Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues
Reexamination Certificate
1997-12-12
2003-01-28
Brusca, John S. (Department: 1637)
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
C435S004000, C435S007100, C436S501000
Reexamination Certificate
active
06512091
ABSTRACT:
INTRODUCTION
1. Field of the Invention
The field of the invention is genetic markers for inheritable breast cancer susceptibility.
2. Background
The largest proportion of inherited breast cancer described so far has been attributed to a genetic locus, the BRCA1 locus, on chromosome 17q21 (Hall et al. 1990 Science 250:1684-1689; Narod et al. 1991 Lancet 338:82-83; Easton et al. 1993 Am J Hum Genet 52:678-701). Background material on the genetic markers for breast cancer screening is found in the Jan 29, 1993 issue of Science, vol 259, especially pages 622-625; see also King et al., 1993 J Amer Med Assoc 269:1975-198. Other relevant research papers include King (1992) Nature Genet 2:125-126; Merette et al. (1992) Amer J Human Genet 50:515-519; NIH/CEPH Collaborative Mapping Group (1992) Science 258:67-86.
Risks of breast cancer to women inheriting the locus are extremely high, exceeding 50% before age 50 and reaching 80% by age 65 (Newman et al. 1988 Proc Natl Acad Sci USA 85:3044-3048; Hall et al. 1992 Amer J Human Genet 50:1235-1242; Easton et al. 1993). Epidemiological evidence for inherited susceptibility to ovarian cancer is even stronger (Cramer et al. 1983 J Natl Cancer Inst 71:711-716; Schildkraut & Thompson 1988 Amer J Epidemiol 128:456-466; Schildkraut et al. 1989 Amer J Hum Genet 45:521-529). According to one study, more than 90% of families with multiple relatives with breast and ovarian cancer trace disease susceptibility to chromosome 17q21 (Easton et al. 1993).
The link between increasing risk of breast and ovarian cancer and inherited susceptibility to these diseases lies in the application of genetics to diagnosis and prevention. Creating molecular tools for earlier diagnosis and developing ways to reverse the first steps of tumorigenesis may be the most effective means of breast and ovarian cancer control.
Our laboratory previously mapped the heritable breast cancer susceptibility gene locus (BRCA1 locus) to a 50 cM region of chromosome 17q (Hall et al. 1990). More recently, we developed new polymorphisms at ERBB2 (Hall and King 1991 Nucl Acids Res 19:2515), THRA1 (Bowcock et al. 1993 Amer J Human Genet 52:718-722), EDH17B (Friedman et al. 1993 Hum Molec Genet 2:821), and multiple anonymous loci (Anderson et al. 1993 Genomics 17:616-623), ultimately developing a high density map of 17q12-q21 (Anderson et al. 1993; see also, Simard et al. 1993 Human Molec Genet 2:1193-1199). We also added families to the genetic study; there are now 100 families for whom transformed lymphocyte lines have been established and all informative relatives genotyped. We used our new markers and the many chromosome 17q polymorphisms developed in the past three years to test linkage in our families, refining the region first to 8 cM (Hall et al. 1992), then to 4 cM (Bowcock et al. 1993), then to 1 Mb based on polymorphisms from our high density map (Anderson et al. 1993; see also Flejter et al., 1993 Genomics 17:624-631). We disclose here a number of mutations in BRCA1 which correlate with disease.
Relevant Literature
The predicted amino acid sequence for a BRCA1 cDNA and familial studies of this gene were described by Miki et al. (1994) Science 266, 66-71 and Futeal et al. (1994) Science 266, 120-122. A study of Canadian cancer families is described in Simard et al. (1994) Nature Genetics 8, 392-398. A collaborative survey of BRCA1 mutations is described in Shattuch-Eidens et al. (1995) JAMA 273, 535-541.
