Whole Exome Sequencing of Thymoma Patients Exhibiting Exceptional Responses to Pemetrexed Monotherapy

SIMPLE SUMMARY: Pemetrexed, a multi-target anti-folate agent, is the treatment choice for advanced or metastatic thymoma at the second or later line setting. Thymoma patients occasionally show an exceptionally durable and deep response to pemetrexed treatment. Recent studies using next-generation sequencing have identified some genomic aberrations in such patients, but the mechanism underlying their sensitivity to pemetrexed remains unclear. This study explores certain somatic single-nucleotide variants or copy number variations (CNVs) in exceptional responders to pemetrexed treatment. To elucidate any genomic changes, we performed whole-exome sequencing in patients with advanced thymomas treated with pemetrexed. We found no differences between the exceptional and typical responders, but the highest number of whole arm gain or the loss of chromosomal CNVs was observed in an exceptional responder to pemetrexed. Our study provides additional genomic findings on thymomas and chemosensitivity. ABSTRACT: Background: Pemetrexed is used for the chemotherapy of advanced thymoma. Exceptional responses of thymoma to pemetrexed treatment are not frequently observed. The underlying genetic mechanism of the exceptional responses remains unclear. We used whole-exome sequencing to explore the specific genomic aberrations that lead to an extreme and durable response. Methods: Whole-exome sequencing using NovaSeq6000 (150 bp paired-end sequencing) was performed on nine formalin-fixed paraffin-embedded tissues from patients with advanced thymomas treated with pemetrexed (two exceptional responders and seven typical responders). Results: We identified 284 somatic single-nucleotide variants (SNVs; 272 missense, 8 missense/splice-site, 3 stop-gain, and 1 stop-gain/splice-site), 34 insertions and deletions (Indels; 33 frameshift and one splice region), and 21 copy number variations (CNVs; 15 gains and six losses). No difference in the number of SNVs variants and distribution of deleterious Indels was observed between the exceptional and typical responders. Interestingly, arm-level chromosomal CNVs (15 gains and six losses) were detected in four patients, including an exceptional responder. The highest number of arm-level CNVs was observed in an exceptional responder. Conclusion: Exceptional responders to pemetrexed for metastatic thymomas may be characterized by arm-level CNVs. Further, whole-genome and RNA sequencing studies should be performed.