Absence of DICER1, CTCF, RPL22, DNMT3A, TRRAP, IDH1 and IDH2 hotspot mutations in patients with various subtypes of ovarian carcinomas

Abstract

Abstract.Cancer is caused by multiple genetic alterations within cells. Recently, large-scale sequencing has identified frequent ribonuclease type III (DICER1), CCCTC-binding factor (CTCF), ribosomal protein L22 (RPL22), DNA (cytosine-5-)-methyltransferase 3α (DNMT3A), transformation/transcription domain-associated protein (TRRAP), isocitrate dehydrogenase (IDH)1 and IDH2 hotspot mutations in diverse types of cancer. However, it remains largely unknown whether these mutations also exist in ovarian carcinomas. In the present study, a collection of 251 patients with distinct subtypes of ovarian carcinomas were recruited and sequenced for the presence of these hotspot mutations. However, no mutations in the seven genes were detected in the samples. These negative results, together with certain recent reports, indicate that the hotspot mutations in the CTCF, RPL22, DNMT3A, TRRAP, IDH1 and IDH2 genes may not be actively involved in the carcinogenesis of ovarian carcinoma. Of note, the DICER1 mutation frequency in Sertoli-Leydig cell tumor in the present study was significantly lower compared to prior observation, and therefore, it is speculated that this discrepancy may be mainly due to the small sample size analyzed in the study. In addition, among these samples, frequent polymerase (DNA directed) ε, catalytic subunit (POLE1) and ring finger protein 43 (RNF43) mutations were identified in endometrioid and mucinous ovarian carcinomas, respectively; thus DICER1, CTCF, RPL22, DNMT3A, TRRAP, IDH1 and IDH2 hotspot mutations may not play synergistic roles with POLE1 or RNF43 mutations in the carcinogenesis of endometrioid or mucinous ovarian carcinomas. IntroductionThe current understanding of human malignancy is that it mainly arises due to the accumulation of multiple genetic alterations, transforming normal cells into malignant cells (1,2). Of these genetic alterations, a myriad of genomic mutation data derived from a high-throughput DNA sequencing technique provided a unique opportunity to profile the mutation spectra underlying human cancers and a large number of significant functional mutations in multiple genes were identified in diverse types of cancer (1,3,4). These genes can be defined as oncogenes or tumor suppressor genes and are being used as molecular markers for diagnosis, staging and prognosis of human cancers (5,6).Ovarian carcinoma constitutes a heterogeneous group of malignancies with significantly different clinical expression, pathological characteristics and genetic etiology (7,8). However, the majority of ovarian carcinomas shared certain common genetic alterations, such as frequent tumor protein p53 (TP53) and PIK3CA, catalytic subunit α mutations (9,10), and patients also exhibited subtype-specific mutations (11-13), which are possibly essential for the differential clinical expression and molecular-targeted therapy in ovarian carcinomas (14,15). These observations emphasized the requirement to identify novel subtype-specific molecular genetic aberrations in ovarian carcinomas.Recently, large-scal...

Spectrum of DICER1 Germline Pathogenic Variants in Ovarian Sertoli–Leydig Cell Tumor

“…In recent years, many studies have investigated the molecular basis of ovarian SLCT. Consistent literature data support the role of DICER1 in the disease pathogenesis [13,14,[34][35][36][37][38][39][40][41][42].…”

“…In the recent years, many studies have investigated the molecular basis of ovarian SCST [ 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 ]. In 2012, using a combination of whole transcriptome and whole exome sequencing analyses, Heravi-Moussavi et al sequenced 14 non-epithelial ovarian tumors identifying closely clustered missense mutations in the region of DICER1 gene encoding the RNase IIIb domain in a total of four samples [ 35 ].…”

The role of MicroRNA molecules and MicroRNA-regulating machinery in the pathogenesis and progression of epithelial ovarian cancer

“…Examination of copy number loss of DICER in TCGA datasets revealed frequent loss of DICER in high-grade serous EOC, consistent with low levels of expression and association with poor clinical outcome (10). However, DICER functional mutations are not recurrent in high-grade serous ovarian cancer (16, 35, 36). Liang et al (37) studied single nucleotide polymorphisms from 8 miRNA processing genes and 134 microRNA-binding sites in genes in 339 EOC cases and 349 healthy controls.…”

Downregulation of DNMT3a expression increases miR-182-induced apoptosis of ovarian cancer through caspase-3 and caspase-9-mediated apoptosis and DNA damage response

“…mRNAs encoding three types of DNA methyltransferase genes and the protein expressed by them are highly expressed (15). Furthermore, a large number of studies indicate that the three can lead to abnormal DNA methylation of suppressor genes in cancer cells and silencing through direct or synergistic effects (15,16). Consequently, DNA transmethylase plays an important role in methylation start-up and maintenance in tumor cells.…”