Genomic characterization of sarcomatoid transformation in clear cell renal cell carcinoma

Abstract

The presence of sarcomatoid features in clear cell renal cell carcinoma (ccRCC) confers a poor prognosis and is of unknown pathogenesis. We performed exome sequencing of matched normal-carcinomatous-sarcomatoid specimens from 21 subjects. Two tumors had hypermutation consistent with mismatch repair deficiency. In the remainder, sarcomatoid and carcinomatous elements shared 42% of somatic single-nucleotide variants (SSNVs). Sarcomatoid elements had a higher overall SSNV burden (mean 90 vs. 63 SSNVs, P = 4.0 × 10 −4 ), increased frequency of nonsynonymous SSNVs in PanCancer genes (mean 1.4 vs. 0.26, P = 0.002), and increased frequency of loss of heterozygosity (LOH) across the genome (median 913 vs. 460 Mb in LOH, P < 0.05), with significant recurrent LOH on chromosomes 1p, 9, 10, 14, 17p, 18, and 22. The most frequent SSNVs shared by carcinomatous and sarcomatoid elements were in known ccRCC genes including von Hippel-Lindau tumor suppressor (VHL), polybromo 1 (PBRM1), SET domain containing 2 (SETD2), phosphatase and tensin homolog (PTEN). Most interestingly, sarcomatoid elements acquired biallelic tumor protein p53 (TP53) mutations in 32% of tumors (P = 5.47 × 10 −17 ); TP53 mutations were absent in carcinomatous elements in nonhypermutated tumors and rare in previously studied ccRCCs. Mutations in known cancer drivers ATrich interaction domain 1A (ARID1A) and BRCA1 associated protein 1 (BAP1) were significantly mutated in sarcomatoid elements and were mutually exclusive with TP53 and each other. These findings provide evidence that sarcomatoid elements arise from dedifferentiation of carcinomatous ccRCCs and implicate specific genes in this process. These findings have implications for the treatment of patients with these poor-prognosis cancers.

Programmed cell death ligand 1 and tumor‐infiltrating lymphocyte status in patients with renal cell carcinoma and sarcomatoid dedifferentiation

“…TCGA data revealed that mRNA CD274 upregulation was significantly correlated with mRNA upregulation of HLA genes and chemokine receptor, suggesting a close link between upregulation of PD-L1 and inflammatory tumor microenvironment in ccRCC. Although we could not find any significant correlation between mRNA upregulation of CD274 and gene alteration which was previously described in sRCC 29, 30 ,TCGA is not the ideal setting to study sRCC and contains only a few sRCC cases. In addition, data on sRCC in TCGA were obtained only from the epithelioid component.…”

Integration of Recurrent Somatic Mutations with Clinical Outcomes: A Pooled Analysis of 1049 Patients with Clear Cell Renal Cell Carcinoma

“…The association with lower RFS was not found to be significant in our multivariable models, which may highlight the importance of this mutation in those with stage IV disease. Other investigators have reported the enrichment of TP53 mutations in patients with metastatic disease [17] and in the aggressive sarcomatoid variant of ccRCC [18]. For the latter, we found TP53 to remain significant even when including this pathologic feature in a multivariable model.…”

Sarcomatoid Renal Cell Carcinoma Has a Distinct Molecular Pathogenesis, Driver Mutation Profile, and Transcriptional Landscape

“…For instance, the National Comprehensive Cancer Network guidelines do not distinguish between sarcomatoid tumors of clear cell or non-clear cell origin in terms of recommendations for management (6). Molecular characterization of SRCC has generally been limited to the clear cell subtype using targeted single platform studies (13,14,26,27). Our multiplatform, genome wide analysis shows subtype specific differences and that SRCC clusters according to parent subtype.…”

“…Genome wide molecular characterization of SRCC has heretofore been based on formalin-fixed, paraffin-embedded (FFPE) tissues and largely confined to the sarcomatoid ccRCC subtype (SccRCC) (11–14). …”