Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Recombinant dna technique included in method of making a...
Reexamination Certificate
1999-03-12
2001-07-31
Whisenant, Ethan (Department: 1655)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Recombinant dna technique included in method of making a...
C435S006120, C435S091100, C530S300000, C530S350000
Reexamination Certificate
active
06268176
ABSTRACT:
FIELD OF INVENTION
The present invention relates to alterations in a novel gene which are associated with certain renal and thyroid tumors. As such, the present invention is directed to the field of molecular genetics of tumor formation. One such alteration involves a chromosomal translocation between chromosomes 3 and 8 (typically referred to simply as t(3;8)). The 3;8 translocation results in the fusion of the novel gene TRC8 (Translocation in Renal Cancer from Chromosome 8) with a known gene named FHIT (Fragile Histidine Triad). A mutation in the 5′ untranslated region has also been associated with certain renal cell carcinomas.
BACKGROUND OF THE INVENTION
The 3;8 chromosomal translocation, t(3;8)(p14.2;q24.1), was described in a family with classical features of hereditary renal cell carcinoma (RCC), i.e., autosomal dominant inheritance, early onset and bilateral disease (see A. J. Cohen, et al.,
N. Engl. J. Med
. 301, 592-595 (1979)). The translocation and RCC segregated concordantly and a follow-up analysis reported the occurrence of thyroid cancer in two translocation carriers with kidney cancer (F. P. Li, et al.,
Ann. Intern. Med
118, 106-111 (1993)). Frequent 3p loss of heterozygosity (LOH) in sporadic clear-cell RCC led to the initial assumption that a critical tumor suppressor gene would be located at 3p14. Identification of the von Hippel-Lindau (VHL) gene at 3p25, frequently mutated in RCCs, provided an alternative explanation for at least some observed 3p LOH and Van den Berg et al. subsequently reported that region p21 may be a primary target for 3p LOH. (A. van den Berg and C. H. Buys,
Genes. Chromosomes. Cancer
19, 59-76 (1997)).
Within 3p14, Ohta et al. identified a putative tumor suppressor gene (TSG), FHIT, which was interrupted in its 5′ untranslated region by the 3;8 translocation (M. Ohta, et al.,
Cell
84, 587-597 (1996)). The human gene, like its yeast homologue, encodes di-adenosine (5′, 5″- P
1
, P
3
-triphosphate) hydrolase activity. (L. D. Barnes, et al.,
Biochemistry
35, 11529-11535 (1996)). Several reports have described FHIT alterations in diverse carcinomas using nested reverse transcriptase-PCR (RT-PCR). (M. Ohta, et al.,
Cell
84, 587-597 (1996); G. Sozzi, et al.,
Cell
85, 17-26 (1996); L. Virgilio, et al.,
Proc. Natl. Acad. Sci. U. S. A
. 93, 9770-9775 (1996); M. Negrini, et al.,
Cancer Res
. 56, 3173 (1996); G. Sozzi, et al.,
Cancer Res
. 56, 2472-2474 (1996)). Other results, however, have been contradictory.
In fact, several lines of evidence make FHIT an unlikely, or at least suspect, causative gene in the hereditary t(3;8) family. For example, the possibility that FHIT functions as a tumor suppressor is at odds with its activity as a di-adenosine hydrolase, an unprecedented tumor suppressor function (Barnes, L. D., et al.,
Biochemistry
35, 11529-11535 (1996)). The lack of substantial mutations in tumors combined with the fact that most FHIT abnormalities occur in the presence of wild-type transcripts and result from low-abundance splicing alterations, similar to those seen for TSG101, further argues against FHIT acting as a tumor suppressor (S. Thiagalingam, et al.,
Cancer Res
. 56, 2936-2939 (1996); K. M. Fong, et al.,
Cancer Res
. 57, 2256-2267 (1997); S. A. Gayther, et al.,
Oncogene
15, 2119-2126 (1997); F. Boldog et al.,
Hum. Mol. Genet
. 6, 193-203 (1997); I. Panagopoulos, et al.,
Genes. Chromosomes. Cancer
19, 215-219 (1997); and A. van den Berg, et al.,
Genes. Chromosomes. Cancer
19, 220-227 (1997); A. Latil, et al.,
Oncogene
16, 1863 (1998)).
