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

The retinoblastoma (RB) tumour suppressor gene has been associated not only with retinoblastoma but also with several other tumours like osteosarcoma, small cell lung carcinoma and prostate and breast cancer. We have studied the incidence of RB gene alterations in 96 primary breast tumours using Southern blotting techniques. The outcome has been related with patient and tumour characteristics, oncogene amplifications, p53 mutations and prognosis. RB gene alterations were found to occur more frequently in estrogen receptor (ER)-positive than in ER-negative tumours and less frequently in tumours with oncogene amplification than in tumours without oncogene amplification of HER2/neu, c-myc or 11q13. RB gene alteration was observed in tumours both with and without a p53 gene mutation. Data on 87 patients (mean age, 59.6 years; median follow-up, 108 months) and RB gene alterations revealed a significant association between the frequency of RB gene alterations and node-negative patients (p < 0.01) or smaller (< 2 cm) tumours (p < 0.01), but no relation with age, differentiation grade or (relapse-free) survival. Patients with and without RB gene alterations showed the same relapse-free and overall survival.
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PMID:Association between RB-1 gene alterations and factors of favourable prognosis in human breast cancer, without effect on survival. 761 56

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

Tumour progression is strongly associated with a series of specific genetic changes in protooncogenes and tumour suppressor genes. One of the potential factors involved in tumorogenesis of squamous cell carcinomas is protooncogene c-erbB-2 (also known as neu or HER2). The authors analysed the expression of c-erbB-2 oncoprotein in 154 cases of laryngeal squamous cell carcinomas and its relationship to the clinical outcome of the patients. The difference in c-erbB-2 oncoprotein expression between the control group and cancer patients was on the statistical borderline (p = 0.0470). There was no significant correlation between c-erbB-2 expression and sex and age of the patients. T stage, lymph node status, site and histopathological grading of the tumour and clinical outcome of the patients. Univariate analysis revealed no correlation between c-erbB-2 expression and survival rates. We conclude that immunohistological examination of c-erbB-2 on paraffin section is not a valuable prognostic factor in laryngeal carcinoma.
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PMID:C-erbB-2 immunostaining in laryngeal cancer. 1038 Jul 48

Immunohistochemistry (IHC) is a rapid morphological method that allows the detection of proteins involved in different mechanisms of cancer development. It is therefore a useful tool in the study of cancerogenesis. The best known example is the product of the p53 gene, a tumour suppressor gene which is altered in 50% of all human tumors. In fact, these p53 gene mutations lead to cell protein accumulation whereas the p53 product is not detectable in normal cells. This method also enables the detection of fusion proteins which result from chimeric transcript like WT1 in desmoplastic small round cell tumors, ALK in anaplastic large-cell lymphomas and FLI-1 in Ewing's sarcomas. On the contrary, gene inactivation can induce loss of immunostaining. hMLH1 and hMSH2, which are committed in DNA mismatch repair, can be altered in familial digestive carcinomas, such as hereditary non polyposis colorectal cancer. Thus IHC, which allows us to focus on the altered gene by loss of its product in tumoral cells, represents a good alternative to molecular analysis. IHC is also useful to detect the product of oncogene overexpression such as HER-2 in some breast carcinomas, which allows appropriate therapeutic protocols. Finally, IHC can be used in diagnostic, prognostic and therapeutic ends. Nevertheless, difficulties can be en- countered in the interpretation of the results. Therefore, IHC must be performed in quality control trials.
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PMID:[Immunohistochemistry and genotype analysis of tumors. First part: Which future for the immunochemical diagnosis of cancer?]. 1212 91

Ovarian cancer is caused by genetic alterations that disrupt proliferation, apoptosis, senescence and DNA repair. Approximately 10% of ovarian cancers arise in women who have inherited mutations in cancer susceptibility genes (BRCA1 or BRCA2). The ability to perform genetic testing allows identification of women at increased risk who can be offered prophylactic oophorectomy or other interventions aimed at preventing ovarian cancer. The vast majority of ovarian cancers are sporadic, resulting from the accumulation of genetic damage over a lifetime. Several specific genes involved in ovarian carcinogenesis have been identified, including the p53 tumour suppressor gene and HER2/ neu andPIC3KA oncogenes. The recent availability of expression microarrays has facilitated the simultaneous examination of thousands of genes, and this promises to extend further our understanding of the molecular events involved in the development of ovarian cancers. Hopefully, this knowledge can be translated into effective screening, treatment, surveillance, and prevention strategies in the future.
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PMID:Molecular aspects of ovarian cancer. 1241 30

