Objectives The molecular processes underpinning distant metastasis in endometrial cancer (EC) are not well understood. We sought to characterize the genomic alterations of primary ECs and matched lung metastases.

Methods Primary ECs, matched lung metastases, and normal tissue from two patients were subjected to whole-exome sequencing. Sequencing data were analyzed using validated bioinformatics tools.

Results In case 1, sequencing analysis of the primary FIGO grade 2 EC and matched lung metastasis, which developed after 3 years, revealed 99 and 95 non-synonymous somatic mutations, respectively, of which 68 were shared. In addition to clonal shared PIK3R1 and PTEN mutations, we observed clonal shifts in the progression to lung metastatic disease, including a CTNNB1 G34V hotspot mutation, which was subclonal in the primary EC and became clonal in the metastasis. The primary dedifferentiated EC of case 2 was MSI-H due to MLH1 hypermethylation. Both the primary and synchronous metastatic lung tumor harbored a large number of somatic mutations (1217 and 1157, respectively), but only 227 were shared, including PIK3CA hotspot, PTEN frameshift, and MSH6 frameshift mutations. In case 2, clonal shifts were also observed in the progression from primary EC to lung metastasis, and multiple CTNNB1mutations were identified: a subclonal CTNNB1 G34R hotspot mutation in the primary EC, and a subclonal CTNNB1G33P hotspot and a clonal CTNNB1 G34E hotspot mutation limited to the metastasis.

Conclusions Clonal shifts, the accumulation of additional mutations and/or hotspot CTNNB1 mutations may play a role in the progression from primary EC to lung metastatic disease.