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Melanoma Studies Reveal Mutations Contributing to Cancerous Transition

NEW YORK (GenomeWeb) – A pair of new studies is spelling out the subtle and not-so-subtle molecular changes that prompt harmless moles to morph into melanoma.

In one study, appearing online today in Cancer Cell, a University of California at San Francisco-led team analyzed hundreds of cancerous and pre-cancerous samples from 82 melanoma patients treated at UCSF or the Dermatology Research Centre in Queensland, Australia, using microdissection to separate primary melanomas and benign mole tissues, also called melanocytic nevi.

"Overall, we identify crucial steps in the development of melanoma, which can be subject to future treatments and can guide biomarker strategies to improve diagnosis and staging," senior author Boris Bastian, a dermatology, cancer, and pathology researcher at UCSF, and his colleagues wrote.

Based on targeted genome sequences generated for a panel of 538 genes with Illumina HiSeq 2500 sequencing in 230 benign skin, primary tumor, or metastatic tumor samples, together with 42 samples from 20 of the patients that were assessed by RNA sequencing, the researchers retraced the genetic alterations accompanying the progression to cancer. In particular, their results pointed to a relatively gradual slide from benign to cancerous tissue features, triggered in part by early activation of the MAP kinase signaling pathway.

"[W]e see that this pathway is turned on just a little early on, then ramped up over the course of tumor evolution," first author Hunter Shain, a dermatology and cancer researcher at UCSF, said in a statement. "We think this may allow cancers to avoid cellular alarm bells until enough genetic changes have accumulated that the alarms no longer function."

Although the researchers did not detect mutations specific to metastatic tumors, their results revealed a rise in point mutations attributed to ultraviolet light exposure as melanomas become more invasive, followed by a jump in representation by copy number changes.

And along with the early activation of the MAP kinase they documented a series of characteristic changes that arise as benign tissue becomes closer to melanoma, including shifts in telomerase regulation and expression, chromatin landscapes, cell cycle checkpoint activity, and even more MAP kinase signaling, combined with mutations affecting TP53 or enhancing PI3K pathway activation.

Among them, for example, the team identified recurrent mutations affecting SWI/SNF chromatin remodeling regulatory genes — a result that harkens back to results reported in Cancer Cell online late last month by a University of Zurich-led team describing recurrent amplifications involving the chromatin regulatory gene EZH2, which also contributes to cilia disassembly.

That study "raises the level of molecular detail and confidence that cilia can play a tumor-suppressor role, calling for broader studies in other tumor types where cilia are notably observed and likely to be important, Peter Jackson, a Stanford University microbiology, immunology, and pathology researcher, wrote in a Cancer Cell commentary article.

In another new melanoma study in Cancer Cell, co-authored by Bastian and Shain, UCSF cancer and dermatology researcher Robert Judson led a team that turned to CRISPR-Cas9 gene editing to introduce known melanoma-related mutations into cancer-free human skin cell cultures. In response to mutations involving the tumor suppressor gene CDKN2A, which were previously linked to metastatic melanoma, the cells did not become cancerous.

On the other hand, the researchers noted that human skin cell mobility and invasiveness seemed to rise in response to the metastatic melanoma-related CDKN2A mutations, in part due to enhanced expression of the lineage-restricted transcription factor BRN2. When BRN2 was inhibited in mice, they reported, human melanoma tumors containing the characteristic CDKN2A alterations had muted mobility.

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