Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
1999-01-22
2002-05-28
Jones, W. Gary (Department: 1655)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S091100, C536S023100
Reexamination Certificate
active
06395479
ABSTRACT:
1. FIELD OF THE INVENTION
The present invention relates to metabolic genes and their role in carcinogenesis. In particular, the invention relates to specified polymorphisms in genes encoding androgen-metabolic enzymes and their role in racial/ethnic susceptibility to prostate cancer.
2. DESCRIPTION OF RELATED ART
Metastatic prostate cancer is a leading cause of cancer-related death in men. In the United States some 334,500 men are anticipated to be diagnosed during this year and over 41,800 to die from the disease (Parker, 1997). This cancer is characterized by a marked racial/ethnic variation in risk. African-American men have the highest prostate cancer incidence rate of any racial/ethnic group, which is two-thirds higher than for White males and more than twice as high as rates for Asian-Americans. However, despite its high prevalence, very little is known regarding genetic predisposition to prostate cancer. Recent biochemical, molecular and epidemiological evidence has produced widespread interest in the role of androgens in prostate cancer pathogenesis because of their important growth regulatory effects on prostate.
Steroid hormones are ubiquitous physiologic regulators that function by modulating gene expression. Their biosynthesis involves initial conversion of cholesterol to pregnenolone which then may be metabolized by a variety of pathways to yield progestins, mineralcorticoids, glucocorticoids, androgens, and estrogens. Androgens are required for normal sexual differentiation, growth and development, and the main sexual characteristics in men. The most abundant androgen, testosterone, is produced in Leydig cells involving cytochrome P450 enzymes. Testosterone can act directly on target cells, or it can be converted into its reduced more potent form, dihydrotestosterone, by the 5&agr;-reductase enzymes or to estradiol by the aromatase enzyme complex. Dihydrotestosterone forms a complex with the androgen receptor (AR), which translocates to the nucleus for transactivation of androgen-responsive genes and subsequent regulation of the growth of prostate cells. Dihydrotestosterone is inactivated by the 3-hydroxysteroid dehydrogenases, further modified and ultimately excreted (Coffey, 1993).
There are compelling reasons to believe that androgens play a central role in prostate carcinogenesis. The growth and maintenance of the prostate are dependent on androgens (Henderson, 1982). Prostate cancer regresses following ablative or antiandrogen therapy (Trunnel, 1950), and exogenous androgen supplementation is required in most animal prostate carcinogenesis models (Pollard, 1989; Shirai, 1995). Similarly, administration of steroid 5&agr;-reductase inhibitors, which diminishes DHT levels, results in a substantial decrease in prostatic secretion of the normal gland and a substantial increase in cell death in normal and transformed prostatic cells (Kadohama, 1984; Lamb, 1992). Racial populations with a higher incidence of prostate cancer were shown to have a higher activity of steroid 5&agr;-reductase (Lookingbill, 1991; Ross, 1992; Wu, 1995), and men with prostatic cancer have an increased conversion rate of testosterone to its reduced potent metabolite, dihydrotestosterone (Meikle, 1987).
Studies of the regulation of androgen biosynthesis in steroidogenic cells have focused on both transcriptional and post-translational regulation of the relevant proteins that catalyze these reactions such as the enzyme P450c17 (Picado-Leonard and Miller, 1987), the prostatic (or type II) steroid 5&agr;-reductase, and both the 3&bgr;-hydroxysteroid dehydrogenase type II and the 17&bgr;-hydroxysteroid dehydrogenase type III. Microsomal cytochrome P450c17 is encoded by the CYP17 locus and is the key branch point in human adrenal steroidogenesis. It mediates both 17 &agr;-hydroxylase and 17,20-lyase activities that are independently regulated (Miller, 1997). The former enzymatic activity leads to precursors of the glucocorticoid cortisol, whereas the latter activity yields precursors to the sex steroids (Brentano, 1990). Various mutations in the CYP17 gene are known that lead to deficiencies in either enzyme activity. Clinical phenotypes of these diseases include autosomal disorders producing an excess of mineralcorticoids and sexual differentiation abnormalities (Yamaguchi, 1997). Recent investigations identified a single base pair change in the 5′ region of the CYP17 gene creating an SP1-type (CCACC box) promoter site in which a thymidine (T) is replaced by a cytosine (C), 34 base pairs upstream from the initiation site of translation. The normal sequence has been designated as the A1 allele and the mutated sequence as the A2 allele (Carey, 1994). It was suggested that the additional promoter site influences promoter activity, thereby increasing levels of transcription leading to elevated synthesis of androgens (Carey, 1994).
