Melanoma mutation research may lead to new treatment therapies

Robin Wulffson MD's picture
melanoma, mutations, TERT, DNA sequencing, genetic research

Two new studies have found mutations in melanomas that are unlike any that have been previously reported. The changes are located in chromosomal regions that control genes not the genes themselves. The findings of the studies might lead to further understanding of how these deadly skin cancers grow. Although they do not immediately suggest new methods of treatment or prevention, they could ultimately lead to them. Both studies were published online on January 24 in the journal Science Express.

The mutations found by both studies are identical to the types caused by exposure to ultraviolet light; thus, they may mark the first DNA changes that can progress to a melanoma. The findings help explain how melanomas, and, possibly, other cancers, develop and what promotes their growth.

One study was conducted by researchers at Harvard Medical School in Boston, Massachusetts and the M.D. Anderson Cancer Center in Houston, Texas. The study authors noted that systematic sequencing of human cancer genomes has identified many recurrent mutations in the protein coding regions of genes but rarely in gene regulatory regions. In their study, they conducted DNA sequencing on 70 melanomas and identified two independent mutations within the core promoter of TERT, the gene coding for the catalytic subunit of telomerase, which collectively occur in 50 of 70 (71%) of melanomas examined. Examination of 150 cancer cell lines derived from diverse tumor types revealed the same mutations in 24 cases (16%), with preliminary evidence of elevated frequency in bladder and hepatocellular (liver cell) cancer cells. They concluded that mutations in regulatory regions of the genome may represent an important mechanism for the generation of tumors.


The other study was conducted by researchers in Germany, Spain, and Sweden. They noted that melanomas occur in both familial and sporadic forms, meaning that some have a ereditary factor while others do not. We investigated a melanoma-prone family through linkage analysis and DNA sequencing; they identified a disease-segregating germ line mutation in the promoter of the telomerase reverse transcriptase (TERT) gene, which encodes the catalytic subunit of telomerase; thus, they were on the same wavelength as the other researchers. They noted that he mutation creates a new binding motif for Ets/TCF transcription factors near the transcription start and in reporter gene assays, caused up to 2-fold increase in transcription. They then screened the TERT promoter in sporadic melanoma and observed recurrent UV signature somatic mutations in 125/168 (74%) of human cell lines derived from metastatic melanomas, corresponding metastatic tumor tissues (45/53, 85%), and in 25/77 (33%) primary melanomas. The majority of those mutations occurred at two positions in the TERT promoter and also generated binding motifs for ETS/TCF transcription factors.

Take home message:
Although both studies are couched in scientific jargon that is difficult to follow for individuals without a background in genetics, they both evaluated genes that regulate other genes. When the German scientist Gregor Mendel conducted his first studies on pea plants in the 19th Century, he founded the study of genetics. At that time, it encompassed the concept that one gene caused one thing such as the color of a flower. Genetics has become vastly more complex with the discovery of the mechanism such as the one described in these studies that some genes control other genes. The further understanding of all these genetic nuances are leading us closer to the prevention and treatment of innumerable diseases.

Beyond studies like this, one must remember that the risk of developing a melanoma is directly related to the amount of ultraviolet exposure from the sun. Limiting time exposed to the sun and the application of sunscreen reduce the risk. In general, fair complected individuals are at greater risk than darker complected individuals.

Reference: Science Express