DICER1 hotspot mutations in non-epithelial gonadal tumours

Witkowski, Leora; Mattina, James; Schönberger, Stefan; Murray, Matthew J.; Choong, Catherine S.; Huntsman, David G.; Reis‐Filho, JS; McCluggage, W. Glenn; Nicholson, James C.; Coleman, Nicholas; Calaminus, Gabriele; Schneider, Dominik T.; Arseneau, Jocelyne; Stewart, Colin J.R.; Foulkes, William D.

doi:10.1038/bjc.2013.637

Cited by 113 publications

(108 citation statements)

References 32 publications

(56 reference statements)

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“…1). Previous studies have found frequent DICER1 p.E1705-D1709 and p.D1810-E1813 mutations in Sertoli-Leydig cell tumors (3,28). However, no DICER1 mutations were detected in the two patients with Sertoli-Leydig cell tumors.…”

Section: Resultsmentioning

confidence: 67%

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

et al. 2014

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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...

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Section: Resultsmentioning

confidence: 67%

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

et al. 2014

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“…DICER1 mutations are associated with pleuropulmonary blastoma, which is the most common lung tumor of infancy and early childhood, as well as with embryonal rhabdomyosarcoma of the uterine cervix, renal tumors, thyroid nodules and carcinoma, nasal chondromesenchymal hamartoma, ciliary body medulloepithelioma, pineoblastoma, and pituitary blastoma. 7,[10][11][12][13][14][15][16][17][18] Typically, these tumors have biallelic DICER1 mutations that are composed of a loss of function in one allele and a missense mutation in the RNase IIIb domain. Biallelic loss of function and missense RNase IIIb DICER1 mutations result in systemic loss of 5p-microRNAs that precludes regulation of growthpromoting gene programs.…”

Section: Dicer1mentioning

confidence: 99%

Ovarian Sex Cord-Stromal Tumors

Schultz

Harris

Schneider

et al. 2016

JOP

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“…Notably, although macrocephaly is common and severe in CS [11], it has recently been identified as a surprisingly common feature of the DICER1 syndrome as well (42% of mutation carriers are macrocephalic) [9]. The patient’s ovarian tumour was a malignant germ cell tumour, which would be highly unusual in the DICER1 syndrome [4]. To our knowledge, no cases of ovarian germ cell tumours have been reported in germ-line DICER1 mutation carriers.…”

Section: Discussionmentioning

confidence: 99%

“…To our knowledge, no cases of ovarian germ cell tumours have been reported in germ-line DICER1 mutation carriers. However, there are reports of somatic DICER1 RNase IIIb mutations in these tumours [3, 4]. Given that the diagnosis of ovarian tumours is often challenging [18], it should be kept in mind that in certain instances, DICER1 mutation analysis may assist in distinguishing between the types of non-epithelial ovarian cancers [19].…”

Section: Discussionmentioning

confidence: 99%

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A Case Report of Syndromic Multinodular Goitre in Adolescence: Exploring the Phenotype Overlap between Cowden and DICER1 Syndromes

Soglio

Kock²,

Gauci

et al. 2017

Eur Thyroid J

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Background: Hereditary tumour predisposition syndromes may increase the risk for development of thyroid nodules at a young age. We present the case of an adolescent female with Cowden syndrome who had some atypical phenotypic features which overlapped with the DICER1 syndrome. Material and Methods: A 17-year-old female presented with a 3-month history of progressive right neck swelling. Fine needle cytology of the thyroid revealed a follicular neoplasm with features suggestive of follicular variant of papillary thyroid carcinoma and she underwent a hemithyroidectomy. Enlarging nodules in the remaining thyroid led to a completion thyroidectomy at 19 years of age. The patient’s past medical history included an ovarian mixed malignant germ cell tumour, pulmonary nodules and cysts, renal cysts, mucocutaneous lesions, an arachnoid cyst, and a fibrous breast lesion. Macrocephaly was noted on physical examination. Results: Based on the patient’s complex phenotype and young age, a hereditary predisposition syndrome was suspected and genetic testing of PTEN and DICER1 was undertaken. A heterozygous truncating germ-line PTEN mutation was identified, which combined with clinical findings, met criteria for the diagnosis of Cowden syndrome. Additional loss of heterozygosity of the wild-type PTEN allele was detected in the right thyroid lesion and ovarian tumour. No DICER1 mutations were identified. Conclusions: Genetic testing was crucial in elucidating this patient’s predisposition to the early development of neoplastic and non-neoplastic conditions. Our report also highlights the phenotypic overlap between the Cowden and DICER1 syndromes and illustrates the importance of recognising the variable phenotypic features of hereditary syndromes in order to enable timely implementation of appropriate care.

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DICER1 hotspot mutations in non-epithelial gonadal tumours

Cited by 113 publications

References 32 publications

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

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

Ovarian Sex Cord-Stromal Tumors

A Case Report of Syndromic Multinodular Goitre in Adolescence: Exploring the Phenotype Overlap between Cowden and DICER1 Syndromes

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