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Markers for breast cancerRelated Patent Categories: Chemistry: Molecular Biology And Microbiology, Measuring Or Testing Process Involving Enzymes Or Micro-organisms; Composition Or Test Strip Therefore; Processes Of Forming Such Composition Or Test Strip, Involving Nucleic AcidMarkers for breast cancer description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070166738, Markers for breast cancer. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS REFERENCE TO RELATED APPLICATIONS [0001] The subject application claims priority to and benefit of U.S. Ser. No. 60/740,971 MARKERS FOR BREAST CANCER by Cox et al., filed Nov. 29, 2005. This application also claims priority to and benefit of U.S. Ser. No. 60/781,483 MARKERS FOR BREAST CANCER by Cox et al., filed Mar. 10, 2006. Each of these prior applications are incorporated herein by reference in their entirety. BACKGROUND OF THE INVENTION [0002] Breast cancer, like other common cancers, shows familial clustering. Numerous epidemiological studies have demonstrated that, overall, the disease is approximately twice as common in first degree relatives of breast cancer patients.sup.1. Family studies, and particularly twin studies, suggest that most if not all of this clustering has a genetic basis.sup.2,3. For example, Peto and Mack.sup.3 estimated that the risk of breast cancer in the MZ twin of an affected woman was approximately four-fold greater than the risk to a sister of a case. [0003] Several breast cancer susceptibility genes have already been identified, most importantly BRCA1 and BRCA2. Mutations in these genes confer a high risk of breast cancer (of the order of 65% and 45%, respectively, by age 70).sup.4. Mutation screening of population-based series of breast cancer cases has shown that only about 15% of the familial risk of breast cancer can be explained by mutations in these genes.sup.5,6. The other known breast cancer susceptibility genes (TP53, PTEN, ATM, CHEK2) make only small contributions to the familial risk (because the predisposing mutations are rare and/or confer only small risks). In total therefore, the known breast cancer susceptibility genes have been estimated to account for no more than 20% of the familial risk.sup.7. [0004] Genetic variation in risk may result from rare highly-penetrant mutations (such as those in BRCA1 and BRCA2) or from variants conferring more moderate risks. Several lines evidence suggest strongly that high penetrance mutations are not major contributors to the residual familial risk of breast cancer. Firstly, mutation screening of multiple case families has found that the large majority of cases with a very strong family history (for example four or more affected relatives) harbor mutations in BRCA1 or BRCA2.sup.8. Secondly, despite extensive efforts over the past nine years, genetic linkage studies have not identified any further linked loci.sup.9,10. Thirdly, segregation analyses of large series of breast cancer families have found, after adjusting for BRCA1 and BRCA2, no evidence for a further major dominant breast cancer susceptibility allele.sup.11,12. In the largest such analysis, Antoniou et al..sup.13 found that the most parsimonious model for breast cancer was a polygenic model, equivalent to a large number of loci of small effect combining multiplicatively. [0005] While the above analyses suggest that several low penetrance breast cancer susceptibility genes remain to be detected, the precise number of such genes is unknown. Moreover, in the prior art, it is unclear whether such susceptibility alleles are common or rare in the population. The subject application focuses on alleles that are relatively common (frequencies greater than 5%) and identification of such loci is performed herein on a genome-wide basis. SUMMARY OF THE INVENTION [0006] The invention includes the identification of polymorphic loci that are correlated with breast cancer phenotypes, such as susceptibility to breast cancer. FIGS. 1 and 2 provides descriptions of the phenotypic loci. FIG. 1 provides descriptions of preferred phenotypic loci. Accordingly, this invention provides previously unknown correlations between various polymorphisms and breast cancer susceptibility phenotypes. The detection of these polymorphisms (or loci linked thereto), accordingly, provides robust and precise methods and systems for identifying patients that are at risk for breast cancer. In