Chemistry: molecular biology and microbiology – Vector – per se
Reexamination Certificate
1997-08-05
2001-09-11
Zitomer, Stephanie (Department: 1655)
Chemistry: molecular biology and microbiology
Vector, per se
C435S069100, C435S173300, C435S325000, C435S252330, C536S023500, C536S024310, C536S024330, C424S280100, C530S300000, C530S350000
Reexamination Certificate
active
06287854
ABSTRACT:
The present invention relates to methods of determining whether a patient has cancer or is susceptible to cancer, and it relates to methods of treating cancer, particularly prostate cancer.
Carcinoma of the prostate has become a most significant disease in many countries. Over the last 20 years the mortality rates have doubled and it is now the second commonest cause of male cancer deaths in England and Wales (Mortality Statistics: Cause England and Wales. OPCS DH2 19, 1993, Her Majesty's Stationery Office). The prevalence of prostate cancer has increased by 28% in the last decade and this disease now accounts for 12% of the total cancers of men in England and Wales (Cancer Statistics: Registrations England and Wales. OPCS MBI No 22, 1994, Her Majesty's Stationery Office). This increase and the recent deaths of many public figures from prostatic cancer have served to highlight the need to do something about this cancer. It has been suggested that the wider availability of screening may limit mortality from prostate cancer.
Prostate cancer screening currently consists of a rectal examination and measurement of prostate specific antigen (PSA) levels. These methods lack specificity as digital rectal examination has considerable inter-examiner variability (Smith & Catalona (1995)
Urology
45, 70-74) and PSA levels may be elevated in benign prostatic hyperplasia (BPH), prostatic inflammation and other conditions. The comparative failure of PSA as a diagnostic test was shown in 366 men who developed prostate cancer while being included in the Physicians Health Study, a prospective study of over 22,000 men. PSA levels were measured in serum, which was stored at the start of the study, and elevated levels were found in only 47% of men developing prostate cancer within the subsequent four years (Gann et al (1995)
JAMA
273, 289-294).
Present screening methods are therefore unsatisfactory.
Cytogenetic and allele loss studies have pointed to a number of chromosomal regions of potential involvement in prostate cancer. Cannon-Albright & Eeles (1995)
Nature Genetics
9, 336-338 (Reference 1) discuss candidate regions for tumour suppressor prostate cancer susceptibility loci from loss-of-heterozygosity (LOH) studies which occur on human chromosome regions 3p, 7q, 8p, 9q, 10p, 10q, 11p, 13q, 16q, 17p, 18q and Y; whereas Broilman et al 1990)
Cancer Res.
50 3795-3803 surveyed cytogenetic information on human prostate adenocarcinoma which indicated loss of chromosomes 1, 2, 5 and Y and gain of 7, 14, 20 and 22, with rearrangements involving chromosome arms 2p, 7q and 10q being most common. Studies by Gao et al 1994)
Oncogene
9, 2999-3003 indicate that a positive mutator phenotype in at least one of chromosomes 3p, 5q, 6p, 7p, 8p, 10q, 11p, 13q, 16q, 17p, 18q and Xq is found in prostate adenocarcinoma; and Massenkeil et al (1994)
Anticancer Res.
14(6B), 2785-2790 indicates that LOH was observed at 8p, 17p, 18q in various prostate tumour samples but no deletions were observed on 10q in fourteen informative prostate tumours. Zenklusen et al (1994)
Cancer Res.
54, 6370-6373 suggests that there is a possible tamour suppressor gene at 7q31.1. In addition, there have been other reports which describe other chromosome loss or abnormalities.
Thus, loss of, or abberations in, most human chromosomes has been implicated in prostate cancer by one research group or another.
A number of tumours exhibit precise loss of the region 10q23-q25 (2, 3), suggesting the presence of a tumour suppressor gene in this area. Mxil, which encodes a negative regulator of the Myc oncoprotein and resides at 10q25, has been proposed as a candidate for the tumour suppressor gene (4); potentially disabling mutations of Mxil in a number of prostate tumours have recently been described. Mxil displays allelic loss and mutation in some cases of prostate cancer and it has been concluded that it may contribute to the pathogenesis or neoplastic evolution of this common malignancy (5).