Array-based comparative genomic hybridization (aCGH) allows the identification of DNA sequence copy number changes at high resolution by co-hybridizing differentially labelled test and control DNAs to a micro-array of genomic clones. The present study has analysed a series of 23 formalin-fixed, paraffin wax-embedded tissue samples of Barrett's adenocarcinoma (BCA, n = 18) and non-neoplastic squamous oesophageal (n = 2) and gastric cardia mucosa (n = 3) by aCGH. The micro-arrays used contained 287 genomic targets covering oncogenes, tumour suppressor genes, and DNA sequences localized within chromosomal regions previously reported to be altered in BCA. DNA sequence copy number changes for a panel of approximately 50 genes were identified, most of which have not been previously described in BCA. DNA sequence copy number gains (mean 41 +/- 25/BCA) were more frequent than DNA sequence copy number losses (mean 20 +/- 15/BCA). The highest frequencies for DNA sequence copy number gains were detected for SNRPN (61%); GNLY (44%); NME1 (44%); DDX15, ABCB1 (MDR), ATM, LAMA3, MYBL2, ZNF217, and TNFRSF6B (39% each); and MSH2, TERC, SERPINE1, AFM137XA11, IGF1R, and PTPN1 (33% each). DNA sequence copy number losses were identified for PDGFB (44%); D17S125 (39%); AKT3 (28%); and RASSFI, FHIT, CDKN2A (p16), and SAS (CDK4) (28% each). In all non-neoplastic tissue samples of squamous oesophageal and gastric cardia mucosa, the measured mean ratios were 1.00 (squamous oesophageal mucosa) or 1.01 (gastric mucosa), indicating that no DNA sequence copy number chances were present. For validation, the DNA sequence copy number changes of selected clones (SNRPN, CMYC, HER2, ZNF217) detected by aCGH were confirmed by fluorescence in situ hybridization (FISH). These data show the sensitivity of aCGH for the identification of DNA sequence copy number changes at high resolution in BCA. The newly identified genes may include so far unknown biomarkers in BCA and are therefore a starting point for further studies elucidating their possible role in Barrett's carcinogenesis.
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PMID:Array-based comparative genomic hybridization for the detection of DNA sequence copy number changes in Barrett's adenocarcinoma. 1522 37

Cancer is a genetic disease. Breast cancer tumorigenesis can be described as a multi-step process in which each step is thought to correlate with one or more distinct mutations in major regulatory genes. The question addressed is how far a multi-step progression model for sporadic breast cancer would differ from that for hereditary breast cancer. Hereditary breast cancer is characterized by an inherited susceptibility to breast cancer on basis of an identified germline mutation in one allele of a high penetrance susceptibility gene (such as BRCA1, BRCA2, CHEK 2, TP53 or PTEN). Inactivation of the second allele of these tumour suppressor genes would be an early event in this oncogenic pathway (Knudson's "two-hit" model). Sporadic breast cancers result from a serial stepwise accumulation of acquired and uncorrected mutations in somatic genes, without any germline mutation playing a role. Mutational activation of oncogenes, often coupled with non-mutational inactivation of tumour suppressor genes, is probably an early event in sporadic tumours, followed by more, independent mutations in at least four or five other genes, the chronological order of which is likely less important. Oncogenes that have been reported to play an early role in sporadic breast cancer are MYC, CCND1 (Cyclin D1) and ERBB2 (HER2/neu). In sporadic breast cancer, mutational inactivation of BRCA1/2 is rare, as inactivation requires both gene copies to be mutated or totally deleted. However, non-mutational functional suppression could result from various mechanisms, such as hypermethylation of the BRCA1 promoter or binding of BRCA2 by EMSY. In sporadic breast tumorigenesis, at least three different pathway-specific mechanisms of tumour progression are recognizable, with breast carcinogenesis being different in ductal versus lobular carcinoma, and in well differentiated versus poorly differentiated ductal cancers. Thus, different breast cancer pathways emerge early in the process of carcinogenesis, ultimately leading to clinically different tumour types. As mutations acquired early during tumorigenesis will be present in all later stages, large-scale gene expression profiling using DNA microarray analysis techniques can help to classify breast cancers into clinically relevant subtypes.
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PMID:Oncogenic pathways in hereditary and sporadic breast cancer. 1943 86

