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  • Vodicka, Pavel, et al. (författare)
  • Interactions of DNA repair gene variants modulate chromosomal aberrations in healthy subjects.
  • 2015
  • Ingår i: Carcinogenesis. - Oxford University Press. - 0143-3334. ; 36:11, s. 1299-1306
  • Tidskriftsartikel (refereegranskat)abstract
    • Human cancers are often associated with numerical and structural chromosomal instability. Structural chromosomal aberrations (CAs) in peripheral blood lymphocytes (PBL) arise as consequences of direct DNA damage or due to replication on a damaged DNA template. In both cases, DNA repair is critical and inter-individual differences in its capacity are probably due to corresponding genetic variations. We investigated functional variants in DNA repair genes (base and nucleotide excision repair, double-strand break repair) in relation to CAs, chromatid-type aberrations (CTAs) and chromosome-type aberrations (CSAs) in healthy individuals. Chromosomal damage was determined by conventional cytogenetic analysis. The genotyping was performed by both restriction fragment length polymorphism and TaqMan allelic discrimination assays. Multivariate logistic regression was applied for testing individual factors on CAs, CTAs and CSAs. Pair-wise genotype interactions of 11 genes were constructed for all possible pairs of single-nucleotide polymorphisms. Analysed individually, we observed significantly lower CTA frequencies in association with XPD Lys751Gln homozygous variant genotype [odds ratio (OR) 0.64, 95% confidence interval (CI) 0.48-0.85, P = 0.004; n = 1777]. A significant association of heterozygous variant genotype in RAD54L with increased CSA frequency (OR 1.96, 95% CI 1.01-4.02, P = 0.03) was determined in 282 subjects with available genotype. By addressing gene-gene interactions, we discovered 14 interactions significantly modulating CAs, 9 CTAs and 12 CSAs frequencies. Highly significant interactions included always pairs from two different pathways. Although individual variants in genes encoding DNA repair proteins modulate CAs only modestly, several gene-gene interactions in DNA repair genes evinced either enhanced or decreased CA frequencies suggesting that CAs accumulation requires complex interplay between different DNA repair pathways.
  • Weiderpass, Elisabete, et al. (författare)
  • Estrogen receptor alpha gene polymorphisms and endometrial cancer risk
  • 2000
  • Ingår i: Carcinogenesis. - 0143-3334 .- 1460-2180. ; 21:4, s. 623-627
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Since the estrogen receptor alpha (ER) is an important mediator of hormonal responses such as proliferation in estrogen-sensitive tissues, we hypothesized that polymorphisms in the ER gene could be functional and associated with endometrial cancer risk. We performed a population-based case-control study in Sweden, focusing on restriction fragment length polymorphisms for XbaI and PvuII and an upstream TA repeat polymorphism. In the main analysis, 154 cases and 205 controls who never used hormone replacement therapy took part and we calculated age-adjusted and multivariate odds ratios (OR) and 95% confidence intervals (CI) using unconditional logistic regression. The XbaI X allele appeared to confer a reduced risk for endometrial cancer. The multivariate OR for the XX genotype was 0.52 (95% CI 0.21-1.29) compared to the xx genotype and there were suggestions of decreasing risk with increasing number of X alleles (P for trend = 0.07). The PvuII PP genotype was also associated with a non-significantly decreased risk for endometrial cancer (multivariate OR 0.70, 95% CI 0.34-1.44) compared with the pp genotype (P for trend = 0.43). The multivariate OR for two short TA (&lt;19 repeats) alleles versus two long alleles was 1.54 (95% CI 0. 73-3.27) and there were suggestions of increasing risk with increasing number of short alleles (P for trend = 0.26). We observed the same pattern of results in an expanded group of subjects, which included women who had used hormone replacement (in total 288 cases and 392 controls). Our data suggest that variants of the ER gene may be associated with an altered risk of endometrial cancer.</p>
  • Wilkening, Stefan, et al. (författare)
  • Interleukin promoter polymorphisms and prognosis in colorectal cancer
  • 2008
  • Ingår i: Carcinogenesis. - Oxford University Press. - 0143-3334 .- 1460-2180. ; 29:6, s. 1202-1206
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>There is strong evidence that cancer-associated inflammation promotes tumor growth and progression. This is especially true for colorectal cancer (CRC). Interleukins (ILs) are important modulators for inflammation. We examined whether promoter polymorphisms in key IL genes (IL4, IL4R, IL6, IL8 and IL10) are associated with the risk or clinical outcome of CRC. Five single-nucleotide polymorphisms (SNPs) were analyzed in genomic DNA from a cohort including 308 Swedish incident cases of CRC with data on Dukes' stage and up to 16 years of follow-up and 585 healthy controls. The selected SNPs have previously been shown to be functional and/or associated with cancer. None of the analyzed SNPs associated with the risk of CRC. When stratifying by tumor stage, significantly more patients carrying at least one G allele of IL10-1082 had tumors with Dukes' stages A + B than with stages C + D (P(trend) = 0.035 for genotype distribution). Analyzing associations with overall survival time, we found the rare T allele of IL4-590 to be related to a longer survival [CT versus CC Cox proportional hazard ratio 0.69, 95% confidence intervals 0.46-1.03, TT versus CC 0.32 (0.10-1.03)]. For IL6-174, the CG genotype was associated with a longer survival when compared with the CC genotype [0.64 (0.40-1.01)]. The present study was particularly suitable for survival analysis because all patients were sampled before the diagnosis of CRC. Our results suggest that the SNPs IL4-590 and IL6-174 may be useful markers for CRC prognosis. The predicted biological effect of these SNPs in relation to promotion of cancer progression is consistent with the observed increased survival time.</p>
  • Wu, Jun, et al. (författare)
  • Identification of one exon deletion of intestinal alkaline sphingomyelinase in colon cancer HT-29 cells and a differentiation-related expression of the wild type enzyme in Caco-2 cells.
