Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Extensive research has led to accumulation of common hereditary evidence concerning ovarian and breast cancer, suggesting that these two cancers can be considered as one type. Subsequently, women with breast cancer are susceptible to the risk of developing ovarian cancer. Highly expressed oncogenes such as bcl-2, HER2/neu and others or mutated suppressor genes such as p53 or BRCA1 have been characterised as hereditary susceptibility genes leading to syndromes such as breast/ovarian cancer syndrome, Li-Fraumeni and others. Furthermore, these genetic alterations can cause potent chemoresistance by inhibiting induction of apoptosis after DNA damage caused by chemotherapy and/or radiotherapy. Presently, molecular onco-biology has enabled us not only to detect susceptibility to ovarian and breast cancer but also ways to inhibit their further progression or even circumventing chemoresistance mechanisms after their development by gene therapy using delivery vectors such as liposomes or viruses, by which we can replace wild-type tumour suppressor genes or by using antigene, antisense oligonucleotides and antisense RNA leading to reduced oncogene expression, enabling induction of apoptosis after DNA damage into chemoresistant tumour cells. Furthermore efflux-genes such as MDR-1 or MRP can be circumvented, suicide-genes can be employed which can facilitate sensitivity by encoding enzymes capable of converting inactive forms of a drug into toxic antimetabolites and immunotherapy can be achieved, by transfection of tumour cells with adenoviral vectors encoding immunomodulators such as IL-2 or MHC molecules. Thus, molecular biology appears to be a very strong element for the screening, diagnosis, therapy and prognosis of ovarian and breast cancer. However, consistent future research is greatly needed because many points concerning ovarian and breast cancer genetics are still unknown. Finally, we strongly believe that gene therapy could be extremely useful when is combined with conventional therapy against ovarian and breast tumours.
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PMID:Molecular aspects of breast and ovarian cancer. 937 59

BRCA1 is a complex gene implicated in familial breast and ovarian cancer. Although it is almost certainly a tumour suppressor, it is also essential for the normal growth and development of embryonic cells. BRCA1 is probably involved in DNA damage and repair, in cell cycle regulation, and in differentiation of cells. It remains to be established whether all these functions are subserved by single mechanism or pathway. Since the cloning of BRCA1 in 1994, much has been learned about the function of the gene. However, a great deal more still has to be uncovered. The size of the protein coded by the BRCA1 gene and the variety of transcripts argues for a complexity of function and regulation that will provide intellectual and technical challenges for years to come.
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PMID:BRCA1: a review of structure and putative functions. 955 42

Within past few years, the investigation of molecular genetic markers has had an increasing influence on clinical decisions about initial treatment and follow-up. This review presents data concerning the most studied and interesting molecular markers in ovarian cancer. p53 tumour suppressor gene, Bcl-2 oncogene, K-ras oncogene, c-erb2 proto oncogene, c-myc oncogene are examples of currently used molecular genetic markers. Some of these markers might be useful adjuncts for monitoring response to therapy, including early detection of tumour reactivation to allow curative therapy and rapid detection of treatment failure. The study of these markers may also lead to a better understanding of the biological characteristics of ovarian cancer. The information derived from studies of these markers also represents the most promising avenue towards new treatment strategies.
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PMID:[Molecular markers in ovarian cancer]. 959 89

There is evidence that ovarian cancer may be derived from the progressive transformation of benign and/or borderline tumours. Mutations involving different oncogenes and tumour suppressor genes accumulate during the process of malignant transformation, and the alterations of genes involved in the pathogenesis of familial ovarian cancer are probably early events in ovarian tumorigenesis. BRCA-1 and BRCA-2 act as classical tumour suppressor genes in hereditary tumours, but their role in sporadic tumours remains controversial; however, a high frequency of allele losses in BRCA-1 (17q) and BRCA-2 (13q) loci has been observed in both familial and sporadic tumours. The possible role of mismatch repair genes and microsatellite instability is also controversial, but a role for them has been proposed in borderline tumours. Mutations in K-ras are specific for mucinous tumours and may be related to mucinous differentiation. Finally, a role in tumour progression has been proposed for both c-erb B-2 and p53, but their practical value in prognosis remains questionable.
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PMID:Molecular pathology of ovarian carcinomas. 973 87

