The implementation of array comparative genomic hybridisation (array-CGH) allows us to describe new microdeletion/microduplication syndromes which were previously not identified. 9q21.13 microdeletion syndrome is a genetic condition due to the loss of a critical genomic region of approximately 750kb and includes several genes, such as RORB and TRPM6. Here, we report a case of a 7-year-old boy affected by 9q21.13 microdeletion syndrome. He presents with global developmental delay, intellectual disability, autistic behaviour, seizures and facial dysmorphism. Moreover, he has severe myopia, which was previously reported in only another patient with 9q21.13 deletion, and brain anomalies which were never described before in 9q21.13 microdeletion syndrome. We also collect 17 patients from a literature search and 10 cases from DECIPHER database with a total number of 28 patients (including our case). In order to better investigate the four candidate genes RORB, TRPM6, PCSK5, and PRUNE2 for neurological phenotype, we make, for the first time, a classification in four groups of all the collected 28 patients. This classification is based both on the genomic position of the deletions included in the 9q21.3 locus deleted in our patient and on the different involvement of the four-candidate gene. In this way, we compare the clinical problems, the radiological findings, and the dysmorphic features of each group and of all the 28 patients in our article. Moreover, we perform the genotype-phenotype correlation of the 28 patients to better define the syndromic spectrum of 9q21.13 microdeletion syndrome. Finally, we propose a baseline ophthalmological and neurological monitoring of this syndrome.

Parathyroid tumors are mostly sporadic but can also occur in familial forms, including different kinds of genetic syndromes with varying phenotypes and penetrance. Recently, somatic mutations of the tumor suppressor gene PRUNE2 were found to be frequent in parathyroid cancer (PC). The germline mutation status of PRUNE2 was investigated in a large cohort of patients with parathyroid tumors from the genetically homogenous Finnish population, 15 of which had PC, 16 atypical parathyroid tumors (APT), and 6 benign parathyroid adenomas (PA). Mutations in previously established hyperparathyroidism-related genes were screened with a targeted gene panel analysis. Nine PRUNE2 germline mutations with a minor allele frequency (MAF) of <0.05 were found in our cohort. Five of these were predicted to be potentially damaging and were identified in two patients with PC, two with APT, and three with PA. The mutational status was not associated with the tumor group nor related to the clinical picture or severity of the disease. Still, the frequent finding of rare germline mutations of PRUNE2 may point to the gene playing a role in the pathogenesis of parathyroid neoplasms.

We have previously shown that the long non-coding (lnc)RNA prostate cancer associated 3 (PCA3; formerly prostate cancer antigen 3) functions as a trans-dominant negative oncogene by targeting the previously unrecognized prostate cancer suppressor gene PRUNE2 (a homolog of the Drosophila prune gene), thereby forming a functional unit within a unique allelic locus in human cells. Here, we investigated the PCA3/PRUNE2 regulatory axis from early (tumorigenic) to late (biochemical recurrence) genetic events during human prostate cancer progression.
The reciprocal PCA3 and PRUNE2 gene expression relationship in paired prostate cancer and adjacent normal prostate was analyzed in two independent retrospective cohorts of clinically annotated cases post-radical prostatectomy: a single-institutional discovery cohort (n=107) and a multi-institutional validation cohort (n=497). We compared the tumor gene expression of PCA3 and PRUNE2 to their corresponding expression in the normal prostate. We also serially examined clinical/pathological variables including time to disease recurrence.
We consistently observed increased expression of PCA3 and decreased expression of PRUNE2 in prostate cancer compared with the adjacent normal prostate across all tumor grades and stages. However, there was no association between the relative gene expression levels of PCA3 or PRUNE2 and time to disease recurrence, independent of tumor grades and stages.
We concluded that upregulation of the lncRNA PCA3 and targeted downregulation of the protein-coding PRUNE2 gene in prostate cancer could be early (rather than late) molecular events in the progression of human prostate tumorigenesis but are not associated with biochemical recurrence. Further studies of PCA3/PRUNE2 dysregulation are warranted.
We received support from the Human Tissue Repository and Tissue Analysis Shared Resource from the Department of Pathology of the University of New Mexico School of Medicine and a pilot award from the University of New Mexico Comprehensive Cancer Center. RP and WA were supported by awards from the Levy-Longenbaugh Donor-Advised Fund and the Prostate Cancer Foundation. EDN reports research fellowship support from the Brazilian National Council for Scientific and Technological Development (CNPq), Brazil, and the Associação Beneficente Alzira Denise Hertzog Silva (ABADHS), Brazil. This work has been funded in part by the NCI Cancer Center Support Grants (CCSG; P30) to the University of New Mexico Comprehensive Cancer Center (CA118100) and the Rutgers Cancer Institute of New Jersey (CA072720).

