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.