Many chromosomal regions undergo loss of heterozygosity (LOH) in ovarian adenocarcinomas but few of the target regions have been finely mapped. One of the chromosome arms likely to harbour one or more tumour suppressor genes inactivated in ovarian cancer is the short arm of chromosome 8 which is frequently deleted in many other solid tumours. We have examined a large panel of microsatellite markers on 8p for LOH in 53 ovarian adenocarcinomas. LOH was observed in 27 tumours (51%), with a significant trend towards a higher frequency of LOH in more advanced tumours. Detailed examination of nine tumours with partial deletions defined three regions of overlap, two in 8p23 and one in 8p22, which suggests that there might be as many as three tumour or metastasis suppressor genes on 8p which are inactivated during ovarian tumorigenesis. LOH on 8p was significantly associated with 9p LOH which suggests that inactivation of target genes on these chromosomes may be cooperative events.
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PMID:Frequent loss of heterozygosity and three critical regions on the short arm of chromosome 8 in ovarian adenocarcinomas. 976 30

Cowden syndrome (CS) or multiple hamartoma syndrome (MIM 158350) is an autosomal dominant disorder with an increased risk for breast and thyroid carcinoma. The diagnosis of CS, as operationally defined by the International Cowden Consortium, is made when a patient, or family, has a combination of pathognomonic major and/or minor criteria. The CS gene has recently been identified as PTEN, which maps at 10q23.3 and encodes a dual specificity phosphatase. PTEN appears to function as a tumour suppressor in CS, with between 13-80% of CS families harbouring germline nonsense, missense, and frameshift mutations predicted to disrupt normal PTEN function. To date, only a small number of tumour suppressor genes, including BRCA1, BRCA2, and p53, have been associated with familial breast or breast/ovarian cancer families. Given the involvement of PTEN in CS, we postulated that PTEN was a likely candidate to play a role in families with a "CS-like" phenotype, but not classical CS. To answer these questions, we gathered a series of patients from families who had features reminiscent of CS but did not meet the Consortium Criteria. Using a combination of denaturing gradient gel electrophoresis (DGGE), temporal temperature gel electrophoresis (TTGE), and sequence analysis, we screened 64 unrelated CS-like subjects for germline mutations in PTEN. A single male with follicular thyroid carcinoma from one of these 64 (2%) CS-like families harboured a germline point mutation, c.209T-->C. This mutation occurred at the last nucleotide of exon 3 and within a region homologous to the cytoskeletal proteins tensin and auxilin. We conclude that germline PTEN mutations play a relatively minor role in CS-like families. In addition, our data would suggest that, for the most part, the strict International Cowden Consortium operational diagnostic criteria for CS are quite robust and should remain in place.
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PMID:Germline PTEN mutations in Cowden syndrome-like families. 983 31

The tumour suppressor gene CDKN2A, located on chromosome 9p21, encodes the cell cycle regulatory protein p16. Inactivation of the CDKN2A gene could lead to uncontrolled cell growth. In order to determine the role of CDKN2A in the development of sporadic ovarian cancer, loss of heterozygosity at 9p21-22, homozygous deletion, mutation and methylation status of the CDKN2A gene as well as CDKN2A expression were examined in a panel of serous papillary ovarian cancer. The frequency of loss of heterozygosity (LOH) for one or more informative markers at 9p21-22 was 65% (15/23). The most common deleted region was located between interferon (IFN)-alpha and D9S171. Homozygous deletions and mutations of the CDKN2A gene were not found. There was no evidence of methylation in exon 1, but methylation in exon 2 of CDKN2A gene was found in 26% (6/23). Absence of CDKN2A gene expression was shown in 27% (6/22) at mRNA level and 21% (4/19) at protein level. These data suggest that the CDKN2A gene is involved in the tumorigenesis of ovarian cancer, but the mechanisms of CDKN2A gene inactivation in serous papillary ovarian cancer remains unclear.
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PMID:CDKN2A gene inactivation in epithelial sporadic ovarian cancer. 1047 Oct 40

