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

The role of gene mutations in tumourigenesis is well understood, however, the mechanism(s) by which they arise are less clear. Indeed, the common assumption that tumourigenic mutations are the result of DNA replication errors is apparently contradicted by the very low division frequency of the cells from which tumours are thought to arise (i.e. deep stem cells). As a potential solution to this paradox, we tested a model whereby clustered DNA lesion sites (CLS) (where several lesions occur within a few base pairs of each other on opposing strands) could give rise to mutations in quiescent cells. We used statistical analyses to search for sets of dinucleotide sequences (designated target sequences) that are present at and in close proximity to mutation sites in four genes associated with human colorectal tumourigenesis (adenomatosis polyposis coli (APC), v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS), phosphoinositide-3-kinase, catalytic, alpha polypeptide (PIK3CA), and tumour protein p53 (TP53)). The dinucleotides CG, AC-GT, TG, and GC were identified as target sequences in at least three of the genes analysed. Consistent with their designation as target sequences, these dinucleotides have all been identified as high probability sites of oxidative damage formation in in vitro studies. Our results strongly suggest a statistical association between the presence of multiple, clustered target sequences and mutational events. We propose that CLS are a major source of mutations during human tumourigenesis.
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PMID:Clustered DNA lesion sites as a source of mutations during human colorectal tumourigenesis. 1882 8

Papillary thyroid microcarcinoma generally carries an excellent prognosis, and fatal cases are becoming increasingly rare. Their pathologic and molecular features, however, remain largely unknown. We describe 3 cases of papillary thyroid microcarcinoma that, despite surgical and radioiodine treatment, recurred, metastasized, and eventually caused the death of the patients. In addition to morphology, immunohistochemical (cyclin D1 and p53) and molecular analyses (BRAF [v-raf Murine sarcoma viral oncogene homolog B1], KRAS [V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog], HRAS [v-Ha-ras Harvey rat sarcoma viral oncogene homolog], NRAS [neuroblastoma RAS viral oncogene homolog], and PIK3CA [phosphoinositide-3-kinase, catalytic, alpha polypeptide]) were performed. Interestingly, all 3 cases presented with massive lymph node metastases that showed morphological evidence of "tumor progression" (tall cell features, poorly differentiated areas, and high-grade cytologic features). Cyclin D1 was consistently immunoreactive in both primary and metastatic site, whereas p53 was negative. BRAF V600E was absent in both sites, and KRAS, HRAS, NRAS, and PIK3CA were consistently wild type. These data suggest that, in cases of metastatic papillary thyroid microcarcinoma, an accurate morphologic analysis of the metastatic deposits could contribute to a more accurate prediction of tumor behavior.
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PMID:Papillary thyroid microcarcinoma with fatal outcome: evidence of tumor progression in lymph node metastases: report of 3 cases, with morphological and molecular analysis. 2396