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  • BREAST-CANCER  (20)
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  • 11
    Keywords: CANCER ; COMBINATION ; Germany ; COMMON ; COHORT ; RISK ; GENE ; polymorphism ; POLYMORPHISMS ; single nucleotide polymorphism ; SUSCEPTIBILITY ; VARIANTS ; BREAST ; breast cancer ; BREAST-CANCER ; IDENTIFICATION ; SNP ; REDUCED RISK ; cancer risk ; TARGETS ; SINGLE ; VARIANT ; CASPASE-8 ; SINGLE NUCLEOTIDE POLYMORPHISMS ; PROMOTER POLYMORPHISM ; ALLELES ; USA ; CANCERS ; CANCER-RISK ; COMMON VARIANT ; CASP8 GENE ; GENOME-WIDE ASSOCIATION
    Abstract: Recent large-scale studies have been successful in identifying common, low-penetrance variants associated with common cancers. One such variant in the caspase-8 (CASPS) gene, D302H (rs1045485), has been confirmed to be associated with breast cancer risk, although the functional effect of this polymorphism (if any) is not yet clear. In order to further map the CASP8 gene with respect to breast cancer susceptibility, we performed extensive haplotype analyses using single nucleotide polymorphisms (SNP) chosen to tag all common variations in the gene (tSNP). We used a staged study design based on 3,200 breast cancer and 3,324 control subjects from the United Kingdom, Utah, and Germany. Using a haplotype-mining algorithm in the UK cohort, we identified a four-SNP haplotype that was significantly associated with breast cancer and that was superior to any other single or multi-locus combination (P = 8.0 x 10(-5)), with a per allele odds ratio and 95% confidence interval of 1.30 (1.12-1.49). The result remained significant after adjustment for the multiple testing inherent in mining techniques (false discovery rate, q = 0.044). As expected, this haplotype includes the D302H locus. Multicenter analyses on a subset of the tSNPs yielded consistent results. This risk haplotype is likely to carry one or more underlying breast cancer susceptibility alleles, making it an excellent candidate for resequencing in homozygous individuals. An understanding of the mode of action of these alleles will aid risk assessment and may lead to the identification of novel treatment targets in breast cancer. [Cancer Res 2009;69(7):2724-8]
    Type of Publication: Journal article published
    PubMed ID: 19318553
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  • 12
    Keywords: RECEPTOR ; CANCER ; EXPRESSION ; Germany ; THERAPY ; POPULATION ; RISK ; SITES ; GENE ; GENES ; HYBRIDIZATION ; PROTEIN ; MESSENGER-RNA ; CARCINOGENESIS ; BINDING ; DOWN-REGULATION ; TYROSINE KINASE INHIBITOR ; ASSOCIATION ; polymorphism ; BREAST ; breast cancer ; BREAST-CANCER ; WOMEN ; TUMOR PROGRESSION ; SNP ; TARGETS ; REPRESSION ; RETINOIC ACID ; VARIANT ; THERAPIES ; SINGLE NUCLEOTIDE POLYMORPHISMS ; BINDING-SITES ; CONFER SUSCEPTIBILITY ; therapeutic ; COMMON VARIANTS ; CHROMOSOME 6Q ; II RECEPTOR
    Abstract: MicroRNAs (miRNAs) negatively regulate expression of target transcripts by hybridization to complementary sites of their messenger RNA targets. Chen et al. have described several putative functional single nucleotide polymorphisms (SNPs) in miRNA target sites. Here, we selected 11 miRNA target site SNPs located in 3' untranslated regions of genes involved in cancer and breast cancer to analyze their impact on breast cancer risk using a large familial study population. Whereas no association was observed for 10 SNPs, a significant association was revealed for the variant affecting a miRNA target site in the estrogen receptor (ESR) 1. Age stratification showed that the association was stronger in premenopausal women [C versus T: odds ratio (OR) = 0.60, confidence interval (CI) = 