Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1997-05-16
2003-04-22
Spector, Lorraine (Department: 1647)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S023500, C435S320100
Reexamination Certificate
active
06552181
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention pertains to the field of oncology. In particular, this invention pertains to the discovery of a tumor suppressor gene implicated in the etiology of nevoid basal cell carcinoma syndrome (NBCCS) and various cancers including basal cell carcinomas.
Many cancers are believed to result from a series of genetic alterations leading to progressive disordering of normal cellular growth mechanisms (Nowell (1976)
Science
194:23, Foulds (1958)
J. Chronic Dis.
8:2). In particular, the deletion or multiplication of copies of whole chromosomes or chromosomal segments, or specific regions of the genome are common (see, e.g., Smith et al. (1991)
Breast Cancer Res. Treat.
18: Suppl. 1: 5-14; van de Vijer & Nusse (1991)
Biochim. Biophys. Acta.
1072: 33-50; Sato et al. (1990)
Cancer. Res.
50: 7184-7189). In particular, the amplification and deletion of DNA sequences containing proto-oncogenes and tumor-suppressor genes, respectively, are frequently characteristic of tumorigenesis. Dutrillaux et al. (1990)
Cancer Genet. Cytogenet.
49: 203-217.
One cancer-related syndrome that appears to have a strong genetic base is the nevoid basal cell carcinoma syndrome (NBCCS). The nevoid basal cell carcinoma syndrome, also known as Gorlin syndrome and the basal cell nevus syndrome, is an autosomal dominant disorder that predisposes to both cancer and developmental defects (Gorlin (1995)
Dermatologic Clinics
13: 113-125). Its prevalence has been estimated at 1 per 56,000, and 1-2% of medulloblastomas and 0.5% of basal cell carcinomas (BCCs) are attributable to the syndrome (Springate (1986)
J. Pediatr. Surg.
21: 908-910; Evans et al. (1991)
British J. Cancer.
64: 959-961). In addition to basal cell carcinomas (BCCs) and medulloblastomas, NBCCS patients are also at an increased risk for ovarian fibromas, meningiomas, fibrosarcomas, rhabdomyosarcomas, cardiac fibromas and ovarian dermoids (Evans et al. (1991) supra., Evans et al. (1993)
J. Med. Genet.
30: 460-464; Gorlin (1995) supra.).
Non-neoplastic features, including odontogenic keratocysts (which are most aggressive in the second and third decades of life), pathognomonic dyskeratotic pittina of the hands and feet, and progressive intracranial calcification (usually evident from the second decade) are very common. There is a broad range of skeletal defects (Gorlin (1995) supra.; Shanley et al. (1994)
Am. J. Med. Genet.
50: 282-290) including rib, vertebral and shoulder anomalies, pectus excavatum, immobile thumbs and polydactyly. Craniofacial and brain abnormalities include cleft palate, characteristic coarse fades, strabismus, dysgenesis of the corpus callosum macrocephaly and frontal bossing (Gorlin (1995) supra.). Generalized overgrowth (Bale et al. (1991)
Am. J. Med. Genet.
40: 206-210) and acromegalic appearance are common, but growth hormone and IGF1 levels are not elevated.
Implications for the affected individual can be severe, predominantly due to the prolific basal cell carcinomas which can number more than 500 in a lifetime (Shanley et al. (1994) supra). Expression of many features of the syndrome is variable, but the severity tends to breed true within families (Anderson et al. (1967)
Am. J. Hum. Genet.,
19:12-22). This variation between families may reflect specific phenotypic effects of different mutations, modifier genes, or environmental factors (sunlight exposure is likely to play a role in the age of onset and incidence of basal cell carcinomas). One third to one half of patients have no affected relatives and are presumed to be the product of new germ cell mutations (Gorlin (1995) supra.). Unilateral and segmental NBCCS are attributed to somatic mutation in one cell of an early embryo (Gutierrez and Mora (1986)
J. Am. Acad. Dermatol.
15: 1023-1029).