Loss of heterozygosity occurs frequently on the short arm of chromosome 8 in many neoplasms, including colorectal and ovarian cancer. Monochromosome transfer experiments into colorectal tumour cell lines have provided functional evidence for a tumour suppressor gene located at 8p22-23. One of the genes from this region that is expressed by our suppressed hybrids is a candidate tumour suppressor gene, DLC1 (deleted in liver cancer), which has homology to rat RhoGAP. We have delineated the structure of the DLC1 gene and used single-stranded conformation polymorphism analysis (SSCP) to look for sequence variants in 126 colorectal and 33 ovarian primary tumours and cell lines. One exonic missense mutation and three intronic insertions/deletions were identified in primary colorectal tumours, as well as many polymorphisms present in germline DNAs. The rarity of exonic missense mutations, and the absence of protein-truncating mutations, indicates that DLC1 is not the target of 8p LOH in colorectal or ovarian tumours. The delineation of the gene structure allows mutation analysis of DLC1 in other tumour types for which it remains a candidate tumour suppressor gene based on its location and homology to rhoGAP.
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PMID:Sequence variants of DLC1 in colorectal and ovarian tumours. 1064 92

Loss of heterozygosity on chromosome 22q was detected in 53% of 123 ovarian carcinomas, suggesting the presence of at least one tumour suppressor gene. We have refined the location of one possible tumour suppressor gene to the region between the microsatellite markers D22S299 and CYP2D. Located within this region are the genes SREBP2 (sterol regulatory element binding protein 2) and NAGA (N-acetyl-alpha-D-galactosaminidase). Investigation of the coding exons of these genes by single stranded conformational polymorphism/heteroduplex analysis failed to identify any somatic genetic alterations in 57 ovarian tumours which exhibited LOH on 22q13. The CYP2D gene locus straddles the distal boundary of the candidate region. Germline variants of the active CYP2D6 gene with differing abilities to metabolise specific substrates have been implicated in the development of various cancers. Comparison of the frequency of the two common germline mutations among 258 ovarian tumours and 231 non-cancer controls did not reveal any significant differences between the two groups. This suggests that the known polymorphic variants of CYP2D6 are not involved in ovarian cancer predisposition. We also conclude that neither NAGA nor SREBP2 are likely to be mutated in ovarian carcinomas.
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PMID:Refinement of an ovarian cancer tumour suppressor gene locus on chromosome arm 22q and mutation analysis of CYP2D6, SREBP2 and NAGA. 1095 88

Individuals with Down syndrome have an increased risk of leukaemia, but reliable estimates of the age-specific risk of leukaemia are lacking and very little is known about the risk of solid tumours. We identified 2814 individuals with Down syndrome from the Danish Cytogenetic Register, and linked the data to the Danish Cancer Registry. Standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were calculated on the basis of age- and sex-specific cancer rates in the general population. Sixty cases of cancer were observed, with 49.8 expected (SIR = 1.20; CI: 0.92-1.55). Leukaemia constituted 60% of the malignancies overall and 97% of the malignancies in children. The SIR for leukaemia varied considerably with age, being 56 (CI: 38-81) at age 0-4 years and 10 (CI: 4-20) at 5-29 years. No cases of leukaemia were observed after age 29. The cumulative risk of leukaemia by the age of 5 years was 2.1% and that by 30 years was 2.7%. Only 24 solid tumours were observed with 47.8 expected (SIR = 0.50; CI: 0.32-0.75). No cases of breast cancer were observed, with 7.3 expected (p = 0.0007). Increased risks of testicular cancer, ovarian cancer, and retinoblastoma were observed but were not statistically significant. The occurrence of cancer in Down syndrome is unique with a high risk of leukaemia in children and a decreased risk of solid tumours in all age groups. The distinctive pattern of malignancies may provide clues in the search for leukaemogenic genes and tumour suppressor genes on chromosome 21.
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PMID:[Occurrence of cancer in individuals with Down syndrome]. 1098 Dec 21


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