Primary malignant melanoma of the esophagus (PMME) is a rare and aggressive disease with high tendency of metastasis. To characterize the genetic basis and intratumor heterogeneity of PMME, we performed multiregion exome sequencing and whole genome SNP array genotyping of 12 samples obtained from a patient with PMME. High intratumor heterogeneity was observed in both somatic mutation and copy-number alteration levels. Nine geographically separate samples including two normal samples were clonally related and followed a branched evolution model. Most putative oncogenic drivers such as BRAF and KRAS mutations as well as CDKN2A biallelic inactivation were observed in trunk clones, whereas clinically actionable mutations such as PIK3CA and JAK1 mutations were detected in branch clones. Ancestor tumor clones evolved into three subclonal clades: clade1 fostered metastatic subclones that carried metastatic features of PIK3CA and ARHGAP26 point mutations as well as chr13 arm-level deletion, clade2 owned branch-specific JAK1 mutations and PTEN deletion, and clade3 was found in two vertical distribution samples below the primary tumor area, highlighting the fact that it is possible for PMME to disseminate by the submucosal longitudinal lymphatic route at an early stage of metastasis. These findings facilitate interpretation of the genetic essence of this rare melanoma subtype as well as the pattern of cancer evolution, thus reinforcing the therapeutic challenges associated with PMME.Significance: This study highlights the use of multiregion exome sequencing and whole genome SNP array genotyping to comprehensively characterize the genetic landscape of a rare type of esophogeal melanoma. Cancer Res; 78(2); 338-47. ©2017 AACR.
©2017 American Association for Cancer Research.