Background: Forkhead box F2, a member of the Forkhead box transcription factor superfamily, plays an important role in several types of cancer. However, the mechanisms of Forkhead box F2 in the progression of colorectal cancer remain unclear. PRUNE2 is closely associated with prostate cancer, neuroblastoma, glioblastoma, and melanoma. The relationship between Forkhead box F2 and PRUNE2 in colorectal cancer remains unknown. Method: We investigated the effects of Forkhead box F2 upregulation on colorectal cancer cell behavior in vitro using Cell Counting Kit-8, colony formation, flow cytometry, Transwell, reverse transcription quantitative polymerase chain reaction and Western blot analyses. Nude mouse xenografts were established to investigate the effect of Forkhead box F2 upregulation on the growth of colorectal cancer cells. Dual-luciferase reporter assays were performed to confirm the Forkhead box F2 regulation of PRUNE2 transcription. A series of in vitro assays was performed in cells with Forkhead box F2 upregulation and PRUNE2 knockdown to elucidate the function and regulatory effects of Forkhead box F2 on PRUNE2 transcription in colorectal cancer. Results: Forkhead box F2 was downregulated in colorectal cancer tissues compared with adjacent tissues. Forkhead box F2 overexpression significantly suppressed the proliferation and invasion of colorectal cancer cells in vitro and in vivo. Moreover, Forkhead box F2 directly targeted PRUNE2 to promote its transcription in colorectal cancer cells. Furthermore, PRUNE2 mediated the Forkhead box F2-regulated proliferation and invasion of colorectal cancer cells. Additionally, we demonstrated a significant positive correlation between Forkhead box F2 and PRUNE2 mRNA levels in colorectal cancer tissues. Conclusion: These results indicated that Forkhead box F2 and PRUNE2 in combination may serve as a prognostic biomarker for colorectal cancer and that Forkhead box F2 upregulation inhibits the proliferation and invasion of colorectal cancer cells by upregulating PRUNE2.

BACKGROUND: Prostate cancer antigen 3 (PCA3) is the most promising diagnostic biomarker for the differential diagnosis of prostate cancer identified to date. As a dominant-negative oncogene, PCA3 negatively regulates the expression of tumor suppressor PRUNE2 (a human homolog of the Drosophila prune gene) gene. Although interaction between PCA3-PRUNE2 was clearly reported, the precise mechanism how PCA3 is upregulated in prostate cancer remained highly elusive. Accordingly, here we aimed demonstrate the role of microRNAs in PCA3 upregulation and interplay between these miRNAs and PCA3-PRUNE2 axis.
RESULTS: We evaluated expression of PCA3, PRUNE2 and miRNAs by quantitative reverse transcription polymerase chain reaction. Overexpression and silencing of miRNAs were achieved by synthetic miRNA mimics and inhibitors, respectively. Colony formation, migration, apoptosis, and cell cycle assays were performed to reveal the effects of miRNA modulation. We identified that PCA3 expression was significantly downregulated in both prostate cancer tissues and cells and inversely correlated with the expressions of miR-19a and miR-421. Restoring the functions of miR-19a and miR-421 by miRNA mimics significantly downregulated the expression of PCA3 and promoted apoptosis and cell cycle blockade and interfered with the proliferation and migration in prostate cancer cells. Conversely, silencing the expressions of these miRNAs yielded the opposite effect.
CONCLUSIONS: Collectively, our results uncover a previously unrecognized novel mechanism on PCA3 upregulation in prostate cancer and proved that miR-19a and miR-421 might be responsible for the increased expression of PCA3, indicating that both miRNAs might be novel candidates for prostate cancer diagnosis and therapy.