The aim of the present study was to evaluate the association between different types of hormone replacement therapy (HRT) and risk of specific breast cancer subgroups. A population-based prospective cohort study including 12,583 peri- or postmenopausal women were followed using record-linkage with national cancer registries. During an average follow-up of 4.5 years, 332 cases of invasive breast cancer were diagnosed. Tumour samples were available from 283 cases. These tumours were re-evaluated according to histological type, grade, and mitotic index. Evaluation of tumours included estrogen and progesterone receptor status (ERalpha, ERbeta and PgR), as well as expression of Ki67, HER2, cyclin D1 and p27. The incidence of breast cancer in current users of combined HRT (CHRT) was significantly higher than in non-users. The difference corresponded to an adjusted relative risk (95% confidence interval) of 3.01 (2.35-3.84) as obtained using a Cox's proportional hazards analysis. CHRT was associated with lobular tumours (3.48:1.99-6.10), grade 1 tumours (4.46:2.79-7.13) and tumours with a low mitotic index (4.35:2.99-6.34). CHRT was not related to any specific subgroup in terms of ERalpha-, ERbeta- or PgR-expression. CHRT was associated with low proliferating tumours, defined by the Ki67 index (3.58:2.60-4.93), HER2 amplified tumours (4.40:1.93-10.06), low expression of the oncogene cyclin D1 (3.14:2.32-4.23) and high expression of the tumour suppressor gene p27 (3.47:2.40-5.01). Use of estrogen-alone HRT (ERT) was not associated with any statistically significant risk of breast cancer. We conclude that the use of CHRT is associated with an increased incidence of breast tumours with comparatively favourable prognostic factors.
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PMID:Breast tumours following combined hormone replacement therapy express favourable prognostic factors. 1727 89

The successful treatment of breast cancer is dependent upon a number of complex factors. Her-2/neu gene amplification is known to be one of the most common genetic alterations associated with breast cancer and its accurate determination has become necessary for the selection of patients for trastuzumab therapy. The aim of this study was to prove the consistency of chromogenic in situ hybridisation (CISH) technique after analyzing the overexpression of the Her-2/neu proto-oncogene in 100 invasive breast carcinomas and by comparing CISH results with immunohistochemistry (IHC) and fluorescence in situ hybridisation (FISH). Moreover, it was done to evaluate the possible correlation of estrogen (ERs) and progesterone receptors (PRs), the proliferation marker Ki67 and the tumour suppressor gene p53 with HER-2/neu status of these breast carcinomas. Of the 100 breast carcinomas that were analysed, 22 cases showed HER-2/neu amplification, 66 cases showed no amplification, whereas 12 cases were non-interpretable in both assays (FISH and CISH). Consequently, the overall concordance between FISH and CISH was 100%. Additionally, it was observed that when HER-2/neu gene was overexpressed, there was an association with negative PRs and ERs status, negative p53 protein expression and high Ki67 labelling index. It is concluded that patients with tumours scoring 2+ with the CBE356 antibody (borderline immunohistochemistry-tested cases) would also benefit from CISH as it is shown to be highly accurate, practical and can be easily integrated into routine testing in any histopathology laboratory. Finally, CISH represents an important addition to the HER2 testing algorithm.
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PMID:Comparison of chromogenic in situ hybridisation with fluorescence in situ hybridisation and immunohistochemistry for the assessment of her-2/neu oncogene in archival material of breast carcinoma. 1863 12

Acquired somatic mutations are responsible for approximately 90% of breast tumours. However, only one somatic aberration, amplification of the HER2 locus, is currently used to define a clinical subtype, one that accounts for approximately 10% to 15% of breast tumours. In recent years, a number of mutational profiling studies have attempted to further identify clinically relevant mutations. While these studies have confirmed the oncogenic or tumour suppressor role of many known suspects, they have exposed complexity as a main feature of the breast cancer mutational landscape (the 'muta-ome'). The two defining features of this complexity are (a) a surprising richness of low-frequency mutants contrasting with the relative rarity of high-frequency events and (b) the relatively large number of somatic genomic aberrations (approximately 20 to 50) driving an average tumour. Structural features of this complex landscape have begun to emerge from follow-up studies that have tackled the complexity by integrating the spectrum of genomic mutations with a variety of complementary biological knowledge databases. Among these structural features are the growing links between somatic gene disruptions and those conferring breast cancer risk, mutually exclusive coexistence and synergistic mutational patterns, and a clearly non-random distribution of mutations implicating specific molecular pathways in breast tumour initiation and progression. Recognising that a shift from a gene-centric to a pathway-centric approach is necessary, we envisage that further progress in identifying clinically relevant genomic aberration patterns and associated breast cancer subtypes will require not only multi-dimensional integrative analyses that combine mutational and functional profiles, but also larger profiling studies that use second- and third-generation sequencing technologies in order to fill out the important gaps in the current mutational landscape.
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PMID:The breast cancer somatic 'muta-ome': tackling the complexity. 1934 93


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