Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Evolving trends in the management of rectal cancer have focused on organ preservation, improved quality of life, and survival of patients. A significant shift is underway in our thinking about what constitutes the true rectum and defining the "proximal" and "distal" segments of the rectum. Tumor mobility remains a dominant prognostic factor in patient selection and choice of surgery. A clinical staging with tumor location in the rectum provides a logical algorithm for treatment decision making with either chemoradiation therapy or surgery as initial treatment of choice. Current rectal cancer management has largely focused on postoperative adjuvant radiation strategies with improvement reported for T3 and N+ cases. Recent data from Europe suggests that preoperative radiation has a significant advantage over surgery alone or postoperative treatment. This appears to be borne out by institutional studies of high-dose preoperative radiation (>45 Gy) in the United States. Aggressive preoperative combined chemoradiation has also led to significant downstaging of cancer with pathological complete response rates of 20% to 30%. This offers new options for surgical management of residual disease with endocavitary radiation or local excision. The development of new agents Gemcitabine, paclitaxel, and CPT-11 may also prove beneficial. New treatment strategies need to be coordinated with evolving knowledge of the biological behavior of the tumor based on its genetic fingerprints. c-Ki-ras and C-myc mutations have been implicated in tumor initiation and progression. A number of other tumor suppressor genes, APC gene, p53, and DCC have also been implicated in colorectal tumor carcigenesis. The modification of biological behavior by mutations in these genes is currently under study. This may guide new treatment strategies significantly reducing the death rates from rectal cancer and improving functional results of treatment.
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PMID:Critical issues in the evolving management of rectal cancer. 942 68

Colorectal cancer is a significant cause of morbidity and mortality in Western populations. This cancer develops as a result of the pathologic transformation of normal colonic epithelium to an adenomatous polyp and ultimately an invasive cancer. The multistep progression requires years and possibly decades and is accompanied by a number of recently characterized genetic alterations. Mutations in two classes of genes, tumor-suppressor genes and proto-oncogenes, are thought to impart a proliferative advantage to cells and contribute to development of the malignant phenotype. Inactivating mutations of both copies (alleles) of the adenomatous polyposis coli (APC) gene--a tumor-suppressor gene on chromosome 5q--mark one of the earliest events in colorectal carcinogenesis. Germline mutation of the APC gene and subsequent somatic mutation of the second APC allele cause the inherited familial adenomatous polyposis syndrome. This syndrome is characterized by the presence of hundreds to thousands of colonic adenomatous polyps. If these polyps are left untreated, colorectal cancer develops. Mutation leading to dysregulation of the K-ras protooncogene is also thought to be an early event in colon cancer formation. Conversely, loss of heterozygosity on the long arm of chromosome 18 (18q) occurs later in the sequence of development from adenoma to carcinoma, and this mutation may predict poor prognosis. Loss of the 18q region is thought to contribute to inactivation of the DCC tumor-suppressor gene. More recent evidence suggests that other tumor-suppressor genes--DPC4 and MADR2 of the transforming growth factor beta (TGF-beta) pathway--also may be inactivated by allelic loss on chromosome 18q. In addition, mutation of the tumor-suppressor gene p53 on chromosome 17p appears to be a late phenomenon in colorectal carcinogenesis. This mutation may allow the growing tumor with multiple genetic alterations to evade cell cycle arrest and apoptosis. Neoplastic progression is probably accompanied by additional, undiscovered genetic events, which are indicated by allelic loss on chromosomes 1q, 4p, 6p, 8p, 9q, and 22q in 25% to 50% of colorectal cancers. Recently, a third class of genes, DNA repair genes, has been implicated in tumorigenesis of colorectal cancer. Study findings suggest that DNA mismatch repair deficiency, due to germline mutation of the hMSH2, hMLH1, hPMS1, or hPMS2 genes, contributes to development of hereditary nonpolyposis colorectal cancer. The majority of tumors in patients with this disease and 10% to 15% of sporadic colon cancers display microsatellite instability, also know as the replication error positive (RER+) phenotype. This molecular marker of DNA mismatch repair deficiency may predict improved patient survival. Mismatch repair deficiency is thought to lead to mutation and inactivation of the genes for type II TGF-beta receptor and insulin-like growth-factor II receptor. Individuals from families at high risk for colorectal cancer (hereditary nonpolyposis colorectal cancer or familial adenomatous polyposis) should be offered genetic counseling, predictive molecular testing, and when indicated, endoscopic surveillance at appropriate intervals. Recent studies have examined colorectal carcinogenesis in the light of other genetic processes. Telomerase activity is present in almost all cancers, including colorectal cancer, but rarely in benign lesions such as adenomatous polyps or normal tissues. Furthermore, genetic alterations that allow transformed colorectal epithelial cells to escape cell cycle arrest or apoptosis also have been recognized. In addition, hypomethylation or hypermethylation of DNA sequences may alter gene expression without nucleic acid mutation.
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PMID:Molecular biology of colorectal cancer. 943 4

