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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Breast cancer is a major contributor to overall morbidity and mortality in women. Several genes predisposing to breast cancer have been identified, but the majority of risk factors remain unknown. Even less is known about the inherited risk factors underlying canine mammary tumors (CMT). Clear breed predispositions exist, with 36% of English springer spaniels (ESS) in Sweden being affected. Here, we evaluate 10 human breast cancer genes (BRCA1, BRCA2, CHEK2, ERBB2, FGFR2, LSP1, MAP3K1, RCAS1, TOX3, and TP53) for association with CMTs. Sixty-three single-nucleotide polymorphisms (SNPs; four to nine SNPs per gene) were genotyped by iPLEX in female ESS dogs, 212 CMT cases and 143 controls. Two genes, BRCA1 and BRCA2, were significantly associated with CMT (Bonferroni corrected P = 0.005 and P = 0.0001, respectively). Borderline association was seen for FGFR2. Benign and malignant cases were also analyzed separately. Those findings supported the association to BRCA1 and BRCA2 but with a stronger association to BRCA1 in malignant cases. Both BRCA1 and BRCA2 showed odds ratios of approximately 4. In conclusion, this study indicates that BRCA1 and BRCA2 contribute to the risk of CMT in ESS, suggesting that dogs may serve as a good model for human breast cancer.
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PMID:Mammary tumor development in dogs is associated with BRCA1 and BRCA2. 1988 19

Personal genome tests are now offered direct-to-consumer (DTC) via genetic variants identified by genome-wide association studies (GWAS) for common diseases. Tests report risk estimates (age-specific and lifetime) for various diseases based on genotypes at multiple loci. However, uncertainty surrounding such risk estimates has not been systematically investigated. With breast cancer as an example, we examined the combined effect of uncertainties in population incidence rates, genotype frequency, effect sizes, and models of joint effects among genetic variants on lifetime risk estimates. We performed simulations to estimate lifetime breast cancer risk for carriers and noncarriers of genetic variants. We derived population-based cancer incidence rates from Surveillance, Epidemiology, and End Results (SEER) Program and comparative international data. We used data for non-Hispanic white women from 2003 to 2005. We derived genotype frequencies and effect sizes from published GWAS and meta-analyses. For a single genetic variant in FGFR2 gene (rs2981582), combination of uncertainty in these parameters produced risk estimates where upper and lower 95% simulation intervals differed by more than 3-fold. Difference in population incidence rates was the largest contributor to variation in risk estimates. For a panel of five genetic variants, estimated lifetime risk of developing breast cancer before age 80 for a woman that carried all risk variants ranged from 6.1% to 21%, depending on assumptions of additive or multiplicative joint effects and breast cancer incidence rates. Epidemiologic parameters involved in computation of disease risk have substantial uncertainty, and cumulative uncertainty should be properly recognized. Reliance on point estimates alone could be seriously misleading.
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PMID:Using lifetime risk estimates in personal genomic profiles: estimation of uncertainty. 1993 Oct 39

Fibroblast growth factor receptor 2 is a tyrosine kinase receptor that is a member of the family of individually distinct fibroblast growth factor receptors involved in cell proliferation, invasiveness, motility, and angiogenesis. Genome-wide association studies have identified FGFR2 as a breast cancer (BC) susceptibility gene in populations of European and Asian descent. After that, a number of studies reported that the rs2981582, rs1219648, and rs2420946 polymorphism in FGFR2 has been implicated in BC risk. However, studies on the association between these polymorphism and BC remain conflicting. To derive a more precise estimation of the relationship, a meta-analysis of 46,747 cases and 87,342 controls from 16 published case-control studies was performed. Overall, significantly elevated BC risk was associated with rs2981582, rs1219648, and rs2420946 risk allele when all studies were pooled into the meta-analysis. Significant results were also observed in heterozygous and homozygous when compared with wild genotype for these polymorphisms. In the subgroup analysis by ethnicity, source of controls, significantly increased risks were found for these polymorphisms in all genetic model. In conclusion, this meta-analysis suggests that rs2981582, rs1219648, and rs2420946 polymorphisms in FGFR2 are associated with elevated BC risk.
Breast Cancer Res Treat 2010 Nov
PMID:Quantitative assessment of the effect of FGFR2 gene polymorphism on the risk of breast cancer. 2036

