Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
1996-05-16
2001-10-09
Sisson, Bradley L. (Department: 1655)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S091100, C435S091200, C536S023100, C536S024310, C536S024330
Reexamination Certificate
active
06300060
ABSTRACT:
BACKGROUND OF THE INVENTION
Prostate cancer is the most common malignant tumors and the second most common cause of cancer death in American males. Schoenberg, M. P., et al., Biochem. and Biophys. Res. Comm. 198: 74-80 (1994). Racial differences in the incidence of disease have also been observed, with the highest incidence in the African-American population, followed by Caucasians. The incidence of the disease is lowest in Asians. Interestingly, the androgen receptor gene contains a highly polymorphic CAG microsatellite in exon 1, resulting in a variable length glutamine repeat. The CAG repeat MEAN lengths observed in African-Americans, Caucasians and Asians are 18, 21 and 22, respectively. While the androgen receptor gene has been speculated to possess some relationship with prostate cancer, the nature of that relationship is unknown and the subject of speculation. Coetzee, G. A. and Ross, R. K., J. Natl. Cancer Inst. 86:872-73 (1994).
The human androgen receptor gene has been assigned chromosomal location Xq11-12 with the polymorphic CAG repeat region located at position 172 following the translation start codon. The polymorphism in the human androgen receptor gene has been used to diagnose families with the Androgen Insensitivity Syndromes, employing the polymerase chain reaction (PCR).
The relationship of the CAG repeat of the androgen receptor (AR) gene and prostate cancer has been studied. Schoenberg, M. P., and colleagues supra, describe a somatic contraction of the repeat region in one patient with prostate cancer, yet the PCR products of the tumor
on-tumor DNA in the remaining 39 patients studied were the same. No correlation of the CAG repeat length to the aggressiveness or mortality of prostate cancer has been suggested.
SUMMARY OF THE INVENTION
The present invention is based upon the discovery that the number of CAG repeats in the androgen receptor determines the aggressiveness of prostate cancer and the likelihood that a patient of at least about 60 years of age will die of the disease. For total prostate cancer, a slight inverse association between androgen receptor CAG repeat length and risk of disease was observed, but this was not statistically significant. However, CAG repeat length was inversely associated with cancers characterized as “aggressive” (extraprostatic extension (stage C or D) and/or high grade). For an increment of six CAG repeats, equivalent to the difference between the median CAG length in the upper versus lower tertile of CAG repeats, the relative risk of “aggressive” prostate cancer was 0.66 (95 percent confidence interval, 0.44-0.96; p=0.03) and the relative risk for developing distant metastatic prostate cancer was 0.41 (95 percent confidence interval, 0.21-0.81; p=0.01). CAG repeat length was not associated with non-aggressive disease. Results presented herein demonstrate an inverse correlation between CAG repeat length and indicators of disease progression (p, trend,=0.005). Risk of advanced, aggressive, or fatal disease was particularly strongly related to CAG length among older men.
The results herein also provide evidence that the variability in the androgen receptor CAG microsatellite influences the risk of developing “aggressive” prostate cancer. As a result, a method of predicting the onset of aggressive prostate cancer and the risk of mortality from the prostate cancer is available.
The present invention additionally relates to the discovery that the length of the TA repeat polymorphism in the 5-alpha reductase gene is directly related with risk of aggressive disease. Thus, the invention relates to a method for prognosis of prostate cancer in a male comprising: (a) determining the length of the TA dinucleotide repeat in the 5-alpha reductase gene and (b) correlating the length of the repeat with the risk of prostate cancer in the male.
DETAILED DESCRIPTION OF THE INVENTION
Cell division in the prostate gland is controlled by testosterone (Coffey D. S.,
UICC Technical Report Series
, 48:4-23, Geneva: International Union Against Cancer, (1979)). In the prostate cell, testosterone is converted to dihydrotestosterone (DHT) through the action of 5-alpha-reductase (Thigpen, A. E., et al.,
N.E. J. Med
., 327:1216-19 (1992)). DHT binds with the androgen receptor (AR) in the cell nucleus, and the DHT-AR complex interacts with specific DNA sequences, resulting in up- or down-regulation of target genes. Encoded in exon 1 of the AR gene on the X-chromosome are polymorphic CAG microsatellites. The CAG repeats, which range normally from about 8 to 31 repeats and average about 20, (Edwards A., et al.
