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The EGFR family consists of 4 receptor tyrosine kinases, EGFR (ERBB1), ERBB2 (HER2), ERBB3 (HER3) and ERBB4 (HER4). Recent reports revealed that the kinase domains of bothEGFR(ERBB1) andERBB2gene were somatically mutated in human cancers, raising the possibility that the other ERBB members possess somatic mutations in human cancers. Here, we performed mutational analysis of theERBB4kinase domain by polymerase chain reaction–single-strand conformation polymorphism assay in 595 cancer tissues from stomach, lung, colon and breast. We detected theERBB4somatic mutations in 3 of 180 gastric carcinomas (1.7%), 3 of 104 colorectal carcinomas (2.9%), 5 of 217 nonsmall cell lung cancers (2.3%) and 1 of 94 breast carcinomas (1.1%). The 12ERBB4mutations consisted of 1 in-frame duplication mutation and 8 missense mutations in the exons, and 3 mutations in the introns. We simultaneously analyzed the somatic mutations ofEGFR, ERBB2, K-RAS, PIK3CAandBRAFgenes in the 12 samples with theERBB4mutations and found that 1 gastric carcinoma withERBB4mutation also harboredK-RASgene mutation. Our study demonstrated that in addition toEGFRandERBB2, somatic mutation of the kinase domain ofERBB4occurs in the common human cancers, and suggested that alterations of ERBB4-mediated signaling pathway byERBB4mutations may contribute to the development of human cancers.