Prostate cancer susceptible CA7 CG04 gene

Details Prostate cancer susceptible CA7 CG04 gene Prostate cancer susceptible CA7 CG04 gene

2000-05-11

2002-08-27

Nguyen, Dave T. (Department: 1635)

Chemistry: molecular biology and microbiology

Micro-organism, tissue cell culture or enzyme using process...

Recombinant dna technique included in method of making a...

C435S320100, C435S325000, C536S023100, C536S023500

Reexamination Certificate

active

06440699

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates generally to the field of human genetics. Specifically, the present invention relates to methods and materials used to isolate and detect a human prostate cancer predisposing gene (identified as CA7 CG04 herein), some mutant alleles of which cause susceptibility to cancer, in particular, prostate cancer. More specifically, the invention relates to germline mutations in the CA7 CG04 gene and their use in the diagnosis of predisposition to prostate cancer. The present invention further relates to somatic mutations in the CA7 CG04 gene in human prostate cancer and their use in the diagnosis of human prostate cancer. Additionally, the invention relates to somatic mutations in the CA7 CG04 gene in other human cancers and their use in the diagnosis and prognosis of human cancers. The invention also relates to the therapy of human cancers which have a mutation in the CA7 CG04 gene. The invention further relates to the screening of drugs for cancer therapy. Finally, the invention relates to the screening of the CA7 CG04 gene for mutations, which are useful for diagnosing the predisposition to prostate cancer.
The publications and other materials used herein to illuminate the background of the invention, and in particular, cases to provide additional details respecting the practice, are incorporated herein by reference, and for convenience, are referenced by author and date in the following text and respectively grouped in the appended List of References.
BACKGROUND OF THE INVENTION
The genetics of cancer is complicated, involving gain or loss of function of three loosely defined classes of genes: (1) dominant, positive regulators of the transformed state (oncogenes); (2) recessive, negative regulators of the transformed state (tumor suppressor genes); (3) recessive genes involved in maintenance of genome integrity (caretaker genes) (Kinzler and Vogelstein, 1997). Over one hundred oncogenes have been characterized. About a dozen tumor suppressor and a similar number of caretaker genes have been identified; the number of genes falling into these last two classes is expected to increase beyond fifty (Knudson, 1993).
The involvement of so many genes underscores the complexity of the growth control mechanisms that operate in cells to maintain the integrity of normal tissue. This complexity is manifest in another way. So far, no single gene has been shown to participate in the development of all, or even the majority of, human cancers. The most common oncogenic mutations are in the H-ras gene, found in 10-15% of all solid tumors (Anderson et al., 1992). The most frequently mutated tumor predisposition genes are the TP53 gene, homozygously deleted or mutated in roughly 50% of all tumors, and CDKN2, which was homozygously deleted in 46% of tumor cell lines examined (Kamb et al., 1994). Without a target that is common to all transformed cells, the dream of a “magic bullet” that can destroy or revert cancer cells while leaving normal tissue unharmed is improbable. The hope for a new generation of specifically targeted antitumor drugs may rest on the ability to identify oncogenes, tumor suppressor, and caretaker genes that play general roles in the process of oncogenesis.
Specific germline alleles of certain oncogenes, tumor suppressor, and caretaker genes are causally associated with predisposition to cancer. This set of genes is referred to as tumor predisposition genes. Some of the tumor predisposition genes which have been cloned and characterized influence susceptibility to: 1) Retinoblastoma (RB 1); 2) Wilms' tumor (WT1); 3) Li-Fraumeni (TP53); 4) Familial adenomatous polyposis (APC); 5) Neurofibromatosis type 1 S(NF1); 6) Neurofibromatosis type 2 (NF2); 7) von Hippel-Lindau syndrome (VHL); 8) Multiple endocrine neoplasia type 2A (MEN2A); 9) Melanoma (CDKN2 and CDK4); 10) Breast and ovarian cancer (BRCA1 and BRCA2); 11) Cowden disease (MMAC1); 12) Multiple endocrine neoplasia (MEN1); 13) Nevoid basal cell carcinoma syndrome (PTC); 14) Tuberous sclerosis 2 (TSC2); 15) Xeroderma pigmentosum (genes involved in nucleotide excision repair); 16) Hereditary nonpolyposis colorectal cancer (genes involved in mismatch repair).
