Dataset Information

RBM10-TFE3 Renal Cell Carcinoma: A Potential Diagnostic Pitfall Due to Cryptic Intrachromosomal Xp11.2 Inversion Resulting in False-negative TFE3 FISH.

ABSTRACT: Xp11 translocation renal cell carcinoma (RCC) are defined by chromosome translocations involving the Xp11 breakpoint which results in one of a variety of TFE3 gene fusions. TFE3 break-apart florescence in situ hybridization (FISH) assays are generally preferred to TFE3 immunohistochemistry (IHC) as a means of confirming the diagnosis in archival material, as FISH is less sensitive to the variable fixation which can result in false positive or false negative IHC. Prompted by a case report in the cytogenetics literature, we identify 3 cases of Xp11 translocation RCC characterized by a subtle chromosomal inversion involving the short arm of the X chromosome, resulting in an RBM10-TFE3 gene fusion. TFE3 rearrangement was not detected by conventional TFE3 break-apart FISH, but was suggested by strong diffuse TFE3 immunoreactivity in a clean background. We then developed novel fosmid probes to detect the RBM10-TFE3 gene fusion in archival material. These cases validate RBM10-TFE3 as a recurrent gene fusion in Xp11 translocation RCC, illustrate a source of false-negative TFE3 break-apart FISH, and highlight the complementary role of TFE3 IHC and TFE3 FISH.

SUBMITTER: Argani P

PROVIDER: S-EPMC5391276 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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RBM10-TFE3 Renal Cell Carcinoma: A Potential Diagnostic Pitfall Due to Cryptic Intrachromosomal Xp11.2 Inversion Resulting in False-negative TFE3 FISH.

Argani Pedram P Zhang Lei L Reuter Victor E VE Tickoo Satish K SK Antonescu Cristina R CR

The American journal of surgical pathology 20170501 5

Xp11 translocation renal cell carcinoma (RCC) are defined by chromosome translocations involving the Xp11 breakpoint which results in one of a variety of TFE3 gene fusions. TFE3 break-apart florescence in situ hybridization (FISH) assays are generally preferred to TFE3 immunohistochemistry (IHC) as a means of confirming the diagnosis in archival material, as FISH is less sensitive to the variable fixation which can result in false positive or false negative IHC. Prompted by a case report in the ...[more]

PMID: 28296677

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Project description:Xp11.2 or TFE3 translocation renal cell carcinomas (RCC) and alveolar soft part sarcoma (ASPS) are characterized by chromosome translocations involving the Xp11.2 breakpoint resulting in transcription factor TFE3 gene fusions. The most common translocations documented in TFE3 RCCs are t(X;1) (p11.2;q21) and t(X;17) (p11.2;q25) which leads to fusion of TFE3 gene on Xp11.2 with PRCC or ASPL respectively. TFE3 immunohistochemistry (IHC) has been inconsistent over time due to background staining problems in part related to fixation issues. Karyotyping to detect TFE3 gene rearrangement requires typically unavailable fresh tissue. Reverse transcriptase-polymerase chain reaction (RT-PCR) is generally very challenging due to degradation of RNA in archival material. The study objective was to develop and validate a TFE3 break-apart fluorescence in situ hybridization (FISH) assay to confirm Xp11 translocation RCCs and ASPS.Representative sections of formalin-fixed paraffin-embedded tissue blocks were selected in 40 possible cases. Approximately 60 tumor cells were analyzed in the targeted region. The validation of TFE3 FISH was done with 11 negative and two positive cases. Cut off for a positive result was validated as >7.15 % positive nuclei with any pattern of break-apart signals. FISH evaluation was done blinded of the immunohistochemical or karyotype data.Three out of forty cases were positive for the TFE3 break-apart signals by FISH. The negative cases were reported as clear cell RCC with papillary features (10), clear cell RCC with sarcomatoid areas (2), Papillary RCC with clear cell areas (9), Chromophobe RCC (2), RCC, unclassified type (3) and renal medullary carcinoma (1). 3 of the negative cases were consultation cases for renal tumor with unknown histology. Seven negative cases were soft tissue tumor suspicious for ASPS.Our study validates the utility of TFE3 break-apart FISH on formalin-fixed paraffin-embedded tissue sections for diagnosis and confirmation of Xp11.2 translocation RCCs and ASPS.

Project description:The subset of CD30-positive anaplastic large cell lymphomas (ALCL) with the NPM-ALK gene fusion arising from the t(2;5)(p23;q35) forms a distinct clinical and prognostic entity. Recently, various cytogenetic, molecular, and protein studies have provided evidence for the existence of several types of variant ALK fusions in up to 20% of ALK+ ALCL, of which only one, a TPM3-ALK fusion resulting from a t(1;2)(q25;p23), has so far been cloned. A cryptic inv(2)(p23q35) has been described as another recurrent cytogenetic alteration involving ALK and an unidentified fusion partner in some ALCL. In a screen for variant ALK gene fusions, we identified two ALCL that were negative for NPM-ALK by reverse transcriptase-polymerase chain reaction, but were positive for cytoplasmic ALK with both polyclonal and monoclonal antibodies to the ALK tyrosine kinase domain, consistent with ALK deregulation by an alteration other than the t(2;5) Case 1 was a T-lineage nodal and cutaneous ALCL in a 52-year-old woman, and Case 2 was a T-lineage nodal ALCL in a 12-year-old girl. FISH analysis confirmed ALK rearrangement in both cases. An inverse polymerase chain reaction approach was then used to identify the ALK translocation partner in Case 1. We found an in-frame fusion of ALK to ATIC, a gene previously mapped to 2q34-q35. We then confirmed by DNA polymerase chain reaction the localization of ATIC to yeast artificial chromosome (YAC) 914E7 previously reported to span the 2q35 break in the inv(2)(p23q35). FISH analysis in Case 1 confirmed rearrangement of YAC 914E7 and fusion to ALK. The ATIC-ALK fusion was confirmed in Case 1 and also identified in Case 2 by conventional reverse transcriptase-polymerase chain reaction using ATIC forward and ALK reverse primers. ATIC encodes an enzyme involved in purine biosynthesis which, like other fusion partners of ALK, is constitutively expressed and appears to contain a dimerization domain. ATIC-ALK fusion resulting from the inv(2)(p23q35) thus provides a third mechanism of ALK activation in ALK+ ALCL.

Dataset Information

RBM10-TFE3 Renal Cell Carcinoma: A Potential Diagnostic Pitfall Due to Cryptic Intrachromosomal Xp11.2 Inversion Resulting in False-negative TFE3 FISH.

Publications

RBM10-TFE3 Renal Cell Carcinoma: A Potential Diagnostic Pitfall Due to Cryptic Intrachromosomal Xp11.2 Inversion Resulting in False-negative TFE3 FISH.

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