addition, the identification of these polymorphisms provides high-throughput systems and methods for identifying modulators of breast cancer. [0007] Therefore, in one aspect, the invention provides methods of identifying a breast cancer phenotype for an organism or biological sample derived therefrom. The method includes detecting, in the organism or biological sample, a polymorphism or a locus closely linked thereto, the polymorphism being selected from a polymorphism of FIG. 1, wherein the polymorphism is associated with a breast cancer phenotype. The methods further include correlating the polymorphism or locus to the phenotype. [0008] The organism is typically a mammal, and is preferably a human patient, most typically a human female patient (although breast cancer does occur in men, and the associations noted herein may be applicable to male patients as well). Similarly, the biological sample is typically derived from a mammal, e.g., a human patient, e.g., following appropriate informed consent practices. The methods can be used to detect breast cancer markers in samples taken from human patients, or can be used to detect markers in biological samples (e.g., cells, including primary and cultured cells) derived therefrom. [0009] The polymorphisms can be detected by any available method, including amplification, hybridization to a probe or array, or the like. In one specific embodiment, Detection includes amplifying the polymorphism, linked locus or a sequence associated therewith (e.g., flanking sequences, transcribed sequences or the like) and detecting the resulting amplicon. For example, in one embodiment, amplifying includes a) admixing an amplification primer or amplification primer pair with a nucleic acid template isolated from the organism or biological sample. The primer or primer pair can be complementary or partially complementary to a region proximal to or including the polymorphism or linked locus, and are capable of initiating nucleic acid polymerization by a polymerase on the nucleic acid template. The primer or primer pair is extended in a DNA polymerization reaction comprising a polymerase and the template nucleic acid to generate the amplicon. In certain aspects, the amplicon is optionally detected by a process that includes hybridizing the amplicon to an array, digesting the amplicon with a restriction enzyme, or real-time PCR analysis. Optionally, the amplicon can be fully or partially sequenced, e.g., by hybridization. Typically, amplification can include performing a polymerase chain reaction (PCR), reverse transcriptase PCR (RT-PCR), or ligase chain reaction (LCR) using nucleic acid isolated from the organism or biological sample as a template in the PCR, RT-PCR, or LCR. Other technologies can be substituted for amplification, e.g., use of branched DNA (bDNA) probes. [0010] In typical embodiments, the polymorphism or linked locus can include a SNP. Example alleles include those described in FIGS. 1 and/or 2. Relevant polymorphisms can be those, e.g., of FIG. 1 (most preferred) or FIG. 2. Preferred polymorphisms include SNPs selected from the group of SNPs described by SNP identification numbers consisting of: SNP ID 2312116, SNP ID 1622530, SNP ID 3712013, SNP ID 1509710, SNP ID 843029, SNP ID 1990126, SNP ID 604819, SNP ID 3025734, SNP ID 1152499, SNP ID 4415909, SNP ID 1732681, SNP ID 4281579, SNP ID 4454457, SNP ID 2616199, SNP ID 1720694, SNP ID 4077723, SNP ID 3711990, SNP ID 3337858, SNP ID 4093095, SNP ID 4213825, SNP ID 3488617, SNP ID 3610210, SNP ID 3451239, SNP ID 1582533, SNP ID 3488150, SNP ID 2770052, SNP ID 4141351, SNP ID 1335030, SNP ID 2211665, and SNP ID 4538418. These identification numbers are Perlegen SNP identification numbers (Perlegen Sciences, Inc. in Mountain View, Calif.), which are publicly available and can be viewed with considerable associated information at Perlegen(dot)com, by using the company's available genome browser at genome(dot)perlegen(dot)com/browser/index(dot)html. Wild card characters (e.g., "*" symbols) can be added at the beginning of the SNP_ID to identify pertinent information for all alleles of the SNP, e.g., following the complete instructions provided. This database also links to the NCBI genomic database, thereby providing considerable additional information for the relevant genes and polymorphisms. These SNPs include SNPs associated with, e.g., the following genes: FGFR2, A2BP1, TNRC9, H19, FSTL5, LSP1, LOC388927, UNQ9391, HCN1, LOC441192, TNRC9, NR3C2, KIAA0826, FLJ31033, AACS, FRMD4A