Stratification according to sex and age exhibited a significant association of Thr(209)Arg with a decreased risk for male heterozygotes (OR, 0.68; 95% CI, 0.46-0.99) and for Arg(209) carriers > or =65 years of age (OR, 0.65; 95% CI, 0.46-0.92) as well as an enhanced risk for female Ala(228) carriers in a allele dose-dependent manner (P(trend) = 0.01). Subsite analysis revealed a protective effect of Thr(209)Arg for rectal cancer risk (OR, 0.67; 95% CI, 0.48-0.95) and a significant risk increase for Ala(228) carriers with advanced colorectal cancer stages (P(trend) = 0.04). Haplotype analysis revealed a 2.4-fold risk for carriers of the rare 626C-683C haplotype (1% prevalence in the general population; OR, 2.37; 95% CI, 0.98-5.76). The score statistic yielded an empirical P of 0.03 of the haplotype-specific test for 626C-683C based on 20,000 simulations, suggesting that DR4 626C-683C may affect colorectal cancer predisposition.
Adult↗
Number of siblings and the risk of lymphoma, leukemia, and myeloma by histopathology.
Epidemiologic evidence indicates that several markers of exposure to childhood infections are inversely associated with the risk of childhood leukemia and lymphomas. We used the Swedish Family-Cancer Database to assess the effects of number of siblings on the risk of non-Hodgkin's (n = 7,007) and Hodgkin's lymphomas (n = 3,115), leukemias (n = 7,650), and multiple myeloma (n = 1,492) by histopathology. Poisson regression models included terms for age, sex, family history, period, and socioeconomic index. Having four or more siblings compared with none was associated with an excess risk of childhood acute lymphoblastic leukemia [ALL; rate ratio (RR), 2.11; P(trend) = 0.001], acute monocytic leukemia (RR, 2.51; P(trend) = 0.002), and multiple myeloma (RR, 1.34; P(trend) = 0.006). Having three or more older siblings compared with none decreased the risk of acute monocytic leukemia (RR, 0.35; P(trend) = 0.001) and childhood ALL (RR, 0.69; P(trend) = 0.01). The risk of Hodgkin's lymphoma for five or more older siblings compared with none was 0.41 (P(trend) = 0.003). Acute myeloid leukemia, chronic lymphocytic leukemia, and other lymphoproliferative malignancies were not associated with number of siblings. In conclusion, we found an excess risk of childhood ALL and acute monocytic leukemia in large families. However, for ALL, acute monocytic leukemia, and Hodgkin's lymphoma, younger siblings were strongly protected compared with older siblings. The remarkable protective effect of number of older siblings on acute monocytic leukemia is a novel finding of potential interest. Possible interpretations of our findings in the context of a putative infectious etiology are discussed.
Adolescent↗
Gene-environment interactions in cancer: do they exist?
Single nucleotide polymorphisms (SNPs) are extensively used in case-control studies of practically all cancer types. In addition to the pure genetic studies, gene-environment studies, which simultaneously consider environmental factors, have been increasingly conducted. All SNP studies aim at the identification of the role of inherited cancer susceptibility genes. However, being genetic markers, they are applicable only on heritable conditions, which is often a neglected fact. Based on the data on the heritability of cancer and the importance of environmental factors in cancer etiology, we discuss the likelihood of successful gene-environment studies. The available evidence is not conclusive, but it consistently points to a minor heritable etiology in cancer, which will hamper the success of SNP-based association studies. We use simulation techniques to examine which situations would favor the application of a gene-environment approach instead of the traditional environmental approach in case-control studies. The results show that well-chosen candidate gene with a relatively low allele frequency may improve the power to detect environmental determinants of a disease. However, this advantage is lost when the number of underlying genes increases. We are concerned about an indiscriminate use of genetic tools for cancers, which are mainly environmental in origin. The likelihood of success for SNP-based gene-environment studies increases if established environmental risk factors are tested on proven candidate genes. Enhancing the likelihood that the disease causation is genetic, for example, by selecting familial cases, may increase the power of the studies, and the rareness of those cases calls for collaborative networks.
Cocarcinogenesis↗
STR markers for kinship analysis.
The analysis of short tandem repeats is a widely used method to estimate relatedness between closely related populations or individuals. The AmpFlSTR PCR Amplification Kit has 15 highly variable autosomal markers of tetranucleotide repeats and is principally made to identify individuals and first- or second-degree relatives. However, in many studies one is searching for individuals who are related through more than one generation. We wanted to test whether the amplification kit can also be used to identify more distantly related individuals. Therefore we compared 16 different methods that calculate genetic distance with regard to each method's ability to cluster more distantly related individuals from two test families. Among all the tested methods Nei et al.'s (1983) DA distance performed well in clustering family members within a group of unrelated individuals for a broad range of scenarios. However, second-degree relatives were difficult to cluster with any of the examined methods when other family members were absent. With a simulation we further estimated how many markers would actually be needed to detect a certain degree of relatedness. According to this simulation, one would need at least 123 independent microsatellite markers to detect third-degree relatives with 90% probability. In conclusion, the 15 STR markers in the amplification kit are suitable for detecting only very closely related individuals or entire families.
Female↗
Familial risks for main neurological diseases in siblings based on hospitalizations in Sweden.