0.41-0.89, P = 0.010]. Furthermore, the effect was stronger in high-risk familial cases (C versus T: OR = 0.42, CI = 0.25-0.71, P = 0.0009). Clinical studies have shown that elimination of ESR1 significantly reduces breast cancer risk. Thus, therapies that inhibit ESR1 are used for breast cancer treatment. According to in silico analysis, ESR1_rs2747648 affects the binding capacity of miR-453, which is stronger when the C allele is present. In contrast, the T allele attenuates the binding of miR-453, which might lead to a reduced miRNA-mediated ESR1 repression, in consequence higher ESR1 protein levels and an increased breast cancer risk. Thus, the breast cancer protective effect observed for the C allele in premenopausal women is biologically reasonable. The analysis of large study populations in multicentre collaboration will be needed to verify the association and answer questions regarding the possible impact of this variant on therapeutic and clinical outcome
    Type of Publication: Journal article published
    PubMed ID: 19028706
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  • 13
    Keywords: CANCER ; Germany ; DISEASE ; POPULATION ; RISK ; MESSENGER-RNA ; IMPACT ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; SUSCEPTIBILITY ; VARIANTS ; BREAST ; breast cancer ; BREAST-CANCER ; BRCA1 ; OVARIAN-CANCER ; MUTATION ; SNP ; cancer risk ; MUTATIONS ; US ; case-control studies ; BRCA1/2 ; case control study ; case-control study ; GENETIC EPIDEMIOLOGY ; BRCA2 ; VARIANT ; SNPs ; MUTATION CARRIERS ; USA ; CANCER-RISK ; NOV ; breast cancer risk ; BRCA1 and BRCA2 ; Codon-usage ; SILENT ; SYNONYMOUS SNP
    Abstract: Mutations in BRCA1 and BRCA2 are associated with increased breast cancer risk. While numerous non-synonymous SNPs in BRCA1/2 have been investigated for breast cancer risk, the impact of synonymous SNPs has not been studied so far. Recently, it has been reported that synonymous SNPs leading to an aberration from the preferred codon-usage can have functional effects and consequently be associated with disease. This motivated us to search for SNPs with the tendency to differential codon-usage in BRCA1/BRCA2. Based on defined criteria, two codon-usage-changing variants, Ser455Ser (1365A 〉 G) and Ser2414Ser (7242A 〉 G), were detected in BRCA2, whereas no such variant could be identified in BRCA1. We investigated the impact of these variants on breast cancer risk in a large case-control study. However, both SNPs, BRCA2 Ser2414Ser (7242A 〉 G) and Ser455Ser (1365A 〉 G), showed no association with breast cancer risk. This indicates that these codon-usage-changing SNPs have no major impact on familial breast cancer risk
    Type of Publication: Journal article published
    PubMed ID: 19229607
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  • 14
    Keywords: RECEPTOR ; CANCER ; Germany ; POPULATION ; GENE ; validation ; FAMILY ; polymorphism ; SUSCEPTIBILITY ; VARIANTS ; BREAST ; breast cancer ; BREAST-CANCER ; BRCA1 ; WOMEN ; SNP ; PROSTATE-CANCER ; HIGH-RISK ; CANCER-PATIENTS ; FUTURE ; ESTROGEN-RECEPTOR ; ONCOLOGY ; VARIANT ; ALLELES ; SUBTYPES ; LOCUS ; PREDISPOSITION ; estrogen receptor ; familial breast cancer ; susceptibility loci ; GENOME-WIDE ASSOCIATION ; breast cancer risk ; COMMON VARIANTS ; CANDIDATE SNPS ; SUSCEPTIBILITY ALLELE ; CGEMS
