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Researchers Uncover Additional Drivers, Pathways Involved in Basal Cell Carcinoma

NEW YORK (GenomeWeb) – A University of Geneva Medical School-led team has uncovered additional drivers of skin basal cell carcinoma through genomic analyses.

While hyperactivation of the Sonic hedgehog (SHh) pathway is a known driver of basal cell carcinoma, the researchers led by Geneva's Sergey Nikolaev noted that it was likely not the only one, as there is variation in disease aggressiveness, morphology, and treatment response. As they reported today in Nature Genetics, he and his colleagues genetically profiled nearly 300 basal cell carcinoma (BCC) samples, and found additional recurrent mutations — including ones in MYCN, PTPN14, and LATS1 — that appear to drive disease.

"In addition to SHh, numerous other genes can contribute to this skin cancer, which evidently complicates the treatment," Geneva researcher and co-author Stylianos Antonarakis said in a statement.

Basal cell carcinoma is one of the most common human cancers, affecting some 2 million people a year in the US, according to the American Academy of Dermatology, and is thought to be mainly caused by exposure to ultraviolet light.

Nikolaev, Antonarakis, and their colleagues performed mutational screening on 293 BCC samples from 236 patients using a combination of matched tumor-normal whole-exome sequencing, targeted panel sequencing, and matched tumor-normal RNA-sequencing. The BCC samples, they noted, included 263 sporadic BCC cases and 30 Gorlin syndrome cases as well as vismodegib treatment-resistant, -sensitive, and -naïve cases.

As expected, 85 percent of the BCCs the researchers examined had somatic mutations affecting the Hh pathway.

But by using an algorithm they developed that accounts for the background mutation rate per nucleotide, the researchers also uncovered 28 significantly recurrent mutations in 14 genes, including mutations in LATS1, SMO, MYCN, STK19, TP53, ERBB2, and PPP6C.

Thirty percent of the BCCs harbored missense mutations in MYCN, an oncogene paralogous to MYC. Similar alterations, the researchers wrote, have been found in Burkitt lymphoma, where they were shown to interact with FBXW7, part of the complex that ubiquitinates Myc to target it for degradation.

A number of the MYCN mutations the researchers uncovered in BCC mapped to a region that interacts with FBXW7 upon phosphorylation. Further, they found that these alterations were associated with reduced polyubiquitination levels in the presence of FBXW7, as compared to wild type.

PTPN14, meanwhile, was mutated in nearly a quarter of the BCC samples studied. PTPN14 typically helps the translocation of YAP1, which is part of the Hippo signaling pathway, from the nucleus to the cytoplasm. That movement is hindered in cells with mutated PTPN14. This, the researchers noted, suggests that PTPN14 is a new tumor-suppressor gene in BCC that works by activating the Hippo-YAP pathway.

The researchers also uncovered recurrent mutations in LATS1 and LATS2. LATS1 is a known tumor-suppressor kinase that's activated by PTPN14 and phosphorylates YAP1 to prevent its translocation to the nucleus. The recurrent LATS1 mutation they uncovered is predicted to affect the protein's structural stability and could affect its activity. Such LATS1-inactivating mutations, Antonarakis and his colleagues added, could be another way in which the Hippo-YAP1 pathway is activated in BCC.

Other putative BCC drivers the researchers uncovered include mutations PPP6C, ATK19, and RB1 as well as mutations in Notch family genes.

BCCs belonging to the non-clonal metatypical and morpheaform histological subtypes have a higher risk of recurrence than other types, the researchers noted And these high-risk BCC tumors are more likely to harbor MYCN, PPP6C, and PTPN14 mutations that tumors with lower risk of recurrence.

In addition, they noted that vismodegib-resistant BCCs had higher frequency of SMO mutations than treatment-naïve samples.

"The identification of new driver genes in BCC suggests a more complex genetic network of cancer-related genes than previously anticipated," they wrote in their paper, adding that these new significantly mutated genes "may explain differences in response to pharmacological treatment."