Importantly, our study demonstrates that LZTR1 and CRKL—two of the top genes associated with 22q11.21 amplification in acral melanoma—facilitate anchorage-independent growth in normal human melanocytes, likely by reducing E-cadherin, increasing N-cadherin, and activating integrin β1. The gene discussed is LZTR1; the disease is acral lentiginous melanoma.