SUMMARY OF THE INVENTION
The invention discloses methods and compositions useful in the diagnosis and treatment of breast and ovarian cancer associated with mutations and/or rare alleles of BRCA1, a breast cancer susceptibility gene. Specific genetic probes diagnostic of inheritable breast cancer susceptibility and methods of use are provided. Labelled nucleic acid probes comprising sequences complementary to specified BRCA1 alleles are hybridized to clinical nucleic acid samples. Linkage analysis and inheritance patterns of the disclosed markers are used to diagnose genetic susceptibility. In addition, BRCA1 mutations and/or rare alleles are directly identified by hybridization, polymorphism and or sequence analysis. In another embodiment, labeled binding agents, such as antibodies, specific for peptides encoded by the subject nucleic acids are used to identify expression products of diagnostic mutations or alleles in patient derived fluid or tissue samples. For therapeutic intervention, the invention provides compositions which can functionally interfere with the transcription or translation products of the breast and ovarian cancer susceptibility associated mutations and/or rare alleles within BRCA1. Such products include anti-sense nucleic acids, competitive peptides encoded by the subject nucleic acids, and high affinity binding agents such as antibodies, specific for e.g. translation products of the disclosed BRCA1 mutations and alleles.
DESCRIPTION OF SPECIFIC EMBODIMENTS
We disclose here methods and compositions for determining the presence or absence of BRCA1 mutations and rare alleles or translation products thereof which are useful in the diagnosis of breast and ovarian cancer susceptibility. Tumorigenic BRCA1 alleles include BRCA1 allele #5803 (SEQUENCE ID NO:1), 9601 (SEQUENCE ID NO:2), 9815 (SEQUENCE ID NO:3), 8403 (SEQUENCE ID NO:4), 8203 (SEQUENCE ID NO:5), 388 (SEQUENCE ID NO:6), 6401 (SEQUENCE ID NO:7), 4406 (SEQUENCE ID NO:8), 10201 (SEQUENCE ID NO:9), 7408 (SEQUENCE ID NO:10), 582 (SEQUENCE ID NO:11) or 77 (SEQUENCE ID NO:12). These nucleic acids or fragments capable of specifically hybridizing with the corresponding allele in the presence of other BRCA1 alleles under stringent conditions find broad diagnostic and therapeutic application. Gene products of the disclosed mutant and/or rare BRCA1 alleles also find a broad range of therapeutic and diagnostic applications. For example, mutant and/or rare allelic BRCA1 peptides are used to generate specific binding compounds. Binding reagents are used diagnostically to distinguish non-tumorigenic wild-type and tumorigenic BRCA1 translation products.
The subject nucleic acids (including fragments thereof) may be single or double stranded and are isolated, partially purified, and/or recombinant. An “isolated” nucleic acid is present as other than a naturally occurring chromosome or transcript in its natural state and isolated from (not joined in sequence to) at least one nucleotide with which it is normally associated on a natural chromosome; a partially pure nucleic acid constitutes at least about 10%, preferably at least about 30%, and more preferably at least about 90% by weight of total nucleic acid present in a given fraction; and a recombinant nucleic acid is joined in sequence to at least one nucleotide with which it is not normally associated on a natural chromosome.
Fragments of the disclosed alleles are sufficiently long for use as specific hybridization probes for detecting endogenous alleles, and particularly to distinguish the disclosed critical rare or mutant alleles which correlate with cancer susceptibility from other BRCA1 alleles, including alleles encoding the BRCA1 translation product displayed in Miki et al (1994) supra, under stringent conditions. Preferred fragments are capable of hybridizing to the corresponding mutant allele under stringency conditions characterized by a hybridization buffer comprising 0% formamide in 0.9 M saline/0.09 M sodium citrate (SSC) buffer at a temperature of 37° C. and remaining bound when subject to washing at 42° C. with the SSC buffer at 37° C. More preferred fragments will hybridize in a hybridization buffer comprising 20% formamide in 0.9 M saline/0.09 M sodium citrate (SSC) buffer at a temperature of 42° C. and remaining bound when subject to washing at 42° C. with 2×SSC buffer at 42° C. In any event, the fragments are necessarily of length sufficient to be unique to the corresponding allele; i.e. has a nucleotide sequence at least long enough to define a novel oligonucleotide, usually at least about 14, 16, 18, 20, 22, or 24 bp in length, though such fra
Friedman Lori
King Mary-Claire
Lee Ming
Lynch Eric
Ostermeyer Beth
Brusca John S.
Kim Young
Osman Richard Aron
The Regents of the University of California
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