Tumor predisposition loci that have been mapped genetically but not yet isolated include genes for: Lynch cancer family syndrome 2 (LCFS2); Neuroblastoma (NB); Beckwith-Wiedemann syndrome (BWS); Renal cell carcinoma (RCC); and Tuberous sclerosis 1 (TSC1). Tumor predisposition genes that have been characterized to date encode products with similarities to a variety of protein types, including DNA binding proteins (WT1), ancillary transcription regulators (RB1), GTPase activating proteins or GAPs (NF1), cytoskeletal components (NF2), membrane bound receptor kinases (MEN2A), cell cycle regulators (CDKN2 and CDK4), tyrosine phosphatases (MMAC 1), as well as others with no obvious similarity to proteins of known function (BRCA2).
In many cases, the tumor predisposition gene originally identified through genetic studies has been shown to be lost or mutated in some sporadic tumors. This result suggests that regions of chromosomal aberration, whether germline, in tumors, or in tumor cell lines, may signify the position of important tumor predisposition genes involved both in genetic predisposition to cancer and in sporadic cancer.
Prostate cancer is the most common cancer in men in many western countries, and the second leading cause of cancer deaths in men. It accounts for more than 40,000 deaths in the U.S. annually. The number of deaths is likely to continue rising over the next 10 to 15 years. In the U.S., prostate cancer is estimated to cost $1.5 billion per year in direct medical expenses. In addition to the burden of suffering, it is a major public-health issue. Numerous studies have provided evidence for familial clustering of prostate cancer, indicating that family history is a major risk factor for this disease (Cannon et al., 1982; Steinberg et al., 1990; Carter et al, 1993).
Prostate cancer has long been recognized to be, in part, a familial disease. Numerous investigators have examined the evidence for genetic inheritance and concluded that the data are most consistent with dominant inheritance for a major susceptibility locus or loci. Woolf (1960), described a relative risk of 3.0 of developing prostate cancer among first-degree relatives of prostate cancer cases in Utah using death certificate data. Relative risks ranging from 3 to 11 for first-degree relatives of prostate cancer cases have been reported (Cannon et al., 1982; Woolf, 1960; Fincham et al., 1990; Meikle et al., 1985; Krain, 1974; Morganti et al., 1956; Goldgar et al., 1994). Carter et al. (1992) performed segregation analysis on families ascertained through a single prostate cancer proband. The analysis suggested Mendelian inheritance in a subset of families through autosomal dominant inheritance of a rare (q=0.003), high-risk allele with estimated cumulative risk of prostate cancer for carriers of 88% by age 85. Inherited prostate cancer susceptibility accounted for a significant proportion of early-onset disease, and overall was responsible for 9% of prostate occurrence by age 85. Recent results demonstrate that at least two loci exist which convey susceptibility to prostate cancer as well as other cancers. These loci are HPC1 on chromosome lq, (Smith et al., 1996), HPCX on chromosome Xp (Xu et al., 1998), and one or more loci responsible for the unmapped residual.
Smith et al., (1996) indicated that the inherited prostate susceptibility in kindreds with early age onset is linked to chromosome 1 (the HPC1 locus or region). Most strategies for cloning a chromosome 1-linked prostate cancer predisposing gene require precise genetic localization studies. The simplest model for the functional role of a prostate cancer predisposing gene holds that alleles of prostate cancer predisposing gene that predispose to cancer are recessive to wild type alleles; that is, cells that contain at least one wild type allele are not cancerous. However, cells th

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