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  • 1
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    Keywords: RECEPTOR ; APOPTOSIS ; CANCER ; KINASE ; MODEL ; GENES ; TIME ; CELL-CYCLE ; ASSOCIATION ; single nucleotide polymorphism ; breast cancer ; PROGRESSION ; AMPLIFICATION ; PROMOTER ; case-control study ; SINGLE NUCLEOTIDE POLYMORPHISMS ; GENOTYPE ; susceptibility loci ; GENOME-WIDE ASSOCIATION ; 20q13 ; B-MYB TRANSCRIPTION
    Abstract: The 20q13 region is frequently amplified/overexpressed in breast tumours. However, the nature of this amplification/overexpression is unknown. Here, we investigated genetic variation in five 20q13 amplicon genes (MYBL2, AURKA, ZNF217, STK4 and PTPN1) and its impact on breast cancer (BC) susceptibility and clinical outcome. As a novel finding, four polymorphisms in STK4 (rs6017452, rs7271519) and AURKA (rs2273535, rs8173) associated with steroid hormone receptor status both in a Swedish population-based cohort of 783 BC cases and in a Polish familial/early onset cohort of 506 BC cases. In the joint analysis, the minor allele carriers of rs6017452 had more often hormone receptor positive tumours (OR 0.57, 95% CI 0.40-0.81), while homozygotes for the minor allele of rs7271519, rs2273535 and rs8173 had more often hormone receptor negative tumours (2.26, 1.30-3.39; 2.39, 1.14-5.01; 2.39, 1.19-4.80, respectively) than homozygotes for the common allele. BC-specific survival analysis of AURKA suggested that the Swedish carriers of the minor allele of rs16979877, rs2273535 and rs8173 might have a worse survival compared with the major homozygotes. The survival probabilities associated with the AURKA genotypes depended on the tumour phenotype. In the Swedish case-control study, associations with BC susceptibility were observed in a dominant model for three MYBL2 promoter polymorphisms (rs619289, P = 0.02; rs826943, P = 0.03 and rs826944, P = 0.02), two AURKA promoter polymorphisms (rs6064389, P = 0.04 and rs16979877, P = 0.02) and one 3'UTR polymorphism in ZNF217 (rs1056948, P = 0.01). In conclusion, our data confirmed the impact of the previously identified susceptibility locus and provided preliminary evidence for novel susceptibility variants in BC. We provided evidence for the first time that genetic variants at 20q13 may affect hormone receptor status in breast tumours and influence tumour aggressiveness and survival of the patients. Future studies are needed to confirm the prognostic value of our findings in the clinic.
    Type of Publication: Journal article published
    PubMed ID: 21630024
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  • 3
    Keywords: CANCER ; EXPRESSION ; SURVIVAL ; RISK ; GENE-EXPRESSION ; GENOME ; METABOLISM ; COMPLEX ; prognosis ; ASSOCIATION ; single nucleotide polymorphism ; METASTASIS ; colorectal cancer ; COLORECTAL-CANCER ; PROGNOSTIC MARKERS
    Abstract: Background: Currently, the TNM classification of malignant tumours based on clinicopathological staging remains the standard for colorectal cancer (CRC) prognostication. Recently, we identified the mitochondrial oxidative phosphorylation chain as a consistently overrepresented category in the published gene expression profiling (GEP) studies on CRC prognosis. Methods: We evaluated associations of putative regulatory single nucleotide polymorphisms (SNPs) in genes from the oxidative phosphorylation chain with survival and disease prognosis in 613 CRC patients from Northern Germany (PopGen cohort). Results: Two SNPs in the 3' untranslated region of UQCRB (complex III), rs7836698 and rs10504961, were associated with overall survival (HR = 0.52, 95% CI 0.32-0.85 and HR = 0.64, 95% CI 0.42-0.99, for TT carriers). These associations were restricted to the group of patients with cancer located in the colon (HR = 0.42, 95% CI 0.22-0.82 and HR = 0.46, 95% CI 0.25-0.83). Multivariate analysis indicated that both markers might act as independent prognostic markers. Additionally, the TT carriers were similar to 2 times more likely to develop tumours in the colon than in the rectum. Two SNPs in COX6B1 (complex IV) were associated with lymph node metastasis in a dominant model (rs6510502, OR = 1.75, 95% CI 1.20-2.57; rs10420252, OR = 1.68, 95% CI 1.11-2.53); rs6510502 was associated also with distant metastasis (OR = 1.67, 95% CI 1.09-2.56 in a dominant model). Conclusions: This is the first report suggesting that markers in genes from the mitochondrial oxidative chain might be prognostic factors for CRC. Additional studies replicating the presented findings are needed.