    Abstract: To validate common low-risk variants predisposing for breast cancer (BC) in a large set of BRCA1/2 negative familial or genetically enriched cases from Germany, we genotyped 1,415 cases and 1,830 healthy women by MALDI-TOF in 105 candidate SNPs. Significantly higher ORs than previously reported for heterozygous unselected cases were found for the minor allele in FGFR2 (OR = 1.43, 95% Cl 1.30-1.59, p-value = 1.24 x 10(-12)) and for TNRC9 (OR = 1.33, 95% Cl 1.19-1.46, p-value = 1.54 x 10(-7)). Most intriguing, however, were the ORs for homozygous carriers from high-risk families for FGFR2 (OR = 2.05, 95% Cl 1.68-2.51, LSP1 (OR = 0.49, 95% Cl 0.28-0.86) and TNRC9 (OR = 1.62, 95% Cl 1.27-2.07). Moreover, the additional validation of 99 CGEMS-SNPs identified putative novel susceptibility alleles within the LSP1 gene (OR = 0.73, 95% Cl 0.61-0.87, p-value = 5.23 x 10(-4)). Finally, we provide evidence for the first time that a low-risk variant located at 6q22.33 (rs6569479) is associated with estrogen receptor negative BC in familial cases (OR = 1.33, 95% Cl 1.06-1.66; p-value = 0.012). Our data confirm the impact of the previously identified susceptibility loci and provide preliminary evidence for novel susceptibility loci in familial BC cases and correlate them to specific histopathological subtypes defined by estrogen receptor status
    Type of Publication: Journal article published
    PubMed ID: 19856316
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  • 15
    Keywords: RECEPTOR ; APOPTOSIS ; CANCER ; Germany ; DEATH ; RISK ; GENE ; GENES ; RELEASE ; ACTIVATION ; COMPLEX ; COMPLEXES ; CARCINOGENESIS ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; SUSCEPTIBILITY ; BREAST ; breast cancer ; BREAST-CANCER ; INDUCED APOPTOSIS ; NUMBER ; SNP ; cancer risk ; CYTOCHROME-C ; case-control studies ; RECEPTORS ; case-control study ; RE ; VARIANT ; assembly ; case control studies ; death receptor ; caspases ; COMMON VARIANT ; SAMPLE-SIZE
    Abstract: Dysregulation of apoptosis plays a crucial role in carcinogenesis. As part of death receptor- and mitochondrion-mediated apoptosis, the homologues caspases 10 and 8 may act as low-penetrance breast cancer (BC) susceptibility genes. In death receptor-mediated apoptosis, engagement of death receptors by their ligands involves the assembly of the death-inducing signalling complex (DISC). In mitochondrion-mediated apoptosis, the release of cytochrome c into the cytosol results in apoptosome formation. Recruitment of both caspases 10 and 8 (CASP10 and CASP8, respectively) to DISC and apoptosome leads to their activation by dimerization. We investigated the influence of the coding CASP10 variant V410I (G1228A) by performing a case-control study - using 511 familial BC cases and 547 control subjects - on BC risk and revealed a significant association of V410I with a reduced risk (OR = 0.62, 95% CI = 0.43-0.88, P = 0.0076) related to the number of variant alleles (P-trend = 0.0039). As CASP10 and CASP8 functionally co-operate during apoptosis, we analysed the mutual effect of both CASP10 V410I and CASP8 D302H, resulting in a significant association between the number of the variant alleles I410 and H302 and a highly decreased familial BC risk (OR = 0.35, P-trend = 0.007), pointing to the interaction between the CASP10 and CASP8 polymorphisms in breast carcinogenesis
    Type of Publication: Journal article published
    PubMed ID: 16251207
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  • 16
    Keywords: CANCER ; EXPRESSION ; Germany ; human ; DISEASE ; RISK ; GENE ; GENES ; GENOME ; IMPACT ; CARCINOGENESIS ; RAT ; SEQUENCE ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; BREAST ; breast cancer ; BREAST-CANCER ; MOUSE ; Drosophila ; NUMBER ; AGE ; SIGNAL-TRANSDUCTION ; cancer risk ; HUMAN GENOME ; REGION ; REGIONS ; SELECTION ; MOLECULAR-CLONING ; ONCOLOGY ; SNPs ; SINGLE-NUCLEOTIDE POLYMORPHISMS ; CANCER-RISK ; familial breast cancer ; ENGLAND ; GENOMES ; CONSERVED NONCODING SEQUENCES ; GENE LOSS ; PROTEIN EVOLUTION ; RAB GTPASES
