FISH is the most widely used method to confirm
ALK gene rupture and rearrangement.
ALK translocation has been identified in all reported 20 cases by FISH. The fusion partner of
ALK has been confirmed in 16 out of 20 cases of
ALK-tRCCs.
VCL, involved in the first three pediatric cases with sickle cell trait was not found in further cases. The most frequent partner was
TPM3 (8 cases, including our case). The
TPM3-ALK fusion was previously reported in inflammatory myofibroblastic tumor and anaplastic large cell lymphoma.
TPM3 encodes the tropomyosin 3, an actin-binding protein that plays a role in cytoskeletal microfilament assembly and cell migration [
28,
29]. The coiled-coil structure of TPM3 could induce homodimerization of the chimeric TPM3-ALK protein and promote auto-phosphorylation of the ALK catalytic domain [
30‐
33]. An increased metastatic potential has been suggested in cell lines harboring
TPM3-ALK compared with other
ALK fusion transcripts [
34], and isolated case reports have suggested a more aggressive clinical behavior in ALCL and IMT harboring
TPM3-ALK fusion transcripts [
18,
35,
36]. To date, survival data are available only for five of the 8
ALK-TPM3-tRCC patients: they were alive for 8, 12, 24, 24 and 6 months after surgery, respectively (Table
1). Although there was one
ALK-TPM3-tRCC patient who showed recurrence 1 year after surgery, current data is insufficient for stating a prognostic value correlated to the fusion partner of
ALK in
ALK-tRCCs. Other fusion partners of
ALK included
STRN (2 cases),
EML4 (2 cases) and
HOOK1 (1 cases). In addition, Ciara Ryan et al. reported one special case demonstrating increased copy number of intact 2p23, the chromosomal region containing the
ALK gene, rather than exhibiting a chromosomal translocation involving
ALK [
17]
. Furthermore, Sukov WR et al. also found that
ALK copy number gain was identified in chromophobe renal cell carcinoma (CCRCC) and PRCC [
11]. Therefore,
ALK expression RCC doesn’t equal to
ALK translocation RCC.
At the same time, 10 out of 20 cases were tested for
TFE3 breakage by FISH, but all the cases were negative. Our case tested
TFEB gene breakage too. Similarly, we didn’t find
TFEB structural alteration. In the case reported by Paul Scott Thorner et al.,
TFE3 arrangement wasn’t found, but three and four copies of
TFE3 were observed in 10 and 42% of nuclei. So, Paul Scott Thorner et al. suggested that gain of the Xp11 locus might be a mechanism of
TFE3 positive expression [
14].
Karyotypic or genomic data were available in only 5 published cases (Table
1). Four cases showed a balanced [
10,
13,
14] or unbalanced [
9] translocation. Yohan Bodokh et al. detected chromosomal losses, including loss of chromosome 3, 9, 14 and 21q [
19]. The loss of chromosome 3 in RCC is a well characterized feature of clear cell RCC, but it has been occasionally described in non-clear cell RCC, such as papillary RCC, tRCC or unclassified RCC [
37‐
39]. In our case, we detected the
ALK-TPM3 translocation by NGS, in addition some genetic mutations with uncertain significance were found, including
BARD1 (c.773 T > C),
MSH3 (c.178G > C),
FANCA (c.1756G > A) and
NF1 (c.4382 T > C). The correlation between these genes’ mutation and
ALK-tRCC occurrence retains unknown. We have performed immunostaining of MisMatch Repair deficiency (dMMR) genes, the results showed all their proteins were expressed in tumor cells. And there was no familial history of neurofibromatosis type 1. So, the current evidences did not support that Lynch Syndrome or NF1 were related with this
ALK-tRCC.