Molecular biology of colorectal cancer and clinical consequences for colorectal cancer syndromes

Because of the accomplishments in biotechnical research in the past few decades our knowledge about the molecular mechanisms of carcinogenesis has grown rapidly. Colorectal cancer has been one of the most intensively investigated tumor entities, and it seems to be well established that colorectal tumor growth is associated with an accumulation of acquired somatic mutational events in tumor suppressor genes and oncogenes. Recent progress in our understanding of the molecular basis of the most prevalent colorectal cancer syndromes, such as hereditary nonpolyposis colorectal cancer (HNPCC) and familial adenomatous polyposis (FAP), is reflected by modifications in diagnosis and therapy. Identification and characterization of the causative genes for these colorectal cancer syndromes have enabled precise presymptomatic detection of mutations in individuals who bear an a priori risk of about 50% of developing colorectal cancer. Genotype-phenotype correlations might further increase the clinical management of hereditary colorectal cancer. Even though developments in cancer research are restricted to the minority of individuals with hereditary cancer syndromes, growing knowledge about the effect of low penetrance variations in tumor suppressor genes may affect the diagnosis and therapy of sporadic colorectal cancer.     

Molecular and cellular biology of prostate cancer

Prostate cancer is an enigmatic disease. Although prostatic-intraepithelial neoplasia appears as early as the third decade and as many as 80% of 80 year old men have epithelial cells in their prostate that fit the morphological criteria for cancer, only about 10% of men will ever have the clinical disease and less than 3% will die from it. There have been no significant proven interventions which have altered the natural history of the disease since hormone down regulation was introduced in the 1940s and new research has been poorly supported. There is however an urgent need to develop new criteria to distinguish those patients with localised disease who will benefit from intervention from those that do not require it or who will have occult extra prostatic metastases. Similarly, there is an urgent need to develop new treatments for those in whom the disease is extra-prostatic and therefore incurable by conventional treatments. This review covers the latest developments in epidemiology, cellular and molecular biology including new areas such as ion channels in the field of prostate cancer.     

Staging of colorectal cancer: biology vs. morphology

PURPOSE: An accurate determination of the extent or staging of a disease is critical, because it provides the basis for making therapeutic decisions. Staging is a collaborative effort by the surgeon and the pathologist. Radioimmunoguided surgery has been evaluated for its ability to help surgeons determine the extent of disease during surgery, when management decisions have the most impact on patient care. This study was done to compare radioimmunoguided surgery "biostaging" with traditional pathologic staging (TNM) as predictors of survival in patients undergoing curative resections for colorectal cancer. METHODS: Ninety-seven patients with colorectal cancer were prospectively enrolled in radioimmunoguided surgery protocols. Evaluation of follow-up survival data was performed. All patients underwent exploratory laparotomy and radioimmunoguided surgery with resection of their primary colorectal tumor. Survival data were analyzed with the Kaplan-Meier method with log-rank comparisons. RESULTS: Of 97 patients enrolled in the study, 59 were evaluable and completely resectable by radioimmunoguided surgery. Mean follow-up was 62 months, with a range of 34 to 89 months. By traditional staging 13 patients were pStage I, 18 patients were pStage II, and 28 patients were pStage III. By radioimmunoguided surgery biostaging, 24 patients were radioimmunoguided surgery-negative whereas 35 patients were radioimmunoguided surgery-positive. Survival rates by pathologic stage approached a significant difference, but did not, as of the conclusion of the study period, reach it (P = 0.12). Survival rates based on radioimmunoguided surgery status demonstrated a highly significant difference (P = 0.0002). CONCLUSIONS: Radioimmunoguided surgery biostaging provides new information intraoperatively on cancer staging that has not been available before. This may lead to new strategies for therapy that can be individualized and optimized for each patient with cancer.     

Molecular biology of Mycoplasma

Mycoplasmas are the smallest free living microorganisms with the smallest genome. The G+C content is in general low (25-33%) and the coding capacity is about 600 proteins. Mycoplasma species are phylogenetically related, they use the genetic codon UGA for tryptophan, and show rapid evolution, with a high rate of divergence. The genomes of Mycoplasma genitalium and Mycoplasma pneumoniae have been fully sequenced. Striking features of the M. genitalium sequencing project are the presence of a high number of membrane proteins with no resemblance to previously sequenced genes and the presence of repeated fragments of the gene encoding the tip-localized 140 kDa adhesin (MgPa). Many Mycoplasma species display a high frequency of antigenic variation, both as phase and size variation of individual antigens. Mycoplasma hominis isolates are known to be antigenic heterogeneous, as reflected in the reactivity with monoclonal antibodies (MAbs). The genetics of the antigenic variation has been studied for three different surface exposed antigens: P120, Lmp, and P50/Vaa. The gene encoding P120 had a hyper-variable region in the N-terminal region. In addition, a second gene with homology to p120 was identified. The gene encoding Lmp, a 135 kDa protein is repeated and both genes are translated and both contain internal repeated sequences. Deletion mutants in the lmp gene were obtained by cultivation of M. hominis PG21 with MAb 552 specific for the repeated part of Lmp. One of the lmp genes had deletions of from four to eight repeats. The other gene was left unaltered. The genes encoding P50/Vaa show a different form of variability where domains of the genes seem to be exchangeable. The genomic maps of five M. hominis strains showed that even though the size of the genomes varied the position of the different genes were in general conserved.     

