The case of basal cell carcinoma

MSU scientists have found out how skin cancer occurs

MSU Press Service

An international group of scientists with the participation of researchers from Lomonosov Moscow State University found out which mutations respond to the formation of the most common type of skin cancer. The results of the work were published in the journal Nature Genetics (Bonilla et al., Genomic analysis identifies new drivers and progression pathways in skin basal cell carcinoma).

Basal cell carcinoma (CD, basal cell carcinoma) is the most common and fifth most expensive type of cancer (it accounts for up to 90% of all epithelial non–melanoma neoplasms). Among the risk factors are genetic disorders, the presence of freckles, X–ray and radioactive radiation, burns, the use of drugs that suppress immunity (for example, during organ transplantation).

Examples of basalomas. Photo: Sergey Nikolaev, Université de Genève

"In this work, an international team of authors found that in more than 80% of cases, CD contains mutations in genes leading to the formation of other types of cancer that were not previously associated with CD. This finding indicates the mechanisms of CD resistance to anticancer therapy and opens the possibility for new clinical trials," explains co–author Vladimir Seplyarsky, junior researcher at the Faculty of Bioengineering and Bioinformatics of Lomonosov Moscow State University.

Supersonic Hedgehog and company

Among the genes and their corresponding proteins whose mutational breakdowns cause cancer, elements of the Sonic Hedgehog (Hh) signaling cascade appear in the "basal carcinoma case". Hh determines the distribution of roles to cells during embryonic development and their subsequent "self-determination", as well as the appearance of left- or right-sided orientation in tissues and organs.

Under normal conditions, the Sonic Hedgehog signaling cascade is triggered by a signaling protein of the same name. First discovered in drosophila, the Sonic Hedgehog gene, the shutdown of which made the embryos of these fruit flies look like spiked balls, was indeed named after Sonic the supersonic blue hedgehog from the comic book and video game series.

The Sonic Hedgehog gene (left) and Sonic the hedgehog from the comic book and video game series.

90% of basal cell carcinomas contain mutations in genes – elements of the Sonic Hedgehog signaling pathway, which lead to its activation without the participation of a "hedgehog regulator". These include the PTCH1 receptor and the SMO protein immersed in the cell membrane, which transmits to the Gli transcription factor the "command" of the Hedgehog protein to turn on protein synthesis from genes. Together with them, a "broken" version of the TP53 gene appears in the "dock" in more than half of the tumor cells, suppressing tumor formation in a normal state and giving the order to cells with defective DNA to "commit suicide" by apoptosis.

Sabotage of treatment: who is behind this?

Suppression of the SMO protein by a drug called vismodegib neutralizes the consequences of a breakdown in the chain of interactions controlled by the Sonic Hedgehog gene. Thanks to this drug, the commands of the "leader" do not reach subordinates, and the work of the entire chain stops: so, by pulling out one of the first dominoes in a row, you can prevent the rest from falling.

However, in 50% of cases, the tumor tissue either does not respond to medication, or develops resistance to it. In one half of these complications, mutations in the SMO protein are to blame, which prevent the interaction of vismodegib and SMO, but in the other half the cause is not clear.

Therefore, scientists have drawn attention to the fact that 80% of basal cell carcinomas have mutations in genes associated with the development of other types of cancer, including much more dangerous ones, such as melanoma.

Following the detection of these oncogenic mutations, scientists confirmed experimentally the activation of the corresponding cancer pathways. One of the observations made in the study is that the identified mutations are particularly common in the subgroup of aggressive basal cell carcinomas.

"We studied the features of the mutation process occurring in basal cell carcinoma cells. More than 100 cancer exomes (a part of the genome consisting of DNA sequences encoding proteins) allow not only to find out which genes are the cause of this cancer, but also to investigate which processes accumulate mutations (most of which, even in cancer samples, do not affect the development of cancer). We compared the mutational profile of basal cell carcinoma with another cancer – melanoma, also caused by ultraviolet radiation. As a result of our analyses, it was possible to conclude that oxidative stress and UV play a more significant role in the mutagenesis of basal cell carcinoma," says Vladimir Seplyarsky.

Criminogenic schemes

To catch the rest of the "accomplices" in this almost detective story at the scene of the crime, biologists analyzed 293 samples of tumor tissue from 236 patients. 30 samples belonged to patients with Gorlin syndrome (a genetic disease that dramatically increases the likelihood of multiple basal cell carcinomas on the body). Among the samples were also 23 resistant to the action of vismodegib and 259 not treated with this drug.

Scientists compared mutations in basal cell carcinomas, melanomas, Wilson's tumors (kidney cancer, most often formed in the first or third year of life) and other types of cancer, in the occurrence of which the Sonic Hedgehog gene and its "accomplices" from the same signaling pathway may be "involved".

The investigation showed that of the 387 genes that appeared in the "list of suspects", several can actually contribute to the occurrence of basal cell carcinoma and the development of tumor resistance to treatment. Among them are the genes that form the Hippo-YAP pathway, and not only related to the path controlled by the Sonic Hedgehog gene, which previously bore almost the entire burden of responsibility. Also, in the basal carcinoma samples, the N-Myc protein content was exceeded, which in this case was caused by a point mutation (replacement of one nucleotide – the "letter" of DNA) in the MB1 site. In other types of tumors, where the N-Myc protein in an increased concentration was "caught in the act" earlier, this was caused by a mutation that causes a multiple increase in the number of copies of the MYCN gene.

According to Vladimir Seplyarsky, "this work represents a turning point in understanding the molecular mechanisms of the origin and development of basal carcinoma. Knowledge about the susceptibility of CD cells to oxidative stress can give impetus to the use of another type of anticancer therapy for basal cell carcinoma."

In addition, as the author of the study explained, the results of the work show which mutagens affect DNA damage in skin cells.

Portal "Eternal youth" http://vechnayamolodost.ru  11.03.2015