Recent successes in identifying the underlying genetic mechanisms for neurological diseases, particularly for their Mendelian forms, have had profound implications for their diagnostics, treatment and classification. However, there has never been an attempt to compare familial risks in a systematic way among and between the main neurological diseases. Familial risks were here defined for siblings who were hospitalized because of a neurological disease in Sweden. A nationwide database for neurological diseases was constructed by linking the Multigeneration Register of 0- to 69-year-old siblings to the Hospital Discharge Register for the years 1987 to 2001. Standardized risk ratios were calculated for affected sibling pairs by comparing them to those whose siblings had no neurological disease. There were three main results. First, it was shown that all disease groups had a familial risk, with the exception of transient ischemic attacks, and the risks could be ranked from the highest (3451) for Huntington's disease to the lowest (2.1) for inflammatory diseases. Second, increased familial risks were shown for disease subtypes for which susceptibility genes or familial clustering have not been demonstrated previously, including multiple sclerosis, sleep apnea, nerve, nerve root and plexus disorders, and cerebral palsy. Third, based on the available sample size there was no convincing evidence for familial comorbidity between the disease groups, suggesting that the factors causing familial aggregation, probably usually heritable genes, are distinct for each subtype. The high familial risks for neurological disease imply heritable etiology and opportunities for identification of further susceptibility genes.
Adolescent↗
Familial risks for diseases of myoneural junction and muscle in siblings based on hospitalizations and deaths in sweden.
Diseases of the myoneural junction and muscle are disabling and some are life-threatening. Recent successes in the identification of the underlying genetic mechanisms have had profound implication for their diagnostics, treatment and classification. We define familial risks for siblings who were hospitalized for or deceased from diseases of the myoneural junction and muscle. A nationwide database on diseases of the myoneural junction and muscle was constructed by linking the Multigeneration Register on 0- to 69-year-old siblings to the Hospital Discharge Register and the Causes of Death Register from years 1987 to 2001. Standardized risk ratios (SIRs) were calculated for affected sibling pairs by comparing to those whose siblings had no diseases of myoneural junction and muscle. Among a total of 2307 patients, myasthenia gravis, muscular dystrophy and myotonic disorders were commonest diagnoses. The sibling risks for these disease were 22, 190 and 198, respectively, when a sibling was diagnosed with any disease of the myoneural junction and muscle. The concordant SIRs, both siblings presenting the same disease, were 42 for myasthenia gravis, 737 for muscular dystrophy, 2000 for congenital myopathy, 1211 for myotonic disorder, 909 for periodic paralysis and 209 for unspecified myopathy. Only a few discordant sibling pairs were noted. The very high overall SIRs for the diseases of the myoneural junction and muscle imply that the sporadic forms of these diseases are relatively rare and these diseases are overwhelmingly heritable.
Adolescent↗
Influence of polymorphism in DNA repair and defence genes on p53 mutations in bladder tumours.
We studied the effects of polymorphisms in nine genes involved in DNA repair and detoxification on occurrence and type of p53 mutation in 327 bladder cancer patients. The included polymorphisms are XPC(Lys939Gln), XPD(Lys751Gln), XPG(Asp1104His), XRCC1(Arg3999Gln), XRCC3(Thr241Met), NBS1(Glu185Gln), cyclin D1(Pro241Pro), MTHFR(Ala222Val and Glu429Ala) and NQO1(Arg139Trp and Pro187Ser). We found increased risk for p53 mutation among cyclin D1 variant allele homozygotes (OR 2.4 CI 0.8-6.7). Among non-smokers, 75% (3/4) with p53 mutation but only 12.5% (3/24) without p53 mutations were XRCC3 241Met homozygotes (P=0.03). Among smokers, all p53 transversions (3/3), but only 41.7% (5/12) of p53 transitions were found among carriers of the XPC 939Gln allele. Individuals carrying the NQO1 187Ser allele showed increased risk for p53 transversions (OR 4.7, CI 0.9-26.1). All (2/2) NQO1 139Trp allele carriers but only 17.5% (7/40) of the Arg139 homozygotes had p53 transversions. Our findings suggest that altered repair and detoxification due to genetic polymorphism may influence the occurrence of p53 mutations in bladder cancer.
DNA Repair↗
c-MYC Asn11Ser is associated with increased risk for familial breast cancer.
c-MYC is a multifaceted protein that regulates cell proliferation, differentiation and apoptosis. Its crucial role in diverse cancers has been demonstrated in several studies. Here, we analysed the influence of the rare c-MYC Asn11Ser polymorphism on familial breast cancer risk by performing a case-control study with a Polish (cases n = 349; controls n = 441) and a German (cases n = 356; controls n = 655) study population. All cases have been tested negative for mutations in the BRCA1 and BRCA2 genes. A joint analysis of the Polish and the German study population revealed a 54% increased risk for breast cancer associated with the heterozygous Asn11Ser variant (OR = 1.54, 95% CI 1.05-2.26, p = 0.028). The breast cancer risk associated with this genotype increases above the age of 50 years (OR = 2.24, 95% CI 1.20-4.21, p = 0.012). The wild-type amino acid Asn of this polymorphism is located in the N-terminal MYC transactivation domain and is highly conserved not only among most diverse species but also in the N-MYC homologue. Due to the pivotal role of c-MYC in diverse tumours, this variant might affect the genetic susceptibility of other cancers as well.
Amino Acid Sequence↗