    Type of Publication: Journal article published
    PubMed ID: 22545919
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  • 4
    Keywords: carcinoma ; DIAGNOSIS ; SITE ; TISSUE ; IDENTIFICATION ; PROGNOSTIC-FACTORS ; microenvironment ; ORIGIN ; PRIMARY TUMORS ; IDENTIFY
    Abstract: Background Cancer of unknown primary (CUP) is diagnosed at the metastatic stage. We aimed to identify hidden primary cancers in CUP patients by comparison with cancers in family members. We take use of the fact that the cause of death in CUP patients is often coded as the cancer in the organ of fatal metastasis. Patients and methods Forty-one thousand five hundred and twenty-three CUP patients were identified in the Swedish Family-Cancer Database, and relative risks (RRs) were calculated for cancer in offspring when family members were diagnosed with CUP and died of the cancer diagnosed in offspring. Results The RR for lung cancer in offspring was 1.85 when a family member was diagnosed with CUP and died of lung cancer. Significant familial associations were found for seven other cancers. Many familial associations were also significant when offspring CUP patients died of the cancer diagnosed in family members. Conclusions The cause of death after CUP diagnosis frequently matched the cancer found in a family member, suggesting that the CUP had originated in that tissue. The metastasis had probably undergone a phenotypic change, complicating pathological tissue assignment. These novel data suggest that some CUP cases are phenotypically modified primary cancers rather than cancers of unknown primaries.
    Type of Publication: Journal article published
    PubMed ID: 22473595
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  • 5
    Keywords: OBESITY ; HUMAN BREAST ; EPIDEMIOLOGIC EVIDENCE ; EUROPEAN POPULATIONS ; COMMON DISEASES ; GENOME-WIDE ASSOCIATION ; GENETIC-VARIATION ; NATURAL-SELECTION ; HUMAN ANGIOTENSINOGEN ; K121Q POLYMORPHISM
    Abstract: Background: The majority of non-syndromic colorectal cancers (CRCs) can be described as a complex disease. A two-stage case-control study on CRC susceptibility was conducted to assess the influence of the ancestral alleles in the polymorphisms previously associated with nutrition-related complex diseases. Methods: In stage I, 28 single nucleotide polymorphisms (SNPs) were genotyped in a hospital-based Czech population (1025 CRC cases, 787 controls) using an allele-specific PCR-based genotyping system (KASPar (R)). In stage II, replication was carried out for the five SNPs with the lowest p values. The replication set consisted of 1798 CRC cases and 1810 controls from a population-based German study (DACHS). Odds ratios (ORs) and 95% confidence intervals (CIs) for associations between genotypes and CRC risk were estimated using logistic regression. To identify signatures of selection, Fay-Wu's H and Integrated Haplotype Score (iHS) were estimated. Results: In the Czech population, carriers of the ancestral alleles of AGT rs699 and CYP3A7 rs10211 showed an increased risk of CRC (OR 1.26 and 1.38, respectively; two-sided p 〈= 0.05), whereas carriers of the ancestral allele of ENPP1 rs1044498 had a decreased risk (OR 0.79; p 〈= 0.05). For rs1044498, the strongest association was detected in the Czech male subpopulation (OR 0.61; p=0.0015). The associations were not replicated in the German population. Signatures of selection were found for all three analyzed genes. Conclusions: Our study showed evidence of association for the ancestral alleles of polymorphisms in AGT and CYP3A7 and for the derived allele of a polymorphism in ENPP1 with an increased risk of CRC in Czechs, but not in Germans. The ancestral alleles of these SNPs have previously been associated with nutrition-related diseases hypertension (AGT and CYP3A7) and insulin resistance (ENPP1). Future studies may shed light on the complex genetic and environmental interactions between different types of nutrition-related diseases.
