An Unusual Benign Uterine Stromal Spindle Cell Tumor Harboring JAZF1::BCORL1.

Uterine mesenchymal lesions demonstrate various underlying genomic alterations involving MED12 , JAZF1 , YWHAE , BCOR , and ALK genes, among others. Recent publications describe a subset of high-grade endometrial stromal sarcoma lesions harboring BCORL1 gene aberrations including JAZF1::BCORL1 . Herein, we present an unusual benign endomyometrial spindle cell lesion that defies classificatory efforts by demonstrating mixed histomorphologic and immunohistochemical features of endometrial stromal nodule, leiomyoma, and uterine inflammatory myofibroblastic tumor while harboring a JAZF1::BCORL1 . The lesion was found in a 43-yr-old woman with pelvic pain and heavy menses as a 5.5 cm well-circumscribed ulcerated mass fungating from the cervical os. Microscopic examination revealed a polypoid, well-circumscribed, moderately cellular endomyometrial tumor composed by bland spindle cells haphazardly disposed within a slightly edematous stroma enriched by a delicate network of thin-walled vessels that were occasionally encircled by the tumor cells. Unequivocal evidence of tongue-like growth pattern into the myometrium, tumor-type necrosis or increased mitotic activity was not identified after sampling the entire lesion. The lesion showed patchy immunoreactivity for both smooth muscle actin-alpha and desmin while negative for CD10, HMB45, ALK (D5F3), and BCOR. An Archer FusionPlex panel assay demonstrated a fusion involving both exons 4 from the JAZF1 and BCORL1 genes. The JAZF1::BCORL1 has not, to the best of our knowledge, been previously reported in a benign/low-grade mesenchymal uterine lesion.

Diagnostic utility of one-stop fusion gene panel to detect TFE3/TFEB gene rearrangement and amplification in renal cell carcinomas.

MiT family translocation renal cell carcinoma (MiT-RCC) harbors translocations involving the TFE3 or TFEB genes. RCC with TFEB amplification is also identified and is associated with a more aggressive clinical course. Accurate diagnosis of MiT-RCC is crucial for patient management. In this study, we evaluated the performance of the Archer FusionPlex assay for detection of MiT-RCC with TFE3 or TFEB translocations and TFEB amplifications. RNA was extracted from 49 RCC FFPE tissue samples with known TFE3/TFEB status (26 TFE3 FISH positive, 12 TFEB FISH positive, 4 TFEB amplified (1 case both split and amplified), and 8 FISH negative) using the Covaris extraction kit. Target enriched cDNA libraries were prepared using the Archer FusionPlex kit and sequenced on the Illumina NextSeq 550. We demonstrate that the age of the specimen, quality of RNA, and sequencing metrics are important for fusion detection. Fusions were identified in 20 of 21 cases less than 2 years old, and TFE3/TFEB rearrangements were detected in all cases with Fusion QC ≥ 100. The assay identified intrachromosomal inversions in two cases (TFE3-RBM10 and NONO-TFE3), usually difficult to identify by FISH assays. TFEB mRNA expression and the TFEB/TFE3 mRNA expression ratio were significantly higher in RCCs with TFEB fusion and TFEB gene amplification compared to tumors without TFEB fusion or amplification. A cutoff TFEB/TFE3 ratio of 0.5 resulted in 97.3% concordance to FISH results with no false negatives. Our study demonstrates that the FusionPlex assay successfully identifies TFE3 and TFEB fusions including intrachromosomal inversions. Age of the specimen and certain sequencing metrics are important for successful fusion detection. Furthermore, mRNA expression levels may be used for predicting cases harboring TFEB amplification, thereby streamlining testing. This assay enables accurate molecular detection of multiple subtypes of MiT-RCCs in a convenient workflow.

Gut Microbiota-Derived Short-Chain Fatty Acids Promote Prostate Cancer Growth via IGF1 Signaling.

Excessive intake of animal fat and resultant obesity are major risk factors for prostate cancer. Because the composition of the gut microbiota is known to change with dietary composition and body type, we used prostate-specific Pten knockout mice as a prostate cancer model to investigate whether there is a gut microbiota-mediated connection between animal fat intake and prostate cancer. Oral administration of an antibiotic mixture (Abx) in prostate cancer-bearing mice fed a high-fat diet containing a large proportion of lard drastically altered the composition of the gut microbiota including Rikenellaceae and Clostridiales, inhibited prostate cancer cell proliferation, and reduced prostate Igf1 expression and circulating insulin-like growth factor-1 (IGF1) levels. In prostate cancer tissue, MAPK and PI3K activities, both downstream of the IGF1 receptor, were suppressed by Abx administration. IGF1 directly promoted the proliferation of prostate cancer cell lines DU145 and 22Rv1 in vitro. Abx administration also reduced fecal levels of short-chain fatty acids (SCFA) produced by intestinal bacteria. Supplementation with SCFAs promoted tumor growth by increasing IGF1 levels. In humans, IGF1 was found to be highly expressed in prostate cancer tissue from obese patients. In conclusion, IGF1 production stimulated by SCFAs from gut microbes influences the growth of prostate cancer via activating local prostate MAPK and PI3K signaling, indicating the existence of a gut microbiota-IGF1-prostate axis. Disrupting this axis by modulating the gut microbiota may aid in prostate cancer prevention and treatment. SIGNIFICANCE: These results suggest that intestinal bacteria, acting through short-chain fatty acids, regulate systemic and local prostate IGF1 in the host, which can promote proliferation of prostate cancer cells.