Growing evidence supports a role for the unfolded protein response (UPR) in carcinogenesis; however, the precise molecular mechanisms underlying this phenomenon remain elusive. Herein, we identified the circadian clock PER1 mRNA as a novel substrate of the endoribonuclease activity of the UPR sensor IRE1α. Analysis of the mechanism shows that IRE1α endoribonuclease activity decreased PER1 mRNA in tumor cells without affecting PER1 gene transcription. Inhibition of IRE1α signaling using either siRNA-mediated silencing or a dominant-negative strategy prevented PER1 mRNA decay, reduced tumorigenesis, and increased survival, features that were reversed upon PER1 silencing. Clinically, patients showing reduced survival have lower levels of PER1 mRNA expression and increased splicing of XBP1, a known IRE-α substrate, thereby pointing toward an increased IRE1α activity in these patients. Hence, we describe a novel mechanism connecting the UPR and circadian clock components in tumor cells, thereby highlighting the importance of this interplay in tumor development.
Central nervous system (CNS)-type tumors and tumor-like proliferations arising in the gynecologic tract and pelvis are rare. Clinicopathologic features of 23 cases are reported using the current WHO classification system for CNS tumors, with selected relevant immunohistochemical and molecular genetic analyses when possible. There were 12 embryonal tumors, including 7 medulloepitheliomas, 2 embryonal tumors (not otherwise specified), 1 embryonal tumor with multilayered rosettes, 1 embryonal tumor with features of nodular desmoplastic medulloblastoma, and 1 medulloblastoma with extensive nodularity, with primary sites including ovary (7), uterus/endometrium (3), and pelvis (2). Six ovarian tumors had associated germ cell tumors (3 immature teratomas [1 also with yolk sac tumor], 2 mature cystic teratomas, and 1 yolk sac tumor). These tumors typically had some expression of synaptophysin (10/10), GFAP (5/9), S100 (3/6), and NeuN (3/3) and were negative for C19MC amplicon by fluorescence in situ hybridization (0/5). There were 6 glial tumors, including 3 ependymomas (1 anaplastic), 1 oligodendroglioma, not otherwise specified, 1 pilocytic astrocytoma, and 1 atypical glial proliferation after therapy of a high-grade high-stage immature teratoma, with primary sites including ovary (4), fallopian tube (1), and pelvic sidewall (1). Four ovarian tumors had associated teratomas (2 immature and 2 mature). These tumors expressed GFAP (5/6), OLIG2 (2/3), and S100 (1/1), and the pilocytic astrocytoma was negative for BRAF (V600E) mutant protein. There were 4 neuronal or mixed glioneuronal tumors, including 3 neurocytomas and 1 malignant (high-grade) glioneuronal neoplasm, all primary ovarian and associated with teratomas (3 mature, 1 immature). These tumors expressed synaptophysin (4/4), GFAP (1/3), NeuN (1/2), and OLIG2 (1/2). Single-nucleotide polymorphism microarray analysis of the malignant glioneuronal neoplasm demonstrated a partial deletion at location (1)(p36.23p35.2) on chromosome 1p, and 2 regions of deletion at locations (19)(q11q13.12) and (19)(q13.41qter) on 19q. One neurocytoma had no 1p and 19q co-deletions. There was 1 meningioma in the pelvis. For 10 patients with embryonal tumors and follow-up, 5 were alive with no evidence of disease (mean/median: 60/52 mo), 4 were alive with recurrent disease (mean/median: 32/31 mo), and 1 died of disease (13 mo). For 5 patients with other tumor types and follow-up, all were alive without evidence of disease (mean/median: 33/30 mo). Diagnostic evaluation and classification per systems used for primary CNS tumors are recommended for the wide spectrum of CNS-type neuroepithelial tumors that can occur in the female genital tract and pelvis.
Supplementary Table 2 from The Neurofibromatosis Type 1 Tumor Suppressor Controls Cell Growth by Regulating Signal Transducer and Activator of Transcription-3 Activity <i>In vitro</i> and <i>In vivo</i>
One of the most important prognostic factors in colorectal cancer is the presence or absence of regional lymph node metastases. In many instances, micrometastatic disease may not be found on routine pathologic analysis using hematoxylin and eosin staining, but may be discovered only with immunohistochemical methods or polymerase chain reaction assay. Lymphoscintigraphy with biopsy of the sentinel nodes, defined as the first nodal basin in the drainage pathway of a tumor, was developed to provide accurate staging without the morbidity associated with the classic lymph node dissections performed for melanoma or breast cancer. This concept has recently been applied to colorectal cancers, but the method used is unique because oncologic principles of resection are still adhered to for the primary tumor along with en bloc resection of the locoregional mesenteric nodes, some of which are sentinel nodes. Sentinel nodes are ideal for sensitive pathologic techniques of detecting micrometastatic disease, as they often reflect the status of the entire locoregional nodal basin. Gross metastatic nodes reveal significant prognostic information and guide the use of adjuvant therapy in affected patients. However, the detection of micrometastatic disease in sentinel nodes by sensitive pathologic methods has not been proven to result in poor prognosis or benefit from adjuvant therapy for colorectal cancer.
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INTRODUCTION: Activating fusions of the serine-threonine-kinase-encoding BRAF gene with the nearby gene KIAA1549 have been described in low-grade pediatric brain tumors, including most cerebellar pilocytic astrocytomas and smaller numbers of other, generally low-grade, CNS tumors. Disseminated oligodendroglial-like leptomeningeal tumors (DOLTs) are slowly progressive pediatric tumors with limited, if any parenchymal involvement. In this series, we assessed the status of BRAF-KIAA1549 and chromosomes 1p and 19q, with deletions of the latter known to variably occur in this tumor type. METHODS: 20 archival DOLTs were examined by FISH for BRAF-KIAA1549 fusion, and 17 cases for deletions of 1p and 19q. One case was additionally interrogated by SNP-array. Testing for BRAF-V600E mutation was also performed in nine cases. RESULTS: Of 14 informative cases for BRAF-KIAA1549, 9 were fusion positive by FISH, and one harbored a duplication by SNP-array suggestive of the gene fusion, for a total of 10 of 14 positive cases (71%). FISH revealed loss of 1p in 10/17 cases (59%), with 3 of those also being co-deleted for 19q (18%). Of the 10 cases with BRAF fusions, 8 had 1p deletion (80%) and 1 had 19q co-deletion (10%). None of 9 tested specimens were positive for BRAF-V600E mutation. CONCLUSION: These findings indicate a high rate of concurrent BRAF-KIAA1549 gene fusions and 1p deletions in DOLTs. Although BRAF fusions are typical of pilocytic astrocytomas, 1p deletions are not, confirming that DOLTs are pathologically and genetically distinct. These findings also further separate these oligodendroglial-like tumors from adult oligodendrogliomas, although some overlap remains since 1p19 codeletion is occasionally found in DOLT and rare BRAF fusions have been recently reported in otherwise classic, 1p19q codeleted oligodendroglioma.
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