and SEC31L2 (See also, FIG. 1). Polymorphisms linked to these genes are, accordingly, also preferred SNPs that can be associated with breast cancer polymorphisms. [0011] Optionally, and, in certain embodiments, preferably, the method includes detecting polymorphisms in more than one such gene (e.g., in certain convenient applications, several polymorphisms can be detected simultaneously for a single patient to more completely determine or assign the relevant phenotype). Thus, in one aspect, the invention includes detecting a plurality of polymorphisms or linked loci in a plurality of said genes. This can include, e.g., detecting at least one polymorphism for each of: SNP ID 2312116, SNP ID 1622530, SNP ID 3712013, SNP ID 1509710 and SNP ID 84302, and/or polymorphism in FGFR2, A2BP1, TNRC9, H19, and FSTL5. Similarly, the method can include detecting at least one polymorphism for each of: SNP ID 2312116, SNP ID 1622530, SNP ID 3712013, SNP ID 1509710, SNP ID 843029, SNP ID 1990126, SNP ID 604819, SNP ID 3025734, SNP ID 1152499, SNP ID 4415909, SNP ID 1732681, SNP ID 4281579, SNP ID 4454457, SNP ID 2616199, SNP ID 1720694, SNP ID 4077723, SNP ID 3711990, SNP ID 3337858, SNP ID 4093095, SNP ID 4213825, SNP ID 3488617, SNP ID 3610210, SNP ID 3451239, SNP ID 1582533, SNP ID 3488150, SNP ID 2770052, SNP ID 4141351, SNP ID 1335030, SNP ID 2211665, and SNP ID 4538418, or at least one polymorphism in each of: FGFR2, A2BP1, TNRC9, H19, FSTL5, LSP1, LOC388927, UNQ9391, HCN1, LOC441192, TNRC9, NR3C2, KIAA0826, FLJ31033, AACS, FRMD4A and SEC31L2. In general, any combination of these or any other polymorphism/gene/locus in the figures herein can be detected, and all such combinations are optionally a feature of the invention, whether listed expressly or not. Probes or primers of the invention useful in detecting the polymorphisms herein can include a nucleotide sequence of a polymorphism of FIGS. 1 and/or 2, a flanking sequence thereof, or a complementary nucleic acid thereof, or a transcribed product thereof (e.g., a nRNA or mRNA form produced from a genomic sequence, e.g., by transcription or splicing). Polymorphisms can also be detected in a polypeptide sequence, e.g., for any polypeptide sequence transcribed from a given allelic form of a nucleic acid. [0012] In general, any polymorphism that is linked to a QTL can be used as a marker for the QTL. Thus, markers linked to a given polymorphism of the Figures can be used as proxy markers for the given polymorphism. In general, the closer the linkage, the better the marker will be for a QTL/polymorphism. Thus, desirably, the linked locus can be a closely linked locus that is about 5 cM or less (and, optionally, 1 cM or less) from the polymorphism. [0013] The methods optionally include correlating the polymorphism or linked locus to the breast cancer phenotype by referencing a look up table that comprises correlation information for alleles of the polymorphism or linked locus and the breast cancer phenotype. Databases that are used for this correlation can be heuristic, or otherwise capable of refining correlations based on information obtained by correlating marker-trait information. [0014] Related compositions are a feature of the invention, e.g., a composition comprising a plurality of marker probes or amplification primers that detect or amplify a plurality of polymorphisms associated with a breast cancer phenotype, e.g., as described herein. The primers/probes can be array based, or free in solution. [0015] In an additional aspect, methods of identifying a modulator of a breast cancer phenotype are also provided. The methods include contacting a potential modulator to a gene or gene product, e.g., wherein the gene or gene product comprises or is closely linked to a polymorphism described herein (e.g., in FIGS. 1 and/or 2). An effect of the potential modulator on the gene or gene product is detected, thereby identifying whether the potential modulator modulates the phenotype. [0016] The gene or gene product optionally includes a particular allele of a polymorphism selected from those listed herein, but modulators can also be tested on other alleles to identify modulators that modulate alleles specifically or non-specifically. The effects that can be tested for include any of: (a) increased or decreased expression of the gene or gene product in the presence of the modulator; (b) increased or decreased activity