Carcinoma is an important complication of ulcerative colitis (UC) and develops from dysplastic precursor lesions. Genetic changes involved in the malignant transformation have not been fully characterized. We studied 19 cases of UC with high-grade dysplasia (HGD) and eight samples of associated carcinoma (CA). Microdissection of normal epithelium, epithelium at the site of chronic inflammation, HGD, and CA was performed. Polymerase chain reaction (PCR) amplification for loss of heterozygosity (LOH) of the following polymorphic microsatellites of putative tumor suppressor gene loci was done: APC (5q), DCC (18q), p16 (9p), p53 (17p), and 8p12. To compare genetic alterations, 22 typical adenomas of the colon were studied with the markers for APC and pl6 gene loci. The results indicated that LOH of p16 and p53 were present in nondysplastic epithelium, HGD, and CA. However, the LOH in nondysplastic epithelium was detected in some associated HGD, but not all. Whereas LOH of p16 was present in 7 of 14 cases of HGD (50%), it was noted in only 1 of 22 adenomas (5.0%). LOH in the APC and DCC gene loci in UC was noted in HGD with associated CA, but LOH of APC was not present either in cases of nondysplastic epithelium or in HGD alone. Conversely, LOH in APC was present in 4 of 19 colonic adenomas. We conclude that LOH of p53 and p16 in nondysplastic epithelium may be associated with chronic reparative processes. These changes may lead to susceptibility to further genetic damage involving the APC and DCC gene loci in the development of dysplasia and progression of CA in UC. The low frequency of LOH in the p16 gene (9p) in adenomas compared with dysplasia in UC combined with infrequent LOH in APC gene loci in cases of pure dysplasia in UC may support this combination of markers as a clinical test for the differentiation of polypoid dysplasia from adenomas in UC.
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PMID:Comparison of genetic alterations in colonic adenoma and ulcerative colitis-associated dysplasia and carcinoma. 949 Feb 71

The usefulness of gene information was studied when used in conjunction with a morphological diagnosis of either dysplasia or carcinoma that later develops into ulcerative colitis (UC). The cases investigated consisted of those operated on for UC with carcinoma complications and those operated on for UC over 7 years previously without carcinoma complications. Ras and DCC were examined for the presence of any point mutations in codon 12 and polymorphism in codon 201 using the PCR-RFLP method, while p53 was also studied immunohistologically. A mutation in ras was found in 25% of the UC-IV cases and also in 17% of the UC-III cases, while no mutation at all was found in the UC-I and UC-II cases. p53 showed a high rate of positivity in the UC-IV and UC-III cases with carcinoma complications, while it was negative in all cases in the control group cases. Gly in DCC codon 201 was also found in many cases including the control group. This study demonstrated that a gene aberration can thus influence the pathophysiology and cancerization of UC and therefore the p53 findings were thus considered to be useful in the morphological diagnosis of dysplasia and carcinoma.
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PMID:[The study of genetic changes in colorectal cancer accompanied with ulcerative colitis]. 951 64

