Balanced Translocations Disrupting SMARCB1 Are Hallmark Recurrent Genetic Alterations in Renal Medullary Carcinomas

Abstract

Background

Renal medullary carcinoma (RMC) is a rare and highly aggressive neoplasm that most often occurs in the setting of sickle cell trait or sickle cell disease (SCD). Most patients present with metastatic disease resistant to conventional chemotherapy, and therefore there is an urgent need for molecular insight to propose new therapies.

Objective

To determine the molecular alterations and oncogenic pathways that drive RMC development.

Design, setting, and participants

A series of five frozen samples of patients with RMC was investigated by means of gene expression profiling, array comparative genomic hybridization, and RNA and whole exome sequencing (WES).

Outcome measurements and statistical analysis

RNA and DNA sequencing read data were analyzed to detect gene fusions and somatic mutations. Gene fusions mutations were validated by real-time polymerase chain reaction and fluorescence in situ hybridization. Gene expression profiling was analyzed by unsupervised hierarchical clustering and Gene Set Enrichment Analysis (Broad Institute, Cambridge, MA, USA).

Results and limitations

We observed inactivation of the tumor suppressor gene SMARCB1 in all tumors. In all four cases developed in patients with SCD, we identified an original mechanism of interchromosomal balanced translocations that disrupt the SMARCB1 sequence and thus contribute to its inactivation. Gene expression profiling revealed that RMC shares common oncogenic pathways with pediatric malignant rhabdoid tumors, another tumor subtype characterized by SMARCB1 deficiency.

Conclusions

RMCs are characterized by an original mechanism of interchromosomal balanced translocations that disrupt the SMARCB1 sequence. WES reveals that RMCs show no other recurrent genetic alteration and an overall stable genome, underscoring the oncogenic potency of SMARCB1 inactivation.

Patient summary

Our comprehensive molecular study supports a pivotal role of the tumor suppressor gene SMARCB1 in the development of renal medullary carcinoma. The use of therapeutic strategies based on the biologic effects of its inactivation should now open new perspectives for this typically lethal malignancy.

Introduction

Renal medullary carcinoma (RMC) is a rare and highly malignant neoplasm that most often occurs in teenagers or young adults with sickle cell trait or disease (hereafter, SCD) [1]. RMCs have a very poor prognosis. Most patients present with metastatic disease resistant to conventional chemotherapy, and a fatal outcome occurs within a few months [1]. There is therefore an urgent need for molecular insight to propose new therapies.

The only recurrent alteration reported so far in RMC is BAF47 loss of immunohistochemical expression [2], [3], [4]. BAF47, encoded by the SMARCB1 gene, is a core component of the ubiquitous SWI/SNF complex that regulates gene transcription by modifying positions of nucleosomes and occupancy along the chromatin [5], [6]. Inactivation of this tumor suppressor gene was first identified in malignant rhabdoid tumors (RTs) [7], a highly aggressive pediatric neoplasm originally described in the kidney.

RTs constantly show biallelic inactivation of SMARCB1 through truncating mutations and/or deletions that invariably results in BAF47 loss of expression [7]. The complete abrogation of SMARCB1 dramatically impairs SWI/SNF function and thus the transcription of genes involved in the cell cycle or differentiating programs [5], [8], [9]. In RMC, however, only hemizygous deletions of SMARCB1 have been reported so far [2], [3]. Hence whether BAF47 loss is a genuine driver for RMC oncogenesis remains elusive, and the molecular mechanisms that underlie RMC development are overall poorly understood.

By investigating five cases of this very rare malignancy by means of array comparative genomic hybridization (array CGH), whole exome sequencing (WES), and RNA sequencing (RNA-seq), our study aimed to determine the molecular alterations that drive RMC development.