    Abstract: Ultraconserved elements (UCEs) are segments of 〉200 bp length showing absolute sequence identity between orthologous regions of human, rat and mouse genomes. The selection factors acting on these UCEs are still unknown. Recent studies have shown that UCEs function as long-range enhancers of flanking genes or are involved in splicing when overlapping with exons. The depletion of UCEs among copy number variation as well as the significant under-representation of single-nucleotide polymorphisms (SNPs) within UCEs have also revealed their evolutional and functional importance indicating their potential impact on disease, such as cancer. In the present study, we investigated the influence of six SNPs within UCEs on familial breast cancer risk. Two out of six SNPs showed an association with familial breast cancer risk. Whereas rs9572903 showed only a borderline significant association, the frequency of the rare [G] allele of rs2056116 was higher in cases than in controls indicating an increased familial breast cancer risk ([G] versus [A]: odds ratio (OR) = 1.18, 95% confidence interval (CI) 1.06-1.30, P = 0.0020; [GG] versus [AA]: OR = 1.41, 95% CI 1.15-1.74, P = 0.0011). Interestingly, comparing with the older age group, the ORs were increased in woman younger than 50 years of age ([G] versus [A]: OR = 1.27, 95% CI 1.11-1.45, P = 0.0005; [GG] versus [AA]: OR = 1.60, 95% CI 1.22-2.10, P = 0.0007) pointing to an age- or hormone-related effect. This is the first study indicating that SNPs in UCEs might be associated with cancer risk
    Type of Publication: Journal article published
    PubMed ID: 18174240
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  • 17
    Keywords: RECEPTOR ; APOPTOSIS ; CANCER ; HISTORY ; RISK ; SAMPLE ; TUMOR-NECROSIS-FACTOR ; FAMILY ; BIOMARKERS ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; single nucleotide polymorphism ; FREQUENCIES ; BREAST ; breast cancer ; BREAST-CANCER ; HEALTH ; AGE ; WOMEN ; SNP ; cancer risk ; GENOTYPES ; HETEROGENEITY ; FAMILIES ; VARIANT ; SINGLE NUCLEOTIDE POLYMORPHISMS ; ESTROGEN ; SINGLE-NUCLEOTIDE POLYMORPHISMS ; ALLELES ; biomarker ; GENOTYPE ; FAMILY-HISTORY ; USA ; CANCER-RISK ; Sample Size ; CONSORTIUM ; ERCC4 ; RECEPTOR STATUS ; PROGESTERONE-RECEPTOR GENE ; CASP8
    Abstract: Previous studies have suggested that minor alleles for ERCC4 rs744154, TNF rs361525, CASP10 rs13010627, PGR rs1042838, and BID rs8190315 may influence breast cancer risk, but the evidence is inconclusive due to their small sample size. These polymorphisms were genotyped in more than 30,000 breast cancer cases and 30,000 controls, primarily of European descent, from 30 studies in the Breast Cancer Association Consortium. We calculated odds ratios (OR) and 95% confidence intervals (95% CI) as a measure of association. We found that the minor alleles for these polymorphisms were not related to invasive breast cancer risk overall in women of European descent: ECCR4 per-allele OR (95% CI) = 0.99 (0.97-1.02), minor allele frequency = 27.5%; TNF 1.00 (0.95-1.06), 5.0%; CASP10 1.02 (0.98-1.07), 6.5%; PGR 1.02 (0.99-1.06), 15.3%; and BID 0.98 (0.86-1.12), 1.7%. However, we observed significant between-study heterogeneity for associations with risk for single-nucleotide polymorphisms (SNP) in CASP10, PGR, and BID. Estimates were imprecise for women of Asian and African descent due to small numbers and lower minor allele frequencies (with the exception of BID SNP). The ORs for each copy of the minor allele were not significantly different by estrogen or progesterone receptor status, nor were any significant interactions found between the polymorphisms and age or family history of breast cancer. In conclusion, our data provide persuasive evidence against an overall association between invasive breast cancer risk and ERCC4 rs744154, TNF rs361525, CASPIO rs13010627, PGR rs1042838, and BID rs8190315 genotypes among women of European descent. (Cancer Epidemiol Biomarkers Prev 2009;18(5):1610-6)
