Genomic Characterization of Renal Medullary Carcinoma and Treatment Outcomes

Abstract

Background Renal medullary carcinoma (RMC) is a rare and aggressive type of kidney cancer that primarily affects young adults with sickle cell trait; outcomes are poor despite treatment. Identifying molecular features of this tumor could provide biologic rationale for novel targeted therapies. The objective was to report on clinical outcomes with systemic therapy and characterize molecular features. Patients and Methods This was a retrospective analysis on 36 patients given a pathologic diagnosis of RMC at one institution from 1995 to 2015. Tumors were analyzed for expression of SMARCB1 through immunohistochemistry and for genomic alterations with fluorescence in situ hybridization for SMARCB1, and targeted next-generation sequencing. Time from initiation of therapy to progression of disease and overall survival were calculated using Kaplan-Meier method. Results and limitations The median age in the cohort was 28 years (range 12–72), and all patients tested had sickle cell trait. Overall survival was 5.8 months (95% CI 4.1–10.9) and for 12 patients who received platinum-based therapy, median progression-free survival was 2.5 months (95% CI 1.2-Not Reached). A total of 10 available tumors underwent analysis with fluorescence in situ hybridization for SMARCB1; this revealed loss of heterozygosity with concurrent translocation in 8, and biallelic loss in 2. Next-generation targeted sequencing showed no recurring mutations. Conclusions Outcome was generally poor in this cohort of patients with RMC. Uniform loss of SMARCB1 is a key molecular feature in this tumor and mechanism of loss appears to be mostly through translocations and deletions.

Non-Clear Cell Renal Cell Carcinoma - Pathology and Treatment Options

“…There is a high genetic overlap with proximal urothelial cancer [39]. No specific mutations are currently known because of small patient numbers; however, in medullary RCC, loss of SMARCB1 [40] or mutations in the ALK gene have been described [41]. A therapeutically targetable genetic mutation is the amplification of the BCR and ABL genes, known from chronic myeloid leukemia, even if BCR/ABL amplifications are only present in a small number of patients with this subtype [39].…”

Genomic classifications of renal cell carcinoma: a critical step towards the future application of personalized kidney cancer care with pan‐omics precision

“…Medullary RCC (mdRCC) occurs in patients with sickle cell hemoglobinopathy . mdRCC is diagnosed with the loss of nuclear staining for the SMARCB1/INI1 tumor suppressor protein , resulting from either loss of heterozygosity (LOH) and balanced translocations or biallelic loss . TFE‐3 or TEF‐B translocation‐associated RCCs (tfeRCCs) exhibit varied histology from clear cell morphology to papillary architecture .…”

High grade infiltrative adenocarcinomas of renal cell origin: New insights into classification, morphology, and molecular pathogenesis

“…Extending these findings to a larger cohort, Carlo et al . have recently observed SMARCB1 rearrangements by FISH in 8/10 tumors tested, with the remaining cases showing biallelic loss of SMARCB1 …”

“…31 Extending these findings to a larger cohort, Carlo et al have recently observed SMARCB1 rearrangements by FISH in 8/10 tumors tested, with the remaining cases showing biallelic loss of SMARCB1. 32 In light of the molecular knowledge lent by these recent studies, the question arises as to whether this carcinoma, in an appropriate morphologic context, is more defined by "SMARCB1-opathy" or by the clinical scenario of hemoglobinopathy. In this regard we have recently studied a group of rare tumors that seem to straddle the molecular and clinical criteria for RMC, principally by being morphologically appropriate tumors for an RMC diagnosis, demonstrating loss of SMARCB1 by immunohistochemistry, yet arising in patients where sickle cell trait or disease has been excluded rigorously.…”