DISCUSSION
In this study, we presented a case of CCSK which underwent 4 relapses. The first relapse occurred in the lung. This is consistent with the previous reports that the lung was the most common site of relapse in patients treated with DD-4A4,5, although the present case relapsed earlier (4 months vs 24 months)1,3. The optimal treatment of relapsed CCSK has not been established as yet. ICE chemotherapy, a salvage regimen for recurrent CCSK6,15, resulted in the achievement of the second remission, however, the second relapse developed. Due to the refractory disease, we performed high dose chemotherapy with aHSCT rescue though its effectiveness is unclear6,15. Because treatment options for relapsed CCSK are limited and survival is poor, we retrospectively analyzed this case in terms of genomics for the possibility of new therapeutic strategies.
In this study, the same BCOR -ITD alteration was observed from diagnosis right up to autopsy with very low tumor mutation burden, suggesting a strong impact not only on CCSK tumorigenesis as previously reported7,8 but also on its relapse. Meanwhile, we could not observe truncal mutations that can be targetable with available FDA-approved drugs. Multi-sample extractions at R4 and autopsy revealed site specific mutations of metastasis in addition to truncal mutations of R3 sample, which suggests the presence of subclones with site specific mutations in each metastases site of the previous samples. Among them, a subclone with selective advantage might relapse as the dominant clone. This is supported by the result that the newly acquired mutations were not detected even as a minor clone in the previous primary samples. Furthermore, our clonal analysis of the metastatic samples also suggested that relapsed tumors were derived from minor clones of the preceding tumors, which had survived chemoradiotherapy and thrived (Fig. 2C). Therefore, acquired genetic abnormalities during tumor progression might be associated with clinical therapeutic resistance16. BRINP1 , lost in the samples of R2 through autopsy, is a tumor suppressor gene, which regulates the G1/S checkpoint and cell cycle17 and its dysregulation is associated with tumor recurrence in other carcinomas18. CNAs such as gain at 1q and loss at 7q and 15q are frequently observed in other neoplasms and related to tumor relapse and metastasis19-22. Moreover, acquired mutations in FLT1 , JAK2 , CDK6 , NF1 , andKDM6A are generally associated with therapeutic resistance and metastasis23-30. Thus, we can estimate that the genetic alterations acquired during disease progression in the present case might contribute to clonal selection and therapeutic resistance. However, our analysis in the present study was limited in genomic abnormalities, and thus, further analyses for other various factors including epigenetic abnormalities and tumor microenvironment are warranted.
Altogether, although we failed to find targetable lesions, our study indicated the importance of BCOR -ITD in both CCSK tumorigenesis and relapse, and suggested that genetic alterations acquired during disease progression might contribute to clonal selection and therapeutic resistance in the present case. However, this report is based on a single case and further studies with more samples will help to detect common mechanisms of relapse and therapy resistance in CCSK, enabling appropriate therapy for relapsed cases considering genetic status.