    Type of Publication: Journal article published
    PubMed ID: 19423537
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  • 18
    Keywords: APOPTOSIS ; CANCER ; CELLS ; EXPRESSION ; proliferation ; CELL ; Germany ; PATHWAY ; PATHWAYS ; COHORT ; RISK ; SITE ; SITES ; GENE ; GENES ; DIFFERENTIATION ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; single nucleotide polymorphism ; BREAST ; breast cancer ; BREAST-CANCER ; MATURATION ; TARGET ; AGE ; OVARIAN-CANCER ; MUTATION ; SNP ; REGION ; REGIONS ; MUTATIONS ; ONCOGENE ; FREQUENT ; REPRESSION ; ESTROGEN-RECEPTOR ; CELL-DIFFERENTIATION ; ONCOLOGY ; case-control study ; TUMOR INVASION ; VARIANT ; TRANSLATION ; development ; cell differentiation ; CANCER-RISK ; familial breast cancer ; miRNA ; MICRORNA ; breast cancer risk ; Genetic ; single nucleotide ; LOOP ; RNA-INTERFERENCE ; TARGET SITE ; MICRORNA PRECURSORS ; REGULATED MICRORNA ; SP PROTEINS
    Abstract: MicroRNAs (miRNAs) regulate pathways involved in cell differentiation, proliferation, development, and apoptosis by degradation of target mRNAs and/or repression of their translation. Although the single nucleotide polymorphisms (SNPs) in miRNAs target sites have been studied, the effects of SNPs in miRNAs are largely unknown. In our study, we first systematically sequenced miRNA genes reported to be involved in breast cancer to identify/verify SNPs. We analyzed four SNPs, one located in the pre-miRNA and the other three located in miRNA flanking regions, for a putative association with breast cancer risk. The SNP rs895819, located in the terminal loop of pre-miRNA-27a, showed a protective effect. In a large familial breast cancer study cohort, the rare [G] allele of rs895819 was found to be less frequent in the cases than in the controls, indicating a reduced familial breast cancer risk ([G] vs. [A]: OR = 0.88, 95% CI 0.78-0.99, P = 0.0287). Furthermore, age stratification revealed that the protective effect was mainly observed in the age group 〈 50 years of age ([G] vs. [A]: OR = 0.83, 95% CI 0.70-0.98, P = 0.0314), whereas no significant effect was observed in the age group a parts per thousand yen 50 years of age, indicating a possible hormone-related effect. It has been shown that artificial mutations in the terminal loop of miR-27a can block the maturation process of the miRNA. We hypothesize that the G-variant of rs895819 might impair the maturation of the oncogenic miR-27a and thus, is associated with familial breast cancer risk
    Type of Publication: Journal article published
    PubMed ID: 19921425
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  • 19
    Keywords: SPECTRA ; CANCER ; SURVIVAL ; tumor ; carcinoma ; Germany ; human ; NEW-YORK ; HYBRIDIZATION ; SAMPLE ; SAMPLES ; TUMORS ; PATIENT ; DNA ; LYMPH-NODES ; chromosome ; BREAST ; breast cancer ; BREAST-CANCER ; COMPARATIVE GENOMIC HYBRIDIZATION ; COPY NUMBER ; COPY-NUMBER ; DIFFERENCE ; AGE ; LINKAGE ANALYSIS ; OVARIAN-CANCER ; WOMEN ; METASTASIS ; ABERRATIONS ; TUMOR-SUPPRESSOR GENE ; REGION ; PROGNOSTIC-FACTORS ; REGIONS ; BREAST-CARCINOMA ; CARCINOMAS ; DNA AMPLIFICATION ; GAINS ; SUSCEPTIBILITY GENE ; ALLELIC LOSS ; CGH ; COPY NUMBER CHANGES ; CARCINOMA IN-SITU ; YOUNG-WOMEN ; early onset breast cancer,comparative genomic hybridization,loss of 8p,gain of 8q ; HETEROZYGOSITY REGION ; HISTOLOGICAL GRADE