Steroid 5&agr;-reductase acts on a variety of androgen responsive target tissues to mediate such diverse endocrine processes as male sexual differentiation in the fetus and prostatic growth in men. It also plays a role in several endocrine abnormalities. There are two isoforms of steroid 5&agr;-reductase, type I and type II, which are encoded by the SRD5A1 and SRD5A2 gene, respectively (Wilson, 1993; Labrie, 1992; Thigpen, 1992). Type I enzyme is expressed mostly in newborn scalp and in skin and liver and is primarily responsible for virilization and male pattern baldness. Type II enzyme is primarily expressed in genital skin and the prostate and is involved in prostate development and growth (Wilson, 1993). The entire cDNA sequence of human type II SRD5A2 has been determined (Andersson, 1991), and is reproduced here:
1 gcggccaccg gcgaggaaca cggcgcgatg caggttcagt gccagcagag cccagtgctg
61 gcaggcagcg ccactttggt cgcccttggg gcactggcct tgtacgtcgc gaagccctcc
121 ggctacggga agcacacgga gagcctgaag ccggcggcta cccgcctgcc agcccgcgcc
181 gcctggttcc tgcaggagct gccttccttc gcggtgcccg cggggatcct cgcccggcag
241 cccctctccc tcttcgggcc acctgggacg gtacttctgg gcctcttctg cgtacattac
301 ttccacagga catttgtgta ctcactgctc aatcgaggga ggccttatcc agctatactc
361 attctcagag gcactgcctt ctgcactgga aatggagtcc ttcaaggcta ctatctgatt
421 tactgtgctg aataccctga tgggtggtac acagacatac ggtttagctt gggtgtcttc
481 ttatttattt tgggaatggg aataaacatt catagtgact atatattgcg ccagctcagg
541 aagcctggag aaatcagcta caggattcca caaggtggct tgtttacgta tgtttctgga
601 gccaatttcc tcggtgagat cattgaatgg atcggctatg ccctggccac ttggtccctc
661 ccagcacttg catttgcatt tttctcactt tgtttccttg ggctgcgagc ttttcaccac
721 cataggttct acctcaagat gtttgaggac taccccaaat ctcggaaagc ccttattcca
781 ttcatctttt aaaggaacca aattaaaaag gagcagagct cccacaatgc tgatgaaaac
841 tgtcaagctg ctgaaactgt aattttcatg atataatagt catatatata tatatatata
901 tatatatata tatatatatg tatatatgta atagtaggtc tcctggcgtt ctgccagctg
961 gcctggggat tctgagtggt gtctgcttag agtttactcc tacccttcca gggaccccta
1021 tcctgatccc caactgaagc ttcaaaaagc cacttttcca aatggcgaca gttgcttctt
1081 agctattgct ctgagaaagt acaaacttct cctatgtctt tcaccgggca atccaagtac
1141 atgtggcttc atacccactc cctgtcaatg caggacaact ctgtaatcaa gaattttttg
1201 acttgaaggc agtacttata gaccttatta aaggtatgca ttttatacat gtaacagagt
1261 agcagaaatt taaactctga agccacaaag acccagagca aacccactcc caaatgaaaa
1321 ccccagtcat ggcttccttt ttcttggtta attaggaaag atgagaaatt attaggtaga
1381 ccttgaatac aggagccctc tcctcatagt gctgaaaaga tactgatgca ttgacctcat
1441 ttcaaatttg tgcagtgtct tagttgatga gtgcctctgt tttccagaag atttcacaat
1501 ccccggaaaa ctggtatggc tattcttgaa ggccaggttt taataaccac aaacaaaaag
1561 gcatgaacct gggtggctta tgagagagta gagaacaaca tgaccctgga tggctactaa
1621 gaggatagag aacagtttta caatagacat tgcaaactct catgtttttg gaaactggtg
1681 gcaatatcca aataatgagt agtgtaaaac aaagagaatt aatgatgagg ttacatgctg
1741 cttgcctcca ccagatgtcc acaacaatat gaagtacagc agaagcccca agcaactttc
1801 ctttcctgga gcttcttcct tgtagttctc aggacctgtt caagaaggtg tctcctaggg
1861 gcagcctgaa tgcctccctc aaaggacctg caggcagaga ctgaaaattg cagacagagg
1921 ggcacgtctg ggcagaaaac ctgttttgtt tggctcagac atatagtttt ttttttttta
1981 caaagtttca aaaacttaaa aatcaggaga ttccttcata aaactctagc attctagttt
Coetzee Gerhard A.
Henderson Brian E.
Makridakis Nick
Reichardt Juergen K. V.
Ross Ronald
Jones W. Gary
McCutchen Doyle Brown & Enersen LLP
Souaya Jehanne
University of Southern California
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