    Type of Publication: Journal article published
    PubMed ID: 23036011
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  • 6
    Keywords: CANCER ; EXPRESSION ; SURVIVAL ; MODEL ; PATHWAY ; RISK ; GENE ; GENES ; GENOME ; prognosis ; ASSOCIATION ; BREAST ; PROGRESSION ; colorectal cancer ; CANCER-PATIENTS ; extracellular matrix ; THICKNESS ; CD47
    Abstract: We identified recently the extracellular matrix (ECM) receptor interaction pathway as a consistently overrepresented category among gene expression profiling studies on colorectal cancer (CRC) prognosis. Putative regulatory single nucleotide polymorphisms (SNPs) in genes from the ECM pathway were genotyped in 613 CRC patients from Northern Germany (PopGen cohort) and tested for association with disease progression and survival. The eSNP (SNP associated with expression) rs12695175 in CD47 associated with CRC specific survival (HR = 2.18, 95 % CI 1.10-4.33, CC versus AA) and with overall survival (HR = 1.99, 95 % CI 1.04-3.81, CC versus AA). This association remained significant after adjustment for age at diagnosis, tumour stage (T) and lymph node status (N). Three polymorphisms in CD47 were associated with distant metastasis in a dominant model: rs9879947 and rs3206652 in the 3'-UTR (OR = 1.64, 95 % CI 1.01-2.64 and OR = 1.88, 95 % CI 1.27-2.80, respectively) and the eSNP rs3804639 (OR = 1.73, 95 % CI 1.17-2.57). The novel associations of eSNPs in CD47 with worse survival and distant metastasis should be confirmed by additional studies, since increased expression of this gene has recently been shown to be an indicator of poor prognosis in cancer patients
    Type of Publication: Journal article published
    PubMed ID: 23011546
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  • 7
    Keywords: EXPRESSION ; PATHWAY ; RISK ; PROTEIN ; DENDRITIC CELLS ; POLYMORPHISMS ; DC-SIGN ; MANNOSE-BINDING LECTIN ; REG-IV ; CD209 PROMOTER
    Abstract: Inflammatory responses play a vital role at different stages of colorectal carcinogenesis. C-type lectins mediate inflammatory/immune responses and participate in immune escape of pathogens and tumors. Our study aimed to evaluate the correlation between polymorphisms in three C-type lectin genes, CD209, MBL2 and REG4, and colorectal cancer (CRC) risk and clinical outcome. We genotyped 15 potentially functional single nucleotide polymorphisms (SNPs) and assessed their associations with CRC risk in a case-control study of 1353 CRC cases and 767 healthy controls from the Czech Republic. We also analyzed these SNPs in relation to overall and event-free survival in 414 patients. Two CD209 SNPs were associated with CRC risk after adjustment for multiple comparison. Minor allele carriers of the promoter SNP rs2287886 had an increased risk of CRC (OR 1.30, 95% CI 1.08-1.56), while minor allele carriers of the 3'UTR SNP, rs7248637, had a decreased risk (OR 0.74, 95% CI 0.60-0.91). Multivariate survival analyses, including age, gender, TNM stage and grade, showed that patients without distant metastasis at the time of diagnosis and carrying the rs2994809 T allele had a decreased overall and event-free survival (HR 2.11, 95% CI 1.20-3.72 and HR 2.00, 95% CI 1.18-3.39, respectively). We show that SNPs in CD209 may affect CRC risk, while a SNP in REG4 may be a useful marker for CRC progression.
    Type of Publication: Journal article published
    PubMed ID: 23650115
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  • 8
    Keywords: CANCER ; COHORT ; RISK ; AGE ; ovarian cancer ; WOMEN ; OBESITY ; cancer risk ; ENDOMETRIAL CANCER ; REPRODUCTIVE FACTORS ; PHYSICAL-ACTIVITY ; BODY-MASS INDEX ; PREGNANCY ; parity ; HORMONES
    Abstract: BACKGROUND: Age at first and last birth and the number of children are known to influence the risk of endometrial and ovarian cancers. However, it remains unknown whether the difference in years between first and last childbirth plays a role. The Swedish Family-Cancer Database allowed us to carry out the largest study ever on reproductive factors in these cancers. MATERIAL AND METHODS: We selected over 5.7 million women from the database. We estimated the effect of number of children, age at birth and difference between age at first and last birth by Poisson regression adjusted for age, period, region and socioeconomic status. RESULTS: The risk for endometrial cancer is negatively associated with increasing number of children and increasing age at first as well as age at last birth. Weaker associations are found for ovarian cancer. Age at last birth is the factor that shows highest influence. A large difference in first and last childbirth shows a protective effect on the risk of endometrial cancer. CONCLUSION: Our findings suggest that the risk of endometrial cancer is significantly decreased for women having at least a difference of 10years between their first and last birth. Ovarian cancer does not seem to be influenced by the time interval between first and last birth.
