Identification of genetic alterations in extramammary Paget disease using whole exome analysis

•Extramammary Paget disease was genetically characterized by whole exome sequencing.•PIK3CA mutations E545 K and H1047R were identified as pathogenic.•ERBB2 S310 F was also identified as a pathogenic mutation.•Novel somatic mutations of TP53 were found in 6 of 18 tumor samples.•Multiple chromosomal alterations were found in extramammary Paget disease. Extramammary Paget disease (EMPD) is a rare cutaneous malignant neoplasm, and the genomic alterations underlying its pathogenesis are unknown. To identify tumor-specific genomic alterations in EMPD. Exome analysis was performed in specimens from three EMPD patients, and target amplicon sequencing was done for genes frequently mutated in other adenocarcinomas. Exome analysis revealed recurrent somatic mutations in several genes, includingTP53, PIK3CA, and ERBB2. We identified additional candidate exons by searching the COSMIC database for exons that are frequently mutated in other adenocarcinomas. We obtained 19 exons in 12 genes as candidate exons, and performed target amplicon sequencing in samples obtained from EMPD patients. New somatic mutations in the TP53 gene were identified in six EMPD patients. Single nucleotide polymorphism analysis revealed multiple chromosomal alterations in three EMPD specimens, and two specimens exhibited amplification of chromosome 12p13 and losses of 3p21–24, 7q22 and 13q12–21. Our comprehensive genetic analysis identified novel genomic alterations, and will inform treatment options for EMPD.