of the gene product in the presence of the modulator; and, (c) an altered expression pattern of the gene or gene product in the presence of the modulator. [0017] A kit for treatment of a breast cancer phenotype can include a modulator identified by the method and instructions for administering the modulator to a patient to treat the phenotype. [0018] In addition to the methods noted above, kits and systems for practicing the methods are also a feature of the invention. For example, a system for identifying a breast cancer phenotype for an organism or biological sample derived therefrom are one feature of the invention. The system includes, e.g., a set of marker probes or primers configured to detect at least one allele of one or more polymorphism or linked locus, e.g., where the polymorphism is any polymorphism noted herein, e.g., in FIGS. 1 or 2. The system optionally additionally includes a detector that is configured to detect one or more signal outputs from the set of marker probes or primers, or an amplicon produced from the set of marker probes or primers, thereby identifying the presence or absence of the allele. System instructions (e.g., software embodied in a computer of the system) that correlate the presence or absence of the allele with a predicted phenotype are typically included as components of the system. [0019] Systems for screening modulators are also a feature of the invention. The systems can include, e.g., genes linked to a polymorphism herein, or an encoded expression products of the gene. The systems will typically include a detector that measures increased or decreased expression of the gene or gene product in the presence of the modulator; increased or decreased activity of the gene product in the presence of the modulator; or an altered expression pattern of the gene or gene product in the presence of the modulator. The systems can also include fluid handling elements for mixing and aliquotting modulator and/or the gene or product, mixing them, performing laboratory operations (e.g., purification, synthesis, cell culture, etc.). System instructions for recording modulator effects and, optionally, for selecting modulators are also an optional feature of these systems. [0020] Kits for performing any of the methods herein are another feature of the invention. Such kits can include probes or amplicons for detecting any polymorphism herein, appropriate packaging materials, and instructions for practicing the methods. [0021] The polymorphisms and genes, and corresponding marker probes, amplicons or primers described above can be embodied in any system herein, either in the form of physical nucleic acids or polypeptides, or in the form of system instructions that include sequence information for the nucleic acids and polypeptides. For example, the system can include primers or amplicons corresponding to (or that amplify a portion of) a gene or polymorphism described herein, such as SNP ID 2312116, SNP ID 1622530, SNP ID 3712013, SNP ID 1509710, SNP ID 843029, SNP ID 1990126, SNP ID 604819, SNP ID 3025734, SNP ID 1152499, SNP ID 4415909, SNP ID 1732681, SNP ID 4281579, SNP ID 4454457, SNP ID 2616199, SNP ID 1720694, SNP ID 4077723, SNP ID 3711990, SNP ID 3337858, SNP ID 4093095, SNP ID 4213825, SNP ID 3488617, SNP ID 3610210, SNP ID 3451239, SNP ID 1582533, SNP ID 3488150, SNP ID 2770052, SNP ID 4141351, SNP ID 1335030, SNP ID 2211665, and SNP ID 4538418, and/or FGFR2, A2BP1, TNRC9, H19, FSTL5, LSP1, LOC388927, UNQ9391, HCN1, LOC441192, TNRC9, NR3C2, KIAA0826, FLJ31033, AACS, FRMD4A and SEC31L2. As in the methods above, the set of marker probes or primers optionally detects a plurality of polymorphisms in a plurality of said genes or genetic loci. Thus, for example, the set of marker probes or primers detects at least one polymorphism in each of these polymorphisms or genes, or any other polymorphism, gene or locus in the Figures herein. Any such probe or primer can include a nucleotide sequence of any such polymorphism or gene, or a complementary nucleic acid thereof, or a transcribed product thereof (e.g., a nRNA or mRNA form produced from a genomic sequence, e.g., by transcription or splicing). Continue reading about Markers for breast cancer... Full patent description for Markers for breast cancer Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Markers for breast cancer patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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