NCI scientists and their colleagues have identified a rare inherited mutation in a gene that can increase the risk of familial melanoma, according to a recent study that appeared in Nature Genetics. Although the finding does not offer immediate benefit to patients, variation in the Protection of Telomeres-1 (POT1) gene provides additional clues as to the origins of melanoma and may open new avenues in prevention and treatment research.
Melanoma is the most lethal form of skin cancer. In the United States, it is estimated that more than 76,000 new cases of melanoma will be diagnosed in 2014, and about 9,700 Americans will die from the disease. Most cases of melanoma are sporadic—that is, patients do not have a family history of the disease. However, in some families, melanoma develops in multiple individuals across many generations. This latter form is known as familial melanoma.
For over 30 years, NCI scientists have been studying familial melanoma and hunting for genes that may play a role in the development of this rarer form of the disease. To date, four susceptibility genes for familial melanoma have been identified: CDKN2A (the most common), CDK4, BAP1, and TERT. However, mutations in these genes account for less than 40 percent of melanoma-prone families.
In this recent study, Maria Teresa Landi, M.D., Ph.D., of NCI’s Division of Cancer Epidemiology and Genetics, and her colleagues, including those in Europe and Canada, sought to identify additional mutations that would explain at least some proportion of the familial cases of melanoma that have yet to be linked to known susceptibility genes. The researchers used a whole exome sequencing approach, which examines the protein coding regions in DNA, to evaluate more than 100 individuals from 56 Italian families with familial melanoma.
“The great challenge in our study was to sift through important rare genetic variants in the midst of the hundreds observed through whole exome sequencing analysis of our melanoma families and then confirm a link with melanoma susceptibility. Since many of the variants observed in exome sequencing are ‘private,’ meaning that they are present in all cases within only a single family but not shared across multiple families, the challenge is to develop enough evidence to conclusively determine that one or more mutations are responsible for melanoma risk in families,” said Landi.
The investigators narrowed the initial results to include only variants associated with coding changes. Further, they looked only for rare variants—those that occurred in the genomes of fewer than one out of every thousand individuals available in existing sequencing databases. Finally, they considered variants that were shared across multiple families and in all affected individuals within the families. This led to the identification of a mutation in the POT1 gene in five of the families. The mutation alters the structure of the POT1 protein, preventing it from functioning normally. The investigators later looked for POT1 mutations in several melanoma-prone American, Spanish, and French families, and found a few additional POT1 variants in a small portion of these families.
The POT1 protein helps maintain the length and integrity of telomeres, which are regions of repetitive DNA at the ends of chromosomes. Telomeres protect chromosome tips from deterioration and from fusion with the ends of other chromosomes. POT1 is the second telomere-associated gene found to be associated with familial melanoma (the first being the telomerase TERT gene), supporting a role for abnormal telomeres in the development of melanoma. Precisely how telomere abnormalities may lead to melanoma is still not clear, according to the scientists.
As next steps, the researchers will continue genomic analyses in the Italian melanoma-prone families included in this study and other melanoma-prone families enrolled from different countries. They are also pursuing collaborations with other scientists worldwide to determine whether POT1 mutations can be found in other melanoma families.