Familial juvenile polyposis (FJP) is a hamartomatouspolyposis syndrome in which affected family members develop upper and lower gastrointestinal juvenile polyps and are at increased risk for gastrointestinal cancer. A genetic locus for FJP has not yet been identified by linkage; therefore, the objective of this study was to perform a focused genome screen in a large family segregating FJP. No evidence for linkage was found with markers near MSH2, MLH1, MCC, APC, HMPS, CDKN2A, JP1, PTEN, KRAS2, TP53, or LKB1. Linkage to FJP was established with several markers from chromosome 18q21.1. The maximum LOD score was 5.00, with marker D18S1099 (recombination fraction of .001). Analysis of critical recombinants places the FJP gene in an 11.9-cM interval bounded by D18S1118 and D18S487, a region that also contains the tumor-suppressor genes DCC and DPC4. These data demonstrate localization of a gene for FJP to chromosome 18q21.1 by linkage, and they raise the possibility that either DCC or DPC4 could be responsible for FJP.
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PMID:A gene for familial juvenile polyposis maps to chromosome 18q21.1. 954 10

Cytogenetic anomalies described in colo-rectal tumors are numerous. Despite the complexity and the number of the anomalies observed, a combined study of their frequency and of the stage of prognosis of the tumors suggests that the evolution from colonic adenoma to carcinoma often follows a sequence of events comprising a 5q15-22 deletion (DCC), and a 17p deletion (P53). It even seems likely that in many cases, these events are not constant and that others might lead to the same phenotypic transformation. Chromosome 1 involvement in structural rearrangements has been demonstrated in numerous forms of cancers, malignant blood disorders and in solid tumors. In colorectal adenocarcinoma anomalies have been described on short and/or long arms. In a case of adenoma with mild dysplasia a deletion of the distal part of the short arm of chromosome 1 was observed as an isolated cytogenetic anomaly, suggesting it would be an early, perhaps triggering, event for the tumour development. A cytogenetic study in a series of colo-rectal tumours, researches on loss of heterozygosity and microsatellite instability lead to consider deletions at chromosome 1p as an early event in human colorectal tumourigenesis.
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PMID:[Colorectal carcinogenesis, frequency and significance of genetic alterations: deletion of the short arm of chromosome 1, and initiating event]. 955 24

Patterns of allele loss (loss of heterozygosity, LOH) have been studied in order to investigate the genetic pathways involved in the pathogenesis of three types of colorectal cancer (CRC): sporadic CRC without replication errors (RER-) (32 cases); sporadic RER+ CRC (23 cases); and ulcerative colitis-associated CRC (UCACRC) (16 cases). Each tumour was assessed for allele loss at ten microsatellite markers which map close to known or putative tumour-suppressor genes: APC (5q21-q22); DCC (18q21.1); 1p35-p36; p16 (9p21); 22q; 8p; E-cadherin (16q22.1); beta-catenin (3p22-p21.3); RB1 (13q14.1-q14.2); and HLA. Overall, high frequencies of allele loss (> 30 per cent) were found near DCC (42 per cent), p16 (38 per cent), 22q (37 per cent), 1p35-p36 (34 per cent) and APC (31 per cent), and low frequencies (< 20 per cent) near RB1 (16 per cent) and E-cadherin (13 per cent). LOH near beta-catenin, HLA, and on 8p occurred at frequencies between 20 and 30 per cent. The overall frequency of allele loss did not differ among the three tumour groups, but some variation was seen at individual loci. There was a significantly higher frequency of LOH at 1p35-36 in RER+ tumours compared to RER- tumours. Allele loss at this site was also associated with a more advanced Dukes' stage at presentation. In addition, RER- tumours showed a higher frequency of allele loss at p16 than RER+ tumours. No significant difference existed at any locus between the frequency of LOH in sporadic CRC and in UCACRC. Pairwise analysis showed a negative association between LOH at APC and DCC, and between LOH at chromosome 22p and p53 overexpression. Thus, there may be specific differences between the mutation spectra of RER+ and RER- CRCs, but there are large degrees of overlap among the underlying genetic pathways of these cancers and UCACRCs.
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PMID:A comparison of the genetic pathways involved in the pathogenesis of three types of colorectal cancer. 960 5