The NBCCS syndrome was mapped to one or more genes at chromosome 9q22-31 (Gailani et al. (1992)
Cell
69: 111-117; Reis et al. (1992)
Lancet
339: 617; Farndon et al. (1992)
Lancet
339: 581-2). In addition, it has been demonstrated that the same region is deleted in a high percentage of basal cell carcinomas and other tumors related to the disorder (Gailani et al. (1992) supra.) thus suggesting that the NBCCS gene functions as a tumor suppressor. Inactivation of NBCCS gene(s) may be a necessary if not sufficient event for the development of basal cell carcinomas (Shanley et al. (1995)
Hum. Mol. Genet.
4: 129-133; Gailani et al. (1996)
J. Natl. Canc. Inst.
88: 349-354).
Since the original mapping of the gene in 1992, linkage studies have narrowed the NBCCS region to a 4 cM interval between D9S180 and D9S196 (Goldstein et al. (1994)
Am. J. Hum. Genet.
54: 765-773; Wicking et al. (1994)
Genomics
22: 505-511). Reported recombination involving an unaffected individual tentatively placed the gene proximal to D9S287 (Farndon et al. (1994)
Genomics
23: 486-489). The 9q22 region, however, is very gene rich and appeared to contain at least two tumor suppressor genes. In addition, Harshman et al. (1995)
Hum. Mol. Genet.
4: 1259-1266, showed that different methods of identifying cDNAs from a genomic region result in a surprisingly different array of candidate genes. Thus, prior to this invention the specific NBCCS gene was unknown.
SUMMARY OF THE INVENTION
This invention provides for a nucleic acid sequence (e.g., a cDNA) associated with nevoid basal cell carcinoma syndrome (NBCCS) and with various cancers including various sporadic basal cell carcinomas (BCCs). The NBCCS gene disclosed herein appears to be a tumor-suppressor gene and is a homologue of the
Drosophila patched
(ptc) gene. The human NBCCS gene is therefore also referred to herein as the human PATCHED (PTC) gene.
Absence, partial inactivation (e.g., through haploinsufficiency or mutation), complete inactivation, or otherwise altered expression of the NBCCS (PTC) gene causes or creates a predisposition to NBCCS and/or to the onset of basal cell carcinomas.
In one preferred embodiment, this invention provides an isolated human nucleic acid encoding a nevoid basal cell carcinoma syndrome (NBCCS) (PTC) protein, wherein said nucleic acid specifically hybridizes, under stringent conditions, to a second nucleic acid consisting of a nucleic acid sequence selected from the group consisting of SEQ ID NOS. 1, 58 and 59, in the presence of a human genomic library under stringent conditions. The isolated nucleic acid is at least 30, preferably at least 50, more preferably at least 100, and most preferably at least 200 nucleotides in length.
In another embodiment, the isolated NBCCS nucleic acid has at least 75 percent sequence identity, preferably at least 85 percent, sequence identity, more preferably at least 90% sequence identity and most preferably at least 95 percent or even at least 98% sequence identity across a window of at least 30 nucleotides, preferably across a window of at least 50 nucleotides, more preferably across a window of at least 80 nucleotides, and most preferably across a window of at least 100 nucleotides, 200 nucleotides, 500 nucleotides or even the full length with the nucleic acid of SEQ ID NOS: 1, 58, or 59.
In one embodiment, the isolated human NBCCS nucleic acid is amplified from a genomic library using any of the primer pairs provided in Table 2. In another embodiment, the NBCCS nucleic acid is identified by specific hybridization with any of the nucleic acids amplified from a genomic library using any of the primer pairs provided in Table 2. In a particularly preferred embodiment the nucleic acid is a nucleic acid selected from the group consisting of SEQ ID NO: 1, SEQ ID NOS: 1, 58 and 59.
In another embodiment, this invention provides for an isolated human nevoid basal cell carcinoma syndrome (NBCCS) (PTC) nucleic acid sequence, wherein said nucleic acid encodes a polypeptide subsequence of at least 10 contiguous amino acid residues of the polypeptide encoded by a nucleic acid sequence selected from the group consisting of SEQ ID NOS: 1, 58 and 59, or conservative substitutions of said polypeptide subsequence. The isolated human NBCCS
Bale Allen E.
Chenevix-Trench Georgia
Chidambaram Abirami
Christiansen Jeffrey
Dean Michael Carlton
Spector Lorraine
The United States of America as represented by the Department of
Townsend and Townsend / and Crew LLP
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