Genome-wide association studies (GWAS) have led to the identification of more than 100 common, low-penetrance loci for cancer. At these loci, common genetic variants are associated with moderate increases in risk, typically <1.5-fold. Almost all loci lie in genomic regions not previously suspected to be involved in cancer. A plausible functional basis for a few loci, such as FGFR2 for breast cancer and MSMB for prostate cancer, has been elucidated, but the majority are not understood and suggest new mechanisms of carcinogenesis. Most loci are specific to a single cancer type, and are often subtype specific (e.g. ER-positive breast cancer). There are notable differences in the genetic architecture for different cancer types, with a greater contribution of common variants for prostate cancer. The clinical utility of variants to predict individual disease risk of disease is currently limited, but this may change as more variants are identified.
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PMID:Genome-wide association studies in common cancers--what have we learnt? 2041 93

Fibroblast growth factor (FGF) cooperates with the Wnt/beta-catenin pathway to promote mammary tumorigenesis. To investigate the mechanisms involved in FGF/Wnt cooperation, we genetically engineered a model of inducible FGF receptor (iFGFR) signaling in the context of the well-established mouse mammary tumor virus-Wnt-1 transgenic mouse. In the bigenic mice, iFGFR1 activation dramatically enhanced mammary tumorigenesis. Expression microarray analysis did not show transcriptional enhancement of Wnt/beta-catenin target genes but instead showed a translational gene signature that also correlated with elevated FGFR1 and FGFR2 in human breast cancer data sets. Additionally, iFGFR1 activation enhanced recruitment of RNA to polysomes, resulting in a marked increase in protein expression of several different Wnt/beta-catenin target genes. FGF pathway activation stimulated extracellular signal-regulated kinase and the phosphorylation of key translation regulators both in vivo in the mouse model and in vitro in a human breast cancer cell line. Our results suggest that cooperation of the FGF and Wnt pathways in mammary tumorigenesis is based on the activation of protein translational pathways that result in, but are not limited to, increased expression of Wnt/beta-catenin target genes (at the level of protein translation). Further, they reveal protein translation initiation factors as potential therapeutic targets for human breast cancers with alterations in FGF signaling.
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PMID:Fibroblast growth factor receptor signaling dramatically accelerates tumorigenesis and enhances oncoprotein translation in the mouse mammary tumor virus-Wnt-1 mouse model of breast cancer. 2050 44

Recent candidate gene and genome wide association studies have revealed novel loci associated with an increased risk of breast cancer. We evaluated the effect of these breast cancer associated variants on ovarian cancer risk in individuals with familial ovarian cancer both with and without BRCA1 or BRCA2 mutations. A total of 158 unrelated white British women (54 BRCA1/2 mutation positive and 104 BRCA1/2 mutation negative) with familial ovarian cancer were genotyped for FGFR2, TNRC9/TOX3 and CASP8 variants. The p.Asp302His CASP8 variant was associated with reduced ovarian cancer risk in the familial BRCA1/2 mutation negative ovarian cancer cases (P = 0.016). The synonymous TNRC9/TOX3 (Ser51) variant was present at a significantly lower frequency than in patients with familial BRCA1/2 positive breast cancer (P = 0.0002). Our results indicate that variants in CASP8 and TNRC9/TOX3 alter the risk of disease in individuals affected with familial ovarian cancer.
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PMID:Breast cancer susceptibility variants alter risk in familial ovarian cancer. 2050 73

GEN1 was recently identified as a key Holliday junction resolvase involved in homologous recombination. Somatic truncating GEN1 mutations have been reported in two breast cancers. Together these data led to the proposition that GEN1 is a breast cancer predisposition gene. In this article we have formally investigated this hypothesis. We performed full-gene mutational analysis of GEN1 in 176 BRCA1/2-negative familial breast cancer samples and 159 controls. We genotyped six SNPs tagging the 30 common variants in the transcribed region of GEN1 in 3,750 breast cancer cases and 4,907 controls. Mutation analysis revealed one truncating variant, c.2515_2519delAAGTT, which was present in 4% of cases and 4% of controls. We identified control individuals homozygous for the deletion, demonstrating that the last 69 amino acids of GEN1 are dispensable for its function. We identified 17 other variants, but their frequency did not significantly differ between cases and controls. Analysis of 3,750 breast cancer cases and 4,907 controls demonstrated no evidence of significant association with breast cancer for six SNPs tagging the 30 common GEN1 variants. These data indicate that although it also plays a key role in double-strand DNA break repair, GEN1 does not make an appreciable contribution to breast cancer susceptibility by acting as a high- or intermediate-penetrance breast cancer predisposition gene like BRCA1, BRCA2, CHEK2, ATM, BRIP1 and PALB2 and that common GEN1 variants do not act as low-penetrance susceptibility alleles analogous to SNPs in FGFR2. Furthermore, our analyses demonstrate the importance of undertaking appropriate genetic investigations, typically full gene screening in cases and controls together with large-scale case-control association analyses, to evaluate the contribution of genes to cancer susceptibility.
Breast Cancer Res Treat 2010 Nov
PMID:Mutation and association analysis of GEN1 in breast cancer susceptibility. 2051 59