    Type of Publication: Journal article published
    PubMed ID: 21055917
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  • 9
    Keywords: CANCER ; carcinoma ; LUNG ; DIAGNOSIS ; SYSTEM ; RISK ; ASSOCIATION ; BREAST-CANCER ; MALIGNANT-MELANOMA ; ENDOMETRIAL CANCER ; CHILDHOOD-CANCER ; TESTICULAR CANCER ; HELICOBACTER-PYLORI INFECTION ; BODY-MASS INDEX ; LIVING-CONDITIONS ; SOCIOECONOMIC-STATUS ; PARENTAL AGE
    Abstract: Background: Family size and birth order are known to influence the risk of some cancers. However, it is still unknown whether these effects change from early to later adulthood. We used the data of the Swedish Family Cancer Database to further analyze these effects. Methods: We selected over 5.7 million offspring with identified parents but no parental cancer. We estimated the effect of birth order and family size by Poisson regression adjusted for age, sex, period, region and socioeconomic status. We divided the age at diagnosis in two groups, below and over 50 years, to identify the effect of family size and birth order for different age periods. Results: Negative associations for increasing birth order were found for endometrial, testicular, skin, thyroid and connective tissue cancers and melanoma. In contrast, we observed positive association between birth order and lung, male and female genital cancers. Family size was associated with decreasing risk for endometrial and testicular cancers, melanoma and squamous cell carcinoma; risk was increased for leukemia and nervous system cancer. The effect of birth order decreased for lung and endometrial cancer from age at diagnosis below to over 50 years. Combined effects for birth order and family size were marginally significant for thyroid gland tumors. Especially, the relative risk for follicular thyroid gland tumors was significantly decreased for increasing birth order. Conclusion: Our findings suggest that the effect of birth order decreases from early to late adulthood for lung and endometrial cancer
    Type of Publication: Journal article published
    PubMed ID: 21554674
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  • 10
    Keywords: DISEASE ; POPULATION ; breast cancer ; family history ; DATABASE ; BRCA2 MUTATIONS ; TWINS ; susceptibility loci ; GENOME-WIDE ASSOCIATION
    Abstract: Family history of first and second-degree relatives is known to increase the risk for breast cancer. Less data are available on the risks between defined multiple affected close and distant relatives for which the reliability of data may be an issue. Data on affected males are sparse. These questions and the probable genetic models were addressed in this study by means of a nationwide Swedish Family-Cancer Database. We estimated the effect of family history of breast cancer by Poisson regression for women of at least 30 years of age after adjusting for age, period, region, socioeconomic status, number of children, and age at first birth. The results of the study showed that relative risk (RR) for breast cancer was associated with a first degree as well as second-degree family history. Having at least two female affected first-degree relatives increased the RR at least to 2.8, favoring an additive interaction. The risk was increased around ten times in women with both parents affected. When either a father or a mother was affected, the RRs were nearly identical (RR = 1.73 and 1.74, respectively). The RR for a woman increased more when a brother was affected (RR = 2.48) compared to when a sister was affected (RR = 1.87). Having an affected grandmother showed lower familial excess risks than having an affected half sister (RR = 1.27, and 1.26; and RR = 1.39, and 1.50; respectively, for maternal and paternal relatives). We concluded that when both parents were diagnosed with breast cancer, the risk for the daughter was increased tenfold. Having an affected brother showed a somewhat higher risk than having an affected sister. The data suggest that male breast cancer has a higher genetic basis than female breast cancer, which invites further search of the underlying mechanisms.
    Type of Publication: Journal article published
    PubMed ID: 22179927
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