Genetic alterations uncovered in development of skin cancer

Genetic alterations uncovered in development of skin cancer
Genetic alterations uncovered in development of skin cancer

The genetic abnormalities that lead the development, progression, and metastasis of mouse skin squamous cell carcinoma were recently described in research published in Nature Medicine (2015; doi:10.1038/nm.3878). The study noted interesting similarities with human cancers.

Squamous cell carcinoma (SCC) of the skin is one of the most frequent cancers in humans, and it affects more than half million new persons every year in the world. The transformation of a normal cell to a cancer cell is caused by an accumulation of genetic abnormalities in the progeny of single cells. Prior studies have described the spectrum of genetic anomalies found in a variety of human cancers.

While SCC has been studied in mouse models of skin cancer for over a century, it has been unclear if these mouse models are mediated by the same spectrum of mutations as human cancer.

This study was led by Cédric Blanpain, MD,PhD, professor at the Université libre de Bruxelles-ULB in Brussels, Belgium, and Diether Lambrechs, PhD, professor at Vlaams Instituut voor Biotechnologie VIB and in Katholieke Universiteit Leuven in Leuven, Belgium.

The scientists used a mouse model of skin SCC induced by a chemical carcinogen, which is the most frequently used mouse model in cancer research. They studied the genetic abnormalities in premalignant and fully malignant tumors, as well as their metastases. They used state-of-the-art high throughput sequencing technologies, known as "next generation sequencing" or NGS.

The study defines the entire landscape of mutations, including point mutations as well as chromosome amplifications and deletions, that lead to mouse skin cancer formation and progression.

The authors commented that they observed striking similarity between mutated genes in carcinogen-induced mouse SCC and human SCCs, which confirms the relevance of mouse models for understanding human cancer.

By analyzing the genetic abnormalities that accompanied the progression from a benign tumor to fully malignant and invasive tumors, the researchers found that tumor progression was not accompanied by additional point mutations but rather by larger chromosomal copy number alterations, leading to the amplification or deletion of important genes controlling tumor formation.

Finally, by reconstructing the lineage tree of primary cancers and their metastasis, the authors demonstrated that very few additional mutations were found in metastasis, suggesting that metastasis could be regulated by other additional non-genetic mechanisms.

"The identification of the genetic landscape of the most frequently used cancer model is an important step forward in our understanding of key genetic events leading to mouse tumorigenesis, which are very similar to the ones found in with human cancers,” said Blanpain. “This information is essential to rationalize and prioritize the development of new models that better mimic human cancer and will be critical to understand the function of all the new cancer drivers recently discovered, and will be helpful for the development of new therapeutic approaches."

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