Noncoding RNA Expression and Targeted Next-Generation Sequencing Distinguish Tubulocystic Renal Cell Carcinoma (TC-RCC) from Other Renal Neoplasms

Abstract

Tubulocystic renal cell carcinoma (TC-RCC) is a rare recently described renal neoplasm characterized by gross, microscopic, and immunohistochemical differences from other renal tumor types and was recently classified as a distinct entity. However, this distinction remains controversial particularly because some genetic studies suggest a close relationship with papillary RCC (PRCC). The molecular basis of this disease remains largely unexplored. We therefore performed noncoding (nc) RNA/miRNA expression analysis and targeted next-generation sequencing mutational profiling on 13 TC-RCC cases (11 pure, two mixed TC-RCC/PRCC) and compared with other renal neoplasms. The expression profile of miRNAs and other ncRNAs in TC-RCC was distinct and validated 10 differentially expressed miRNAs by quantitative RT-PCR, including miR-155 and miR-34a, that were significantly down-regulated compared with PRCC cases (n = 22). With the use of targeted next-generation sequencing we identified mutations in 14 different genes, most frequently (>60% of TC-RCC cases) in ABL1 and PDFGRA genes. These mutations were present in <5% of clear cell RCC, PRCC, or chromophobe RCC cases (n > 600) of The Cancer Genome Atlas database. In summary, this study is by far the largest molecular study of TC-RCC cases and the first to investigate either ncRNA expression or their genomic profile. These results add molecular evidence that TC-RCC is indeed a distinct entity from PRCC and other renal neoplasms.

WHO/ISUP classification, grading and pathological staging of renal cell carcinoma: standards and controversies

“…These tumours express AMACR and CK7 on immunohistochemistry. On molecular analysis, there have been conflicting reports, but in recent series of RCCs with a pure tubulocystic morphology, trisomy of chromosomes 7 and 17 observed in papillary RCCs was not present and these tumours have also been shown to have a molecular signature distinct from the more common RCC tumour types [45–47]. Other tumours may show areas with a tubulocystic pattern, including papillary RCCs, hereditary leiomyomatosis renal cell carcinoma-associated RCC, the MiT family translocation RCCs, collecting duct carcinoma and unclassified RCCs, causing diagnostic difficulty, but such tumours with mixed morphology are not included in this tumour category.…”

Current Concepts of Non-Coding RNAs in the Pathogenesis of Non-Clear Cell Renal Cell Carcinoma

“…One study focused on tcRCC and compared miRNA expression levels with other RCC subtypes, namely ccRCC, pRCC and ccpRCC [107]. miR-138, miR-200c and miR-182 were found to be upregulated in tcRCC compared to the other subtypes; however, the difference for miR-182 was not significant [107].…”

“…Additionally, downregulated expressions of miR-210, miR-34a and miR-155 were noted; however, only the expression levels of miR-155 were significantly decreased compared to both ccRCC and pRCC, whereas miR-210 and miR-34a were significantly downregulated compared to both ccRCC or pRCC [107]. The roles of miR-155 and miR-210 in cancer have already been discussed.…”

Genetic Alterations in Renal Cancers: Identification of The Mechanisms Underlying Cancer Initiation and Progression and of Therapeutic Targets

“…Recent studies support the existence of TCRCC as a rare peculiar subtype of RCC. In fact, Lawrie et al performed miRNA expression analysis and targeted next-generation sequencing mutational profiling on 13 cases of TCRCC: the expression profile of some miRs, such as miR-155 and miR-34a , that were downregulated was clearly different from that observed in PRCC; the gene sequencing showed recurrent mutations of ABL1 and PDGFRA genes, both genes being only rarely mutated in other RCC types [ 198 ]. More recently, Sarungbam et al performed a molecular characterization of 10 cases of pure TCRCC by targeted next-generation sequencing and FISH analysis for X and Y chromosomes: all these carcinomas displayed combined losses at chromosomes 9 and gains at chromosome 17 , and loss of chromosome Y; none of these tumors displayed mutational profiles typical of other RCCs; recurrent mutations in chromatin-modifying genes, KMT2C and KDM5C , were detected in about 25% of tumors; non ABL1 and PDGFRA mutations were detected [ 199 ].…”