Basal cell carcinoma, the most common form of skin cancer, most often occurs as a result of aberrant Hedgehog signaling. However, new research suggests that additional molecular drivers may be involved, including mutations that lead to N-Myc accumulation and oncogenic YAP1 activity.
In a new study from the University of Geneva (UNIGE) in Switzerland, researchers have pinpointed additional molecular drivers of basal cell carcinoma (BCC)—the most common form of skin cancer, albeit one that's rarely fatal.
Led by geneticist Sergey Nikolaev, PhD, and Stylianos Antonarakis, MD, DSc, chair of genetic medicine at UNIGE, the team analyzed 293 BCCs with a battery of molecular methods, including whole-exome and RNA sequencing. They found an average of 65 mutations per million bases in their samples, corroborating previous observations that BCC has one of the highest mutation rates among cancers. These were mostly single-base changes, with C to T being particularly prevalent, followed by C to A mutations.
When the researchers compared this BCC data with melanoma data from other studies, they noted that sun exposure is a key culprit in both types of skin cancer: Approximately 90% and 85% of BCCs and melanomas, respectively, exhibited mutation patterns consistent with ultraviolet-induced DNA damage. They found, however, that transcription-coupled repair—the detection and removal of damaged DNA from transcriptionally active genomic regions—is more efficient in BCC than in melanoma.
The team also uncovered other drivers of BCC development—beyond aberrant Hedgehog signaling, its primary driver—including mutations in MYCN, PTPN14, and LATS1. MYCN mutations result in excessive amounts of the protein N-Myc that would otherwise undergo proteasomal degradation; this accumulation is associated with tumorigenesis. Meanwhile, inactivated PTPN14 and LATS1 can no longer restrain YAP1, an oncoprotein involved in the Hippo signaling pathway. Instead of being held at bay in the cytoplasm, YAP1 is free to head to the nucleus, where it initiates transcription of genes that promote cell proliferation and inhibit apoptosis.
These findings suggest “a more complex genetic network of cancer-related genes than previously anticipated,” the researchers write, and could explain why approximately 30% of BCCs don't respond or become resistant to the Hedgehog inhibitor vismodegib (Erivedge; Genentech).
Thomas Kupper, MD, chair of dermatology at Brigham and Women's Hospital in Boston, MA, thinks this study “nicely segregates BCC and melanoma, and shows that biological aggressiveness is not just about the number or accumulation of mutations—other factors must be in play.”
“BCC is almost always curable, but it can leave significant disfigurement and loss of function as a result of curative surgery,” he adds. “With the identification of new driver mutations, targeted therapies beyond vismodegib may be forthcoming for this disease.” –Alissa Poh