DICER1 mutations in childhood cystic nephroma and its relationship to DICER1-renal sarcoma

Abstract

The pathogenesis of cystic nephroma of the kidney has interested pathologists for over 50 years. Emerging from its initial designation as a type of unilateral multilocular cyst, cystic nephroma has been considered as either a developmental abnormality or a neoplasm or both. Many have viewed cystic nephroma as the benign end of the pathologic spectrum with cystic partially differentiated nephroblastoma and Wilms tumor, while others have considered it a mixed epithelial and stromal tumor. We hypothesize that cystic nephroma, like the pleuropulmonary blastoma in the lung, represents a spectrum of abnormal renal organogenesis with risk for malignant transformation. Here we studied DICER1 mutations in a cohort of 20 cystic nephromas and 6 cystic partially differentiated nephroblastomas, selected independently of a familial association with pleuropulmonary blastoma and describe four cases of sarcoma arising in cystic nephroma, which have a similarity to the solid areas of type II or III pleuropulmonary blastoma. The genetic analyses presented here confirm that DICER1 mutations are the major genetic event in the development of cystic nephroma. Further, cystic nephroma and pleuropulmonary blastoma have similar DICER1 loss of function and “hotspot” missense mutation rates which involve specific amino acids in the RNase IIIb domain. We propose an alternative pathway with the genetic pathogenesis of cystic nephroma and DICER1-renal sarcoma paralleling that of type I to type II/III malignant progression of pleuropulmonary blastoma.

Nasal chondromesenchymal hamartomas arise secondary to germline and somatic mutations of DICER1 in the pleuropulmonary blastoma tumor predisposition disorder

“…This appears to be similar to the historical experience with DICER1 -associated cystic nephroma (CN) and in contrast to the natural history of lung cysts where there is a known risk for progression to high grade sarcoma (Priest et al 1997; Priest et al 2006). As a potential note of caution, sarcomatous transformation in CN has been recently described in DICER1 mutation carriers (Doros et al 2014) and a recent report documents one adult patient with malignant transformation in an NCMH (Li et al 2013b). …”

“…However, phased (determination of cis or trans ) biallelic DICER1 mutations or loss of heterozygosity of DICER1 has been established only in Wilms tumor (Wu et al 2013), pineoblastoma (Sabbaghian et al 2012), SLCT (Heravi-Moussavi et al 2012), primitive germ-cell tumor of the yolk-sac type (Heravi-Moussavi et al 2012) and PPB (Pugh et al 2014). Somatic missense mutations of certain “hotspot” residues (E1705, D1709, G1809, D1810 and E1813) have been detected in CN (Doros et al 2014), SLCT, nonseminomatous testicular germ-cell tumors, ERMS and rare epithelial ovarian and endometrial carcinomas (Heravi-Moussavi et al 2012) and PPB (de Kock et al 2013; Pugh et al 2014). The hotspot mutations affect amino acids in the DICER1 RNase IIIb domain, the protein site that is critical for miRNA interaction and cleavage of mature miRNA from the 5’ arm of the precursor miRNA hairpin.…”

Ovarian Sex Cord-Stromal Tumors

“…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.…”

Gene mutations in Cushing's disease

“…Hill et al (44) suggested that almost all patients with pleuropulmonary blastoma exhibit germline mutations of DICER1. In addition, mutations in DICER1 are involved in the development of cystic nephroma (45). As mutated DICER1 participates in diverse types of tumors, previous studies have indicated that DICER1 mutations result in tumors of the pituitary gland.…”