Tuesday, May 21, 2013

Genetic Mutations Associated with Human Melanoma

As we have described in previous articles, there is a strong association between cancer and genetic mutations that disrupt the normal constraints placed upon cell growth and division.  In this article, evidence will be presented that links a particular set of unusual genetic mutations with human melanoma. 

Melanoma is a particularly deadly cancer of the skin.  The cells that become cancerous in melanoma are the so-called melanocytes that elaborate melanin – the pigment responsible for skin color.  The precise etiology of melanoma is not known; however, exposure to ultraviolet (UV) radiation either from natural sunlight or derived artificially from tanning beds increases the risk of developing this cancer.  The particular danger inherent in melanoma is the propensity of cancerous cells to travel from the initial site of development to other tissues of the body – a process referred to as metastasis.  It is therefore important to detect the presence of the cancerous mass before it has the opportunity to spread.

The research to date has revealed that most genetic mutations associated with various cancers seem to reside within the protein-coding regions of genes or at the splice junctions.  However Dr. Franklin W. Huang and his colleagues at the Broad Institute of Harvard and MIT, Cambridge MA were interested in determining whether any mutations consistent with tumor production appeared outside of the protein-coding regions.

To arrive at an answer to this question, the investigators performed an exhaustive analysis of whole-genome sequencing data from 70 individual cancerous melanomas.  From this analysis they discovered two independent mutations that reside within the promoter region – the promoter region of the genome lies outside of the protein coding region of the genes and is responsible for the initiation of gene transcription – for that region of the genome responsible for the production of the telemorase reverse transcriptase enzyme (TERT).  These mutations were found in 71% of the melanomas examined – this represents a remarkably high association.    In addition, they found an elevated frequency of these mutations in human bladder and liver cancer cells grown in culture.  TERT is of particular significance because this enzyme is responsible for lengthening telomeres in DNA strands and promoting cells to grow out of control.  It would, therefore, be a reasonable candidate for the mechanism of tumorigenesis. 

Friday, May 3, 2013

Single Nucleotide Polymorphisms and Intestinal Cancer

The complete sequencing of the human genome has revolutionized the study of human biology especially in relation to the understanding of the etiology of cancer.  This has been made possible by the fact that data can be accumulated from the DNA of cancer patients and studied to determine if there are any underlying patterns in regards to genetic anomalies that correlate with the different types of cancers.  Cancer results from a particular cell type growing out of control of the usual biological restraints placed upon such growth.  Cancer can arise from any tissue in the human body. 

For many years it has been known that there are certain genes that correlate with cancer development; these genes are referred to as oncogenes.  One such oncogene is referred to as myc found on human chromosome 8 (there are 23 chromosome pairs that make up the human genome – 22 pairs are so-called somatic chromosomes and 1 pair is the sex chromosomes).  It has been clearly shown that the activated product of the deregulated myc oncogene interferes with controlled cell growth and apoptosis – programmed cell death.  The net effect of these actions is uncontrolled cell growth and ultimately carcinogenesis.  Furthermore, single nucleotide polymorphisms (SNPs) – SNPs are alterations in genetic structure that represent a change in a single nucleotide – have been found upstream from the myc gene that strongly correlate with increased incidences  of different types of human cancer, including cancers of the breast, bladder and prostate.

The hypothetical causal relationship of the existence of myc-related SNPs to cancer has been extremely difficult to unambiguously confirm.  For this reason, Dr. Inderpreet Kaur Sur and his colleagues at the Science for Life Center at the Department of Biosciences and Nutrition, Karolinska Institutet in Stockholm, Sweden studied in detail the relationship between SNPs associated with the myc oncogene and intestinal tumors using the mouse model.  For the purposes of this study, the team generated mice deficient in a myc regulatory element called rs6983267.  This element is, in fact, a known SNP that is associated with more human cancer-related deaths than any other studied genetic mutation.

In addition, the investigators discovered that myc transcripts – mRNAs generated from the myc gene locus - were expressed in the intestinal crypts indicating that the myc gene was active in these genetically modified mice but at lower levels.  Most importantly, these mice proved to be remarkably resistant to the expression of intestinal tumors even when they were crossed with mice possessing the APCmin mutation – a mutation known to cause spontaneous intestinal tumors.

These results are extremely important.  They confirm the relationship between a particular SNP associated with the myc oncogene and tumorigenesis.  Although these results were obtained using the mouse as the model organism, for obvious reasons, the SNP studied has been well-established in human cancers.  Furthermore, these results show the immense benefits now being realized from the exhaustive study of the human genome; for, the etiology of cancer has been strongly linked to genetic anomalies.