Genomics
12:241-53 (1992)) encode for polyglutamine chains in the transactivation region of the AR. In transfection assays, the lengths of these polyglutamine chains correlate inversely with transactivation of the AR (Chamberlain, N. L., et al.,
Nucleic Acids Res
., 22:3181
14
6
(1994); Kazemi-Esfarjani P., et al.,
Human Molecular Genetics
, 4:523-7 (1995)). Expansion of the CAG microsatellite to 40 to 62 repeats, which causes X-linked spinal and bulbar muscular atrophy (Kennedy's disease), leads to signs of relative androgen insensitivity, including hypogonadism, reduced fertility with oligospermia or azoospermia, and gynecomastia despite normal serum testosterone levels in men (LaSpada, A. R., et al.,
Nature
, 352:77-9 (1991); Arbizu, T., et al.,
J. Neurol. Sci
., 59:371-82 (1983); Igarashi, S., et al.,
Neurology
, 42:2300-2 (1992)).
Because of their role in prostate cell division, androgens are believed to influence the initiation or promotion of prostate Cancer (Ross, R. K., et al.,
cancer
, 75:1778-1782 (1995)). Moreover, the variation in androgen receptor transactivation related to polymorphism in CAG repeat length could influence occurrence or progression of prostate cancer. Coetzee and Ross have hypothesized that the generally shorter CAG repeat lengths in the AR among African-Americans may contribute to their high incidence of prostate cancer, particularly advanced cancer (Coetzee, G. A., Ross, R. K.,
J. Natl. Cancer Inst
., 86:872-3 (1994)). A slight inverse association between CAG repeat length and risk of prostate cancer has been reported, but this finding was based on only 47 cases and was not statistically significant (Irvine, R. A., et al.,
Cancer Res
., 55:1937-40 (1995)). Hence, the relationship between polymorphism in CAG repeat length in the AR and prostate cancer development and progression in a large cohort study was examined, the Physician's Health Study.
As set forth above, the invention relates to a method for prognosis of prostate cancer in a male comprising: (a) determining the length of the CAG trinucleotide repeat of exon 1 of the androgenic receptor gene and/or the length of the TA dinucleotide repeat in the 5-alpha reductase gene obtained from DNA of the male and (b) correlating the length of the repeat with the aggressiveness and mortality risk of the cancer in the male.
The invention also relates to a method for determining length of a CAG trinucleotide repeat in exon 1 of the androgenic receptor gene and/or the length of the TA dinucleotide repeat in the 5-alpha reductase gene or its complement in a male patient having prostate cancer comprising: (a) obtaining DNA from the patient wherein the DNA comprises the CAG trinucleotide repeat of exon 1 of the androgenic receptor gene and/or the length of the TA dinucleotide repeat in the 5-alpha reductase gene or its complement; (b) determining the length of the repeat; and (c) comparing the length of the repeat with the length of the repeat in a significant number of individuals; wherein the length of the repeat is prognostic of the aggressiveness and mortality of the prostate cancer.
As detailed above, the length of the AR CAG repeat in the germline is inversely related to the onset of aggressive prostate cancer and mortality due to prostate cancer, particularly in males over about 60 years of age. The male to be tested can be of any race, including African-American, Caucasian or Asian. A suitable controllor comparison can be
Brown Myles
Giovannucci Edward
Kantoff Philip W.
Dana-Farber Cancer Institute Inc.
Hamilton Brook Smith & Reynolds P.C.
Sisson Bradley L.
LandOfFree
Method for predicting the risk of prostate cancer morbidity... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Method for predicting the risk of prostate cancer morbidity..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Method for predicting the risk of prostate cancer morbidity... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2571781