Molecular biology of glycinergic neurotransmission

Glycine is a major inhibitory neurotransmitter in the spinal cord and brainstem of vertebrates. Glycine is accumulated into synaptic vesicles by a proton-coupled transport system and released to the synaptic cleft after depolarization of the presynaptic terminal. The inhibitory action of glycine is mediated by pentameric glycine receptors (GlyR) that belong to the ligand-gated ion channel superfamily. The synaptic action of glycine is terminated by two sodium- and chloride-coupled transporters, GLYT1 and GLYT2, located in the glial plasma membrane and in the presynaptic terminals, respectively. Dysfunction of inhibitory glycinergic neurotransmission is associated with several forms of inherited mammalian myoclonus. In addition, glycine could participate in excitatory neurotransmission by modulating the activity of the NMDA subtype of glutamate receptor. In this article, we discuss recent progress in our understanding of the molecular mechanisms that underlie the physiology and pathology of glycinergic neurotransmission.     

Molecular biology diagnosis of sarcoma

Sarcomas are a heterogeneous group of malignant tumours, primarily in connective and supportive tissues, that can be difficult to distinguish from other tumour types. Recent knowledge of gene rearrangements resulting from specific translocations in several groups of sarcomas now enables the molecular diagnosis of these subtypes. Increasing knowledge of molecular defects that may be of importance to therapy response and prognosis may in the future become important tools in the clinic, although these tumours are relatively rare, making it difficult to investigate large numbers of comparable groups of patients.     

Molecular biology of pediatric gliomas

The genes involved in the genesis and progression of adult astrocytic tumors have been an area of considerable investigation. The tumor suppressor gene, p53, has been implicated, as has the epidermal growth factor receptor gene. Additional currently unidentified genes lie on chromosomes 10 and 19. Interestingly, work on pediatric astrocytomas suggests that the genes involved are different. p53 is rarely mutated in pediatric tumors, the epidermal growth factor receptor gene is rarely amplified or mutated, and chromosome 10 deletions are rare. The only pediatric tumor that seems to mimic the findings in adult tumors is brainstem glioma, perhaps explaining the uniformly grim prognosis in this type of tumor. In the pilocytic astrocytoma of childhood, mutations in the neurofibromatosis type I gene have been implicated in tumor development. In this review, the oncogenesis of pediatric gliomas is discussed and compared and contrasted to what is known about tumors.     

Molecular biology of thyroid diseases

Recent developments in molecular biology and the accessibility of techniques for clinical research have led to a better understanding of the background of common thyroid diseases. The cloning and sequencing of the thyroid stimulating hormone receptor, thyroid peroxidase and thyroglobulin, and the characterization of the protein-DNA interaction during thyroid hormone action, as well as the discovery of intracellular signal transduction pathways were the most important steps which resulted in new diagnostic and therapeutic approaches. New explanations of thyroid autoimmune processes are being investigated.     

Molecular biology of muscle development

The UL52 and UL53 genes of herpes simplex virus type-1 are both located in the BamHI-L DNA fragment, with an overlap of 14 amino acids. An RNase protection experiment was designed to determine the 5' termini of both the UL52 and UL53 mRNAs. The 5' end of the UL52 mRNA was found to be located 100 bp upstream of its ATG initiation codon. Surprisingly, the 5' terminus of the UL53 gene was found to be downstream of its putative initiation codon. Therefore, it was suggested that the translation of the UL53 open reading frame (ORF) starts at an internal initiation codon that is located 55 codons downstream of the putative one. A hybrid selection experiment was performed in which the UL53-specific mRNA was selected from BSC-1 cells infected with HSV-1 KOS and translated in vitro. The translation product of the UL53 message was found to be 32 kD (shorter than the original 37.5 kD ORF). The size of the protein obtained corresponds with the expected translation product starting at the downstream initiation codon. Analysis of the sequence upstream of this initiation codon reveals the presence of a promotor sequence. Therefore, we suggest that the UL53 protein is 54 amino acids shorter than was previously suggested and is located at coordinates 112,341-113,193.