Objects of the invention are to provide better methods for the diagnosis of cancer and for determining susceptibility to cancer, especially prostate cancer; to provide nucleic acids which are useful in such methods; and to provide a tumour suppressor gene associated with prostate cancer.
SUMMARY OF THE INVENTION
Using fluorescence based allelotyping with highly informative microsatellite CA repeat markers, we have generated a detailed deletion map spanning 10q23-q25, allowing stricter definition of the region of 10q loss likely to be involved in tumour advancement. In addition, we have assessed the frequency of loss and mutation of Mxil in prostate tumours in order to clarify the role of this gene in prostate tamour progression.
Our data indicate the presence of a prostate tumour suppressor gene (or genes) near the 10q23-q24 boundary, which was deleted in the overwhelming majority (22/23) of tumours showing loss. In contrast, specific loss of Mxil, as opposed to loss of other 10q23-q25 regions or of the entire region, was observed in only 1/23 tumours, and was accompanied by loss of markers at the 10q23-q24 boundary.
Furthermore, we failed to detect any mutations in Mxil in those tumours showing Mxil-associated marker loss by either single-strand conformation polymorphism (SSCP) analysis or direct DNA sequencing, and our data indicate that AMril is
20
centiMorgans away from the area of chromosome 10 that we have identified. We have found that all tumours which have a loss of 10q have loss of the region specified below.
A first aspect of the invention provides a nucleic acid capable of selectively hybridising to the region of human chromosome 10 which region is bounded by DNA defined by the markers D10S541 and D10S215 provided that the nucleic acid is not any one of the yeast artificial chromosomes (YACs) 746-H-8, 821-D-2, 831-E-5, 921-F-8, 738-B-12, 796-D-5, 829-E-1, 678-F-1, 839-B-1, 734-B-4, 7B-F12, 757-D-8, 773-C2, 787-D-7, 831-E-9, 855-D-2, 855-G-4, 876-G-11, 894-H-5, 922-E-6, 934-D-3, 964-A-8, 968-E-6 or 24G-A10 and is not any one of the expressed sequence tags (ESTs) as described in Tables 3 to 22, and is not any one of the bacterial artificial chromosomes (BACs) or P1-derived artificial chromosomes (PACs) B2F20, P40F10, P72G8, P74N2, P274D21, B76I10, B79A19, B7901, B93F12, B122L22, P201J8, P201P5, P209K3, P316N14, B46B12, B60C5, B145C22, B150K4, B150N3, B181F15, and 188L22.
It is also preferred if the nucleic acid is not any one of the expressed sequence tags (ESTs) as described in Tables 23 to 37.
The position of various markers on human chromosome 10, including D10S541 and D10S215 (541 and 215, respectively), is as defined in FIG.
5
. When we refer to these ESTs we mean the sequence that is disclosed in the referenced Tables, and more particularly the specific cDNA clones from which the sequence is derived.
By “selectively hybridising” we mean that the nucleic acid has sufficient nucleotide sequence similarity with the said chromosome 10 DNA that it can hybridise under moderately or highly stringent conditions. As is well known in the art, the stringency of nucleic acid hybridization depends on factors such as length of nucleic acid over which hybridisation occurs, degree of identity of the hybridizing sequences and on factors such as temperature, ionic strength and CG or AT content of the sequence.
Nucleic acids which can selectively hybridise to the said chromosome 10 DNA include nucleic acids which have >95% sequence identity, preferably those with >98%, more preferably those with >99% sequence identity, over at least a portion of the nucleic acid with the said chromosome 10 DNA. As is well known, human genes usually contain introns such that, for example, a MRNA or cDNA derived from a gene within the said chromosome 10 DNA would not match perfectly along its entire length with the said chromosome 10 DNA but would nevertheless be a nucleic acid capable of selectively hybridising to the said region of chromosome 10.
Typical moderately or highly stringent hybridisation conditions which lead to selective hybridisati
Gray Ian C
Spurr Nigel K
Stewart Lorna M
Imperial Cancer Research Technology Limited
Nixon & Vanderhye P.C.
Zitomer Stephanie
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