Von Hippel-Lindau (VHL) disease is an inherited autosomal dominant neoplastic disorder causing central nervous system haemangioblastomas. The VHL gene (3p25-3p26) is known to be a tumour suppressor gene, with its inactivation being responsible for a predisposition to tumour development. As far as we know, the present report of VHL disease manifestation in identical twins is unique. Genetic inquiry into the family background did not reveal this disease among their progenitors. For presymptomatic diagnosis of 17 presently unaffected family members, constitutional DNA of the twins was screened for VHL germline mutations, using loss of heterozygosity studies and exon-specific DNA sequencing. To determine the influence of somatic mutations of the VHL gene in tumourigenesis, DNA of five surgically removed intracerebral haemangioblastomas of the identical twins was analyzed in comparison with their constitutional DNA by DNA sequencing of the complete VHL coding region. However, no allelic losses were found for the VHL gene or for various other tumour suppressor genes (p53, BRCA1, BRCA2, DCC, and MCC). Furthermore, no mutations were found in the constitutional DNA of either twin sister or in the DNA of all five tumour lesions. Based on our observations, we conclude that in certain VHL families, presymptomatic molecular diagnosis of the disease is not feasible and requires close clinical surveillance of all individuals at risk.
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PMID:Multiple intracerebral haemangioblastomas in identical twins with von Hippel-Lindau disease--a clinical and molecular study. 963 66

A microsatellite assay was used to screen 31 potentially malignant oral lesions presenting as leukoplakia and erythroplakia, with histological evidence of dysplasia, for genetic abnormalities at loci which frequently show allelic imbalance when oral squamous cell carcinomas (SCC) are examined. The microsatellite and restriction fragment length polymorphism (RFLP) markers selected were at 3p21, 8p21-23, 9p21 and included sequences within the Rb (13q14.2), p53 (17p13.1) and DCC (18q21.1) tumour suppressor genes. 8 patients subsequently developed an invasive tumour at the same site, or within 2 cm of the premalignant lesion. A further 8 patients developed SCC at a distant site. Seventy-seven per cent (24/31) of these potentially malignant lesions showed allelic imbalance (AI) and 55% (17/31) of cases showed microsatellite instability (msi). The probability of developing SCC was much greater for patients with lesions showing AI at two or more relevant loci (P = 0.008 by the logrank test) than the group with AI at fewer loci. The estimated probability of development of SCC in this group by 5 years was 73% (95% Cl: 50-92%). This suggests that determining the number of genetic abnormalities in a potentially malignant lesion can help identify patients with true precancers who should be followed closely to ensure that they receive chemoprevention and appropriate advice to limit risk factors, and to allow the early detection of invasive lesions.
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PMID:Allelic imbalance at chromosomal loci implicated in the pathogenesis of oral precancer, cumulative loss and its relationship with progression to cancer. 968 68

Colorectal carcinogenesis is widely thought to follow the adenoma-adenocarcinoma sequence. However, there are two morphologically distinct subtypes of colorectal cancer (CRC), polypoid and ulcerative. We conducted a comparative study to clarify whether different combinations of some commonly involved genetic alterations (including mutations in K-ras, p53, DCC, APC, and Rb genes) may exist between polypoid- and ulcerative-type CRCs, the two morphologically distinct types of CRC. By using PCR-based RFLP, single-strand conformational polymorphism, and loss of heterozygosity analysis, we found that K-ras codon 12 mutation was preferentially involved in polypoid tumor (P < 0.0001). There were no other significant correlations with p53 point mutation or loss of heterozygosity in chromosomes 5q, 17p, and 18q and Rb gene, which have been suggested to be involved in the progression of CRC of both morphological types. Therefore, different combinations of molecular genetic alterations may be involved in morphologically distinct types of colorectal carcinogenesis, and the K-ras codon 12 mutations may play an important role in polypoid growth of CRC. These results shed light on the function of K-ras oncogenes involved in colorectal carcinogenesis and may be important in the future design of genetic screening programs, determination of prognosis, and treatment for patients with CRC.
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PMID:K-ras codon 12 mutation determines the polypoid growth of colorectral cancer. 969 57


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