Germline variants might predict cancer progression. Bevacizumab improves overall survival (OS) in patients with advanced cancers. No biomarkers are available to identify patients that benefit from bevacizumab. A meta-analysis of genome-wide association studies (GWAS) was conducted in 1,520 patients from Phase III trials (CALGB 80303, 40503, 80405 and ICON7), where bevacizumab was randomized to treatment without bevacizumab. We aimed to identify genes and single nucleotide polymorphisms (SNPs) associated with survival independently of bevacizumab treatment or through interaction with bevacizumab. A cause-specific Cox model was used to test the SNP-OS association in both arms combined (prognostic), and the effect of SNPs-bevacizumab interaction on OS (predictive) in each study. The SNP effects across studies were combined using inverse variance. Findings were tested for replication in advanced colorectal and ovarian cancer patients from The Cancer Genome Atlas (TGCA). In the GWAS meta-analysis, patients with rs680949 in PRUNE2 experienced shorter OS compared to patients without it (P = 1.02 × 10-7 , hazard ratio [HR] = 1.57, 95% confidence interval [CI] 1.33-1.86), as well as in TCGA (P = .0219, HR = 1.58, 95% CI 1.07-2.35). In the GWAS meta-analysis, patients with rs16852804 in BARD1 experienced shorter OS compared to patients without it (P = 1.40 × 10-5 , HR = 1.51, 95% CI 1.25-1.82) as well as in TCGA (P = 1.39 × 10-4 , HR = 3.09, 95% CI 1.73-5.51). Patients with rs3795897 in AGAP1 experienced shorter OS in the bevacizumab arm compared to the nonbevacizumab arm (P = 1.43 × 10-5 ). The largest GWAS meta-analysis of bevacizumab treated patients identified PRUNE2 and BARD1 (tumor suppressor genes) as prognostic genes of colorectal and ovarian cancer, respectively, and AGAP1 as a potentially predictive gene that interacts with bevacizumab with respect to patient survival.

PRUNE2 has been identified as a susceptible gene for Alzheimer\'s disease and a marker for leiomyosarcomas. Isoforms of Prune2 regulate neuronal cell differentiation and synaptogenesis. Although expression pattern of Prune2 has been reported in the murine brain, its expression patterns and regulation along vertebrate embryogenesis remain to be further investigated. We thus defined the expression profiles and transcriptional regulation of prune2 in zebrafish embryos. prune2 exhibits maternal expression, but is increased in later embryonic stages, and expressed in the telencephalon, epiphysis cluster, nucleus of the tract of the post optic commissure, spinal cord, cerebellum, tegmentum, anterior lateral line ganglion, posterior lateral line ganglion and rhombomeres 2 through 5. Two color WISH with a post-mitotic neuron specific marker, huC defined that prune2 is expressed in the post mitotic neurons. The level of prune2 transcripts is upregulated in Notch signaling homozygous mutant, mib1-/-(mibta52b), indicating that Notch signaling regulates transcription of prune2. Interestingly, in silico analysis of prune2 promoter found retinoic acid (RA) response elements (AGGTCAcaTGACCA) located at -3 to -16 relative to the first exon. It turned out that RA signaling altered the expression pattern of prune2 in the hindbrain. We further propose that Prune2 might be a putative regulator for CNS development in zebrafish embryogenesis.

BACKGROUND: Parathyroid carcinoma (PC) is a rare endocrine disorder, commonly causing severe primary hyperparathyroidism (PHPT). PC is mainly a sporadic disease, but it may occur in familial PHPT. Patients with PC usually present markedly elevated serum calcium and PTH. The clinical features are mostly due to the effects of the excessive secretion of PTH rather than to the spread of tumor. At times, the diagnosis can be difficult.
OBJECTIVE: The aim of this work is to review the available data on PC, and focus its molecular pathogenesis and the clinical utility of CDC73 genetic testing and immunostaining of its product, parafibromin. The pathological diagnosis of PC is restricted to lesions showing unequivocal growth into adjacent tissues or metastasis. Inactivating mutations of the cell division cycle 73 (CDC73) gene have been identified in up to 70 % of apparently sporadic PC and in one-third are germline. Loss of parafibromin immunostaining has been shown in most PC. The association of CDC73 mutations and loss of parafibromin predicts a worse clinical outcome and a lower overall 5- and 10-year survival.
CONCLUSIONS: The treatment of choice is the en bloc resection of the tumor. The course of PC is variable; most patients have local recurrences or distant metastases and die from unmanageable hypercalcemia.

Prostate cancer antigen 3 (PCA3) is the most specific prostate cancer biomarker but its function remains unknown. Here we identify PRUNE2, a target protein-coding gene variant, which harbors the PCA3 locus, thereby classifying PCA3 as an antisense intronic long noncoding (lnc)RNA. We show that PCA3 controls PRUNE2 levels via a unique regulatory mechanism involving formation of a PRUNE2/PCA3 double-stranded RNA that undergoes adenosine deaminase acting on RNA (ADAR)-dependent adenosine-to-inosine RNA editing. PRUNE2 expression or silencing in prostate cancer cells decreased and increased cell proliferation, respectively. Moreover, PRUNE2 and PCA3 elicited opposite effects on tumor growth in immunodeficient tumor-bearing mice. Coregulation and RNA editing of PRUNE2 and PCA3 were confirmed in human prostate cancer specimens, supporting the medical relevance of our findings. These results establish PCA3 as a dominant-negative oncogene and PRUNE2 as an unrecognized tumor suppressor gene in human prostate cancer, and their regulatory axis represents a unique molecular target for diagnostic and therapeutic intervention.