  • 2004
  • Ingår i: Carcinogenesis. - Oxford University Press. - 0143-3334. ; 25:8, s. 1327-1333
  • Tidskriftsartikel (refereegranskat)abstract
    • phingomyelin (SM) metabolism in the gut has been implicated in colonic tumorigenesis. Intestinal alkaline sphingomyelinase (alk-SMase) hydrolyses SM in the intestinal content and at the brush border. The enzyme activity is decreased in the tissues of human colorectal tumours. This study examines whether site or chain-mutation of alk-SMase occurs in colon cancer HT-29 cells and Caco-2 cells. Total RNA was isolated and the cDNA of alk-SMase was amplified by RT–PCR. The size of the cDNA from HT-29 cells was smaller than that of the wild-type cDNA. DNA sequencing identified a deletion of exon 4 in alk-SMase cDNA in HT-29 cells. No mutation in genomic alk-SMase DNA from exon 3 to 5 was identified. The exon 4 deletion was caused by a shift of RNA splice site in chromosome 17q25. In Caco-2 cells, no mutation of alk-SMase cDNA was identified. Transient expression in COS-7 cells showed that the enzyme from the cDNA in HT-29 cells had little alk-SMase activity whereas that in Caco-2 cells was as active as the wild-type alk-SMase. The deleted region included residue His353, which is predicted to form a substrate-binding site of alk-SMase. H353A substitution resulted in a protein with no alk-SMase activity. In monolayer cultured Caco-2 cells and HT-29 cells the alk-SMase activities were low. However, to culture the cells under polarizing conditions increased alk-SMase activity and reduced SM level in Caco-2 cells. The alk-SMase activity varied in parallel with alkaline phosphatase activity. In conclusion, we identified an inactive deletion in alk-SMase in HT-29 cells, and a differentiation-related expression of the enzyme in Caco-2 cells. The results provide a molecular mechanism related to previous findings of reduced alk-SMase activity in human colon cancers.
  • Wulaningsih, Wahyu, et al. (författare)
  • Prediagnostic serum inflammatory markers in relation to breast cancer risk, severity at diagnosis and survival in breast cancer patients
  • 2015
  • Ingår i: Carcinogenesis. - 0143-3334 .- 1460-2180. ; 36:10, s. 1121-1128
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Inflammation has been linked to cancer but its role in breast cancer is unclear. We investigated common serum markers of inflammation: C-reactive protein (CRP), albumin, haptoglobin and white blood cells (WBC) in relation to breast cancer incidence, severity and survival. A total of 155179 women aged 20 and older without any history of cancer were selected from a large Swedish cohort. Hazard ratios (HRs) for breast cancer were estimated with Cox regression, adjusting for potential confounders. Ordered and binomial logistic regression models were used to assess the associations of serum inflammatory markers with breast cancer severity and oestrogen receptor (ER) positivity at diagnosis, on the other. Cumulative incidence functions by levels of inflammatory markers were assessed for early death from breast cancer and all causes. During a mean follow-up of 18.3 years, 6606 women were diagnosed with breast cancer, of whom 1474 died. A positive association with incident breast cancer was seen for haptoglobin ≥ 1.4g/l [HR 1.09; 95% confidence interval (CI): 1.00-1.18] compared to lower levels. No association was observed between inflammatory markers and breast cancer severity or ER positivity. Higher haptoglobin was linked to risk of early death from breast cancer (HR: 1.27, 95% CI: 1.02-1.59), whereas higher risk of early death from all causes was additionally found with CRP ≥ 10mg/l (HR: 1.19, 95% CI: 1.04-1.36) and WBC ≥ 10×10(9)/l (HR: 1.57, 1.14-2.16). Our findings indicate that prediagnostic serum inflammatory markers were weakly linked to incident breast cancer but corresponded to worse survival after diagnosis.</p>
  • Yang, Rongxi, et al. (författare)
  • Genome-wide analysis associates familial colorectal cancer with increases in copy number variations and a rare structural variation at 12p12.3
  • 2014
  • Ingår i: Carcinogenesis. - Oxford University Press. - 0143-3334. ; 35:2, s. 315-323
  • Tidskriftsartikel (refereegranskat)abstract
    • Colorectal cancer (CRC) is one of the most common cancer worldwide. However, a large number of genetic risk factors involved in CRC have not been understood. Copy number variations (CNVs) might partly contribute to the missing heritability of CRC. An increased overall burden of CNV has been identified in several complex diseases, whereas the association between the overall CNV burden and CRC risk is largely unknown. We performed a genome-wide investigation of CNVs on genomic DNA from 384 familial CRC cases and 1285 healthy controls by the Affymetrix 6.0 array. An increase of overall CNV burden was observed in familial CRC patients compared with healthy controls, especially for CNVs larger than 50kb (case/control ratio 1.66, P 0.025). In addition, we discovered for the first time a novel structural variation at 12p12.3 and determined the breakpoints by strategic PCR and sequencing. This 12p12.3 structural variation was found in four of 2862 CRC cases but not in 6243 healthy controls (P 0.0098). RERGL gene (RERG/RAS-like), the only gene influenced by the 12p12.3 structural variation, sharing most of the conserved regions with its close family member RERG tumor suppressor gene (RAS-like, estrogen-regulated, growth inhibitor), might be a novel CRC-related gene. In conclusion, this is the first study to reveal the contribution of the overall burden of CNVs to familial CRC risk and identify a novel rare structural variation at 12p12.3 containing RERGL gene to be associated with CRC.
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