Collecting duct carcinoma of the kidney is associated with CDKN2A deletion and SLC family gene up-regulation.

Jianmin Wang,Manuela Costantini,Carl Morrison,Biao Liu,Song Liu,Sean T Glenn,Qiang Hu,Michele Gallucci,Sreenivasulu Chintala,Jeffrey M Conroy,Maria Luana Poeta,Lei Wei,Steno Sentinelli,Sabina Signoretti,Kiersten Marie Miles,Cristina Magi‐Galluzzi ,Toni K Choueiri ,Antonios Papanicolau‐Sengos ,Vito Michele Fazio ,Роберто Пили

doi:10.18632/oncotarget.9093

Abstract

The genetic landscape and molecular features of collecting duct carcinoma (CDC) of the kidney remain largely unknown. Herein, we performed whole exome sequencing (WES) and transcriptome sequencing (RNASeq) on 7 CDC samples (CDC1 −7). Among the 7 samples, 4 samples with matched non-tumor tissue were used for copy number analysis by SNP array data. No recurrent somatic SNVs were observed except for MLL, which was found to be mutated (p.V297I and p.F407C) in 2 samples. We identified somatic SNVs in 14 other cancer census genes including: ATM, CREBBP, PRDM1, CBFB, FBXW7, IKZF1, KDR, KRAS, NACA, NF2, NUP98, SS18, TP53, and ZNF521. SNP array data identified a CDKN2A homozygous deletion in 3 samples and SNV analysis showed a non-sense mutation of the CDKN2A gene with unknown somatic status. To estimate the recurrent rate of CDKN2A abnormalities, we performed FISH screening of additional samples and confirmed the frequent loss (62.5%) of CDKN2A expression. Since cisplatin based therapy is the common treatment option for CDC, we investigated the expression of solute carrier (SLC) family transporters and found 45% alteration. In addition, SLC7A11 (cystine transporter, xCT), a cisplatin resistance associated gene, was found to be overexpressed in 4 out of 5 (80%) cases of CDC tumors tested, as compared to matched non-tumor tissue. In summary, our study provides a comprehensive genomic analysis of CDC and identifies potential pathways suitable for targeted therapies.

Highlights

Collecting duct renal carcinoma (CDC), known as Bellini duct carcinoma, is a rare histological subtype of renal cell carcinoma with unique clinical, histological, and pathological characteristics [1,2,3]
Since cisplatin based therapy is the common treatment option for collecting duct carcinoma (CDC), we investigated the expression of solute carrier (SLC) family transporters and found 45% alteration
To determine the genetic alterations associated with chemo sensitivity, a preclinical study with human cell lines established from CDC patients revealed topoisomerase I (TOPI) expression to be associated with high in vitro sensitivity to TOPI and TOPII inhibitors, such as topotecan, doxorubicin, and epirubicin, suggesting TOP1 as a potential molecular target for CDC [12]

Summary

Introduction

Collecting duct renal carcinoma (CDC), known as Bellini duct carcinoma, is a rare histological subtype (less than 2%) of renal cell carcinoma with unique clinical, histological, and pathological characteristics [1,2,3]. These tumors arise from the distal collecting ducts and are positioned in the renal pelvis with a gray or whitish appearance without considerable necrosis or hemorrhage [2, 3]. To determine the genetic alterations associated with chemo sensitivity, a preclinical study with human cell lines established from CDC patients revealed topoisomerase I (TOPI) expression to be associated with high in vitro sensitivity to TOPI and TOPII inhibitors, such as topotecan, doxorubicin, and epirubicin, suggesting TOP1 as a potential molecular target for CDC [12]

Methods

Results

Conclusion