Here, we described a case with a huge tumor located in the stomach. Morphological feature revealed that tumor tissue from the spindle cells and collagen fiber bundles cutting through. Besides, IHC results showed that the spindle cells expressed CD117, DOG1, CD34, SDHA, SDHB, while a-SMA and other markers were negative. Given the immunophenotype of Cajal cell differentiation, which was confirmed to express CD117 and DOG-1 , as well as the location of this lesion, the diagnosis of GIST was first taken into consideration.
In order to further confirm the diagnosis of GIST, genetic analysis was carried out, and the results revealed a KIT and PDGFRA wild type GIST. NGS sequencing of a recent study claimed that  TP53, RB and ALK mutations could be detected in 72 Chinese patients with quadruple-negative GISTs (devoid of KIT, PDGFRA, BRAF, and SDH alterations). Besides, as it is known to all, wild type GIST is not sensitive to TKIs. Previous studies have suggested that the resistance to imatinib can be restored by other gene inhibitions, including FGFR3  and NTRK3 . Therefore, NGS was performed to identify driver mutations in GIST so as to find the potential therapeutic targets. To our surprise, a novel CDC42BPB-ALK fusion type (CDC42BPB exon 24-ALK in exon 20) with involvement of ALK exon 20 was identified. The function of the fusion protein is still unknown for the reason that CDC42BPB has not been reported as a fusion partner of ALK in any ALK-rearranged tumor. The result of RNA sequencing showed that CDC42BPB gene might be a fusion partner to ALK in some GIST cases. CDC42BPB, a member of the small Rho GTPase family , was located on 14q32.3 chromosome by FISH . Shivashankar et al  discovered that CDC42BPB was a kind of non-cancer associated gene, and would serve as potential drug target and diagnostic or prognostic markers if the cancer association was established. In addition, there is no previous report of any causal mutation of CDC42BPB in cancer. However, ALK fusion after exon 20 on the ALK side, which includes the complete ALK kinase domain, has been reported to activate a carcinogenic kinase in various ALK-rearranged tumors , including NSCLC , IMT , peritoneal mesothelioma and various other carcinomas . Previous study demonstrated that wild type GIST with the ETV6-NTRK3 fusion gene could be suppressed by ALK inhibitors, which could also inhibit NTRK3 . Similarly, we supposed that ALK inhibitors might serve as a new strategy for the targeting therapy of GIST in this case, which required further exploration and research.
FISH analysis (using FISH break-apart probes) and IHC methods were performed to identify ALK gene status. We found that a significant proportion of ALK genes were split. According to the relevant researches, the relation between the expression of ALK protein and ALK rearrangement was not sure. In 2020, Jun et al  reported a case of GIST with PDGFRA p. D842V mutation, which showed ALK protein overexpression (both of D5F3 and 5A4 clones) but lacked ALK rearrangement by FISH analysis. However, Lei et al  presented GIST with an ALK gene rearrangement (PPP1R21-ALK) which was examined by NGS. One possibility accounts for this confusing phenomenon is that some cases harbor cryptic structural variants that cannot be resolved by FISH . Besides, according to the standard methods which were advocated by the US Food and Drug Administration (FDA), as well as the China Food and Drug Administration (CFDA), FISH basing on break-apart FISH probes and IHC using D5F3 antibody were standard methods for ALK arrangement detection in NSCLC . In our study, we found that ALK overexpression could only be observed with the usage of D5F3 antibody, and this ALK (D5F3)-positive GIST had ALK gene rearrangement. Our current findings indicated that the use of different immunohistochemical antibody clones of ALK could also affect results, and the in-frame rearrangement might result in expression of a CDC42BPB-ALK fusion protein.
Our findings suggest that ALK fusion in the GIST starts at the canonical exon 20, and this type of ALK fusion has been reported as a possible therapeutic target in other cancers [35, 36]. Therefore, we supposed that ALK inhibitors would be a therapeutic option for patients with ALK-rearranged GIST who were insensitive to or resistant to TKIs. In this case, given that Kit and PDGFRA wild type GIST was proved to be not sensitive to TKIs, and this female patient is still in lactation, follow-up was suggested for this patient. During 4 months of following up, there was no recurrence after excision. If this patient develops recurrence/metastases in the future, it would seem reasonable to try targeted therapy using ALK inhibitors. However, the frequency of ALK rearrangement in GIST appears to be low and there were too few samples of patient cohorts. To date, ALK fusion has not been examined in GIST with intention (even using ALK immunohistochemistry for a preliminary screening). Thus, further research needs to be done in larger patient cohorts.
In conclusion, we identified a GIST with a novel fusion of CDC42BPB-ALK. Our results, combining with previously described 2 cases of GIST (with ALK gene rearrangement or ALK overexpression), also expanded the molecular spectrum of this tumor beyond the well-known GIST driver genes. These oncogenic events may have implications for therapeutic targets in patients with ALK rearranged GIST, which deserves our further investigation.