Our understanding of hereditary forms of breast cancer has made enormous advances over the past 15 years, based on epidemiological and molecular genetic studies, and the development of a vast number of informative genetic markers. These studies have involved women with both familial and sporadic forms of breast cancer. Genetic susceptibility to breast cancer can involve several modes of inheritance: Mendelian inheritance, mostly involving autosomal dominant mutations with high penetrance and a high risk of malignancy (the BRCA1, BRCA2, TP53, PTEN and STK11 genes); dominant mutations associated with a lower risk (ATM, BRIP1, PALB2, etc), and multigenic patterns involving common susceptibility variants, i.e., polymorphisms located within predisposing gene loci (FGFR2, TNRC9, MAP3K1, LSP1, etc.) or intergenic regions. Other predisposing factors remain to be discovered, as genetic factors associated with a high breast cancer risk (BRCA1, BRCA2, TP53, PTEN STK11, etc) are only found in about 20% of genetically screened breast cancer families. So far, only the first class of genes have found clinical applications, guiding the choice of medical or surgical treatment. More refined individual risk profiles will benefit from genome-wide polymorphic DNA variant studies anda better understanding of the impact of non genetic factors, such as the obstetrical and gynaecological history, and mutagen exposure.
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PMID:[Implications of genetic risk factors in breast cancer: culprit genes and associated malignancies]. 2069 Feb 7

The heterogeneity of multiple case breast cancer families that do not carry mutations in BRCA1 or BRCA2 (non-BRCA1/2 families) poses a challenge to the identification of breast cancer susceptibility genes. The aim of this study was to determine whether intrafamilial concordance in breast cancer pathology could identify subgroups of non-BRCA1/2 families with consistent genotypic features. Invasive breast cancers were reviewed from 84 individuals belonging to 30 multiple-case families; BRCA1 (n = 9), BRCA2 (n = 10), and non-BRCA1/2 (n = 11). Hierarchical cluster analysis based on histopathology and age at first diagnosis was then used to specify three subgroups designated Clusters 1-3. The genomic features of non-BRCA1/2 families were examined by genome wide linkage and FGFR2 SNP genotyping, according to whether they showed cluster-concordant or cluster-mixed familial pathology. The majority of pathogenic BRCA1 mutation carriers (80%) fell into a single cluster. In contrast pathogenic BRCA2 mutation carriers were distributed across all three clusters and within families, cluster groups were also generally mixed. Most non-BRCA1/2 mutation carriers belonged to Cluster 3 (71%). Genome wide linkage data from five non-BRCA1/2 Cluster 3-concordant families were compared with four mixed cluster non-BRCA1/2 families. This revealed a number of distinct linkage peaks, including some regions previously associated with breast cancer susceptibility. The distribution of low risk alleles in FGFR2 was not different between these two subgroups (P = 0.237). The pattern of breast cancer pathology concordance amongst family members may assist the investigation of breast cancer susceptibility in multiple case families.
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PMID:Familial concordance of breast cancer pathology as an indicator of genotype in multiple-case families. 2081 29

Evaluation of: Turner N, Pearson A, Sharpe R et al. FGFR1 amplification drives endocrine therapy resistance and is a therapeutic target in breast cancer. Cancer Res. 70(5), 2085-2094 (2010). FGF receptor (FGFR) family members are aberrantly activated during carcinogenesis due to gene amplification, chromosomal translocation and missense mutation. FGFR1 is preferentially amplified in estrogen receptor-positive breast cancer, whereas FGFR2 is amplified in triple-negative breast cancer and diffuse-type gastric cancer. Gene amplification of FGFRs results in ligand-independent FGFR signaling to RAS-ERK, PI3K-AKT and JAK-STAT cascades due to the overexpression of wild-type or C-terminally deleted FGFRs. Cediranib, TKI258, Ki23057, MK-2461 and brivanib are broad-range tyrosine kinase inhibitors targeting FGFRs and other receptors. Clinical application of small-molecule FGFR inhibitors could improve the prognosis of FGFR-driven cancer patients. Diagnostic detection of tumors with FGFR genetic alterations in primary lesion, peritoneal effusion, pleural effusion and bone marrow is necessary to select patients for FGFR-targeted therapeutics.
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PMID:Genetic alterations of FGF receptors: an emerging field in clinical cancer diagnostics and therapeutics. 2017 96


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