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They can grow as large as a hen's egg: Trichilemmal cysts are benign tumors that develop from hair follicles on the scalp. An international team led by researchers from the Institute of Human Genetics at the Freiburg University Medical Center has described a new mechanism of tumor development in these cysts. In complex experiments, they demonstrated that it is sufficient for only one of two gene copies in a cell to be defective. Using genetic and functional laboratory tests, they were able to show that some of these gene errors were inherited. However, the cyst only developed if other errors in the same gene copy were added in the course of life. Such combined damage in just one gene copy had not been observed before. The researchers published their findings, which could also be important for understanding other cyst-like diseases, in the Journal of Investigative Dermatology on May 10, 2019.

Double hit on one gene

"Our results show that a single pre-damaged gene copy can be sufficient to cause severe diseases when exposed to unfavorable environmental influences," says study leader Prof. Dr. Judith Fischer, Director of the Institute of Human Genetics at the Freiburg University Medical Center. The study thus extends the so-called Knudson hypothesis. Each cell contains the genetic information in duplicate, from the father and from the mother. These gene copies are known as alleles. The Knudson hypothesis states the following: If one of the two alleles contains tumor-promoting changes, the second, functional gene can suppress tumor development. If the second gene copy also loses its function in the course of life due to acquired mutations, the cells can degenerate and a tumor develops. However, the researchers have now shown for the first time that the combination of inherited and acquired errors in the same gene copy can also lead to tumor development without the second allele being damaged. The study was carried out as part of Steffen Hörer 's scientific doctoral thesis and in collaboration with scientists from Freiburg, Graz and Sfax, Tunisia.

In order to elucidate the novel mechanism, the scientists first examined the genetic material of degenerated cells from patients with trichilemmal cysts and their relatives. They discovered that there are individuals in the human population who carry a specific variant of the PLCD1 gene in one allele. "These so-called risk alleles are not harmful on their own. But these individuals are more susceptible to further mutations on the same allele, which then lead to the development of trichilemmal cysts in hair follicles," says Hörer. Why these additional mutations ("second hit") occur is not yet fully understood. What is certain, however, is that people who carry both the risk allele and the additional acquired mutation develop trichilemmal cysts.

"The discovery of this novel mechanism is an important step in tumor research. It is very likely that other tumors or cyst-like diseases such as polycystic kidney disease may also be subject to this mechanism," says Fischer. With this study, the researchers now have a new starting point for understanding these diseases.

Trichilemmal cysts - common, but usually harmless

Trichilemmal cysts are very common benign tumors that develop from an area of the hair root and mainly occur on the head. Around two to five percent of the population are affected. Normally these cysts are harmless, but in individual cases they can severely affect the affected person due to their size or inflammation. In these cases, the cyst is removed by a minor surgical procedure.

Original title of the study: A monoallelic two-hit mechanism in PLCD1 explains the genetic pathogenesis of hereditary trichilemmal cyst formation

DOI: 10.1016/j.jid.2019.04.015

Link to the study: https://www.jidonline.org/article/S0022-202X(19)31554-4/fulltext 

Contact: 
Prof. Dr. Dr. Judith Fischer 
Medical Director 
Institute of Human Genetics 
University Medical Center Freiburg 
Phone: 0761 270-70510 
judith.fischer@uniklinik-freiburg.de