Moreover, there is little support for the involvement of FHIT in renal cancers (See, A. van den Berg, et al.,
Genes Chromosomes Cancer
19, 220-227 (1997); P. Bugert, et al.,
Genes Chromosomes Cancer
20, 9-15 (1997)). Similarly, the reintroduction of FHIT into tumorigenic cell lines was inconsistent in suppressing tumors, including the fact that a hydrolase “dead” mutant appeared active (Z. Siprashvili, et al.,
Proc. Natl. Acad. Sci. USA
94, 13771-13776 (1997)). Otterson et al. (
J. Natl Cancer Inst
. 90, 426-432 (1998)) introduced FHIT into six carcinoma cell lines and observed no effects on proliferation, morphology, cell-cycle kinetics, or tumorigenesis.
In earlier work, the present inventors also identified a series of 3p14 deletions, many not involving FHIT exons, which overlapped FRA3B in various carcinoma cell lines (F. Boldog, et al.,
Hum. Mol. Genet
. 6, 193-203 (1997)). However, spontaneous deletions also were observed in nontumor backgrounds. Thus, the close association of FHIT exon 5 with FRA3B suggested that its loss might be primarily related to genomic instability, in contrast to negative selection during tumor development. Although another 3p14 gene might exist, sequence data totaling 160 kb from FRA3B (F. Boldog, et al.,
Hum. Mol. Genet
. 6, 193-203 (1997)) (plus GenBank updates AF023460 and AF023461), together with 135 kb of nonoverlapping sequence from Inoue et al. (
Proc. Natl. Acad. Sci. USA
94, 14584-14589 (1997)), failed to show any additional definitive genes.
It was also noted that FHIT, in one parotid adenoma, underwent fusion with the high mobility group protein gene (HMGIC), the causative gene in a variety of benign tumors (J. M. Geurts, et al.,
Cancer Res
. 57, 13-17 (1997)). That HMGIC was involved in translocations with other unrelated genes indicated that FHIT could be a bystander in the FHIT/HMGIC fusion.
Given this evidence arguing against FHIT as the causative gene in the hereditary t(3;8) family, there remained a need to identify the gene or genes involved in the 3;8 translocation that results in the formation of tumors, especially renal and thyroid cancers. Given the correspondence between the 3;8 translocation and certain tumors, identification of the gene involved in the 3;8 translocation could also have value in the diagnosis of other tumors which result from other types of alterations to the gene involved in the 3;8 translocation.
SUMMARY OF THE INVENTION
The present invention satisfies the need identified above by describing the cloning and sequencing of human DNA sequences which are rearranged in the t(3;8)(p14.2;q24.1) chromosomal translocation which occurs in renal and thyroid carcinomas. This chromosomal translocation or rearrangement was shown to fuse sequences from a novel gene which the present inventors have named TRC8 (short for Translocation in Renal Cancer from Chromosome 8) on chromosome 8q with the FHIT gene on chromosome 3p (the FHIT gene sequence is set forth as SEQ ID NO:8; the corresponding amino acid sequence is set forth as SEQ ID NO:9). The sequence of the novel TRC8 gene and the TRC8 protein, as well as the sequence of the t(3;8) fusion genes (5′TRC8/3′ FHIT and 5′FHIT/3′ TRC8) and the fusion proteins encoded by these fused genes are disclosed herein. A summary of certain aspects the present invention has recently been published in the scientific literature (R. M. Gemmill, et al.,
Prot. Natl. Acad. Sci
. 95, 9572-9577 (1998)).
Identification of this gene is important because various types of alterations or mutations of TRC8 appear to be involved with different types of tumors and cancers. As just noted, the 3;8 translocation is involved in certain renal cancers. As described in greater detail below, a tumor-specific mutation in the 5′ untranslated region is associated with certain renal carcinomas. Additionally, recent work by B. T. Teh and coworkers (Genes Chromosomes Cancer 21, 260-264 (1998)) suggests that another rearrangement involving TRC8 (a (8;9)(q 24.1;q 34.3) translocation) may be associated with certain renal oncocytomas. Thus, detection of alterations in TRC8 has utility in the detection of tumor formation.
More particularly, the present invention provides an isolated polynucleotide molecule encoding the polypeptide comprising the amino acid sequence of SEQ ID NO:2. In one particular aspect, the polynucleotide is the polynucleotide molecule of SEQ ID NO:1, or variants thereof. In another aspect, the polynucleotide comprises nuc
Drabkin Harry A.
Gemmill Robert M.
Lu Frank
Townsend and Townsend / and Crew LLP
University Technology Corporation
Whisenant Ethan
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