    Abstract: Sporadic breast cancer in young women is different from the one in older patients regarding pathological features and aggressiveness of the tumors, but the spectrum of genetic alterations are largely unknown. We used comparative genomic hybridization (CGH) to analyze DNA copy number changes in 88 tumor samples from women less than or equal to35 years of age. Findings were compared to histopathological data including tumor type, grading, lymph nodes and metastasis. Genomic gains clustered to chromosome arms 1q (64.8%), 8q (61.4%), 17q (50.0%), 20q (33.0%), 3q (20.5%), 1p (17.0%), 5p (17.0%) and 15q (17%). Losses were commonly located on 8p (19.3 %), 11q (11.4%), 16q (11.4%), 17p (1 1.4%) and 18q (10.2%). A comparison with published CGH data from breast carcinomas of similar type and grade showed the following differences: (1) gains were much more frequent than losses, and (2) losses on 8p22-p23 were more prevalent in patients with positive lymph node metastasis (p = 0.02), and Grade III tumors were associated with gains on the long arm of chromosome 8 (p = 0.01). Therefore, alterations in these genomic regions may be responsible for the reduced survival of patients with early onset breast cancer. (C) 2003 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 14520696
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  • 20
    Keywords: CANCER ; EXPRESSION ; Germany ; human ; RISK ; SITE ; GENE ; GENES ; PATIENT ; IMPACT ; RISK-FACTORS ; BINDING ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; SUSCEPTIBILITY ; VARIANTS ; BREAST ; breast cancer ; BREAST-CANCER ; ACID ; OVARIAN-CANCER ; MUTATION ; risk factors ; p53 ; cancer risk ; MUTATIONS ; HIGH-RISK ; EXCHANGE ; CANCER-PATIENTS ; CANCER PATIENTS ; DISORDERS ; RE ; VARIANT ; BINDING-SITE ; INCREASED RISK ; RISK-FACTOR ; CANCER-RISK ; FAMILIAL BREAST ; familial breast cancer ; RARE ; MspI ; DNA HELICASE ; FUNCTIONAL INTERACTION ; HOLLIDAY JUNCTIONS ; JAPANESE POPULATION ; POLYMORPHIC VARIANT ; RECQ HELICASES ; ROTHMUND-THOMSON-SYNDROME ; SYNDROME PROTEIN
    Abstract: Mutations of the human RecQ helicase genes WRN and BLM lead to rare autosomal recessive disorders, Werner and Bloom syndromes, which are associated with premature ageing and cancer predisposition. We tested the hypothesis whether three polymorphic, non-conservative amino acid exchanges in WRN and BLM act as low-penetrance familial breast cancer risk factors. Moreover, we examined the putative impact of p53 MspI 1798G 〉 A, which is completely linked to p53PIN3, a 16 bp insertion/duplication that has been associated with reduced p53 expression, on familial breast cancer risk. Genotyping analyses, performed on 816 BRCA1/2 mutation-negative German familial breast cancer patients and 1012 German controls, revealed a significant association of the WRN Cys1367Arg polymorphism with familial breast cancer (OR = 1.28, 95% CI 1.06-1.54) and high-risk familial breast cancer (OR = 1.32, 95 % CI 1.06-1.65). The analysis of p53 MspI 1798G 〉 A, which is completely linked to p53PIN3, showed a significantly increased familial breast cancer risk for carriers of the 16 bp insertion/duplication, following a recessive mode (OR = 2.15, 95% CI = 1.124.11). WRN Cys1367Arg, located in the C-terminus, the binding site of p53, is predicted to be damaging. The joint effect of WRN Cys1367Arg and p53 MspI resulted in an increased breast cancer risk compared to the single polymorphisms (OR = 3.39, 95% CI 1.19-9.71). In conclusion, our study indicates the importance of inherited variants in the WRN and p53 genes for familial breast cancer susceptibility
    Type of Publication: Journal article published
    PubMed ID: 16501249
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