The endothelin signaling pathway plays a crucial role in melanocyte 
differentiation and migration. In this study, we investigated whether germline 
mutations of endothelin receptor B (EDNRB), a gene involved in Hirschsprung 
disease (HSCR), could also predispose for malignant melanoma (MM). The coding 
region of EDNRB was sequenced in 137 MM patients and in 130 ethnically matched 
Caucasian control subjects. Six nonsynonymous EDNRB variants were found in 15 
patients (11%), but only two were found in four control subjects (3%, odds ratio 
[OR] = 3.87, 95% confidence interval [CI] = 1.25 to 12; P = .012). Overall, 14 
out of 15 MM patients carried EDNRB mutations reported in HSCR, some of which 
had previously been shown to lead to loss of function. In multivariable logistic 
regression analysis including skin type, eye and hair color, number of nevi, and 
dorsal lentigines (freckles), the association between EDNRB mutations and MM 
risk remained statistically significant (OR = 19.9, 95% CI = 1.34 to 296.2; P = 
.03). Our data strongly suggest that EDNRB is involved in predisposition for two 
different multigenic disorders, HSCR and melanoma.