Molecular analysis of aggressive renal cell carcinoma with unclassified histology reveals distinct subsets

Abstract

Renal cell carcinomas with unclassified histology (uRCC) constitute a significant portion of aggressive non-clear cell renal cell carcinomas that have no standard therapy. The oncogenic drivers in these tumours are unknown. Here we perform a molecular analysis of 62 high-grade primary uRCC, incorporating targeted cancer gene sequencing, RNA sequencing, single-nucleotide polymorphism array, fluorescence in situ hybridization, immunohistochemistry and cell-based assays. We identify recurrent somatic mutations in 29 genes, including NF2 (18%), SETD2 (18%), BAP1 (13%), KMT2C (10%) and MTOR (8%). Integrated analysis reveals a subset of 26% uRCC characterized by NF2 loss, dysregulated Hippo–YAP pathway and worse survival, whereas 21% uRCC with mutations of MTOR, TSC1, TSC2 or PTEN and hyperactive mTORC1 signalling are associated with better clinical outcome. FH deficiency (6%), chromatin/DNA damage regulator mutations (21%) and ALK translocation (2%) distinguish additional cases. Altogether, this study reveals distinct molecular subsets for 76% of our uRCC cohort, which could have diagnostic and therapeutic implications.

Genomic landscape and evolution of metastatic chromophobe renal cell carcinoma

“…Thus, TP53 mutation, PTEN mutation, and ICD might have prognostic value in chRCC. Likewise, BAP1, PBRM1, SETD2, and TP53 mutations in ccRCC (43)(44)(45), the CpG island methylator phenotype (CIMP) in pRCC (4), and the NF2 mutations in uRCC (8) are genomic features that have been shown to carry clinical significance in an RCC-subtype-specific manner. Thus far, all these genomic discoveries were made in retrospective studies utilizing archived tumor samples, which warrant further validation.…”

“…Renal cell carcinoma (RCC) consists of morphologically, molecularly, and clinically distinct subtypes, including clear cell RCC (ccRCC, ~75%), papillary RCC (pRCC, ~15%), chromophobe RCC (chRCC, ~5%), unclassified RCC (uRCC, ~5%), and few extremely rare entities such as medullary RCC (mdRCC) and MiT-translocation RCC (tRCC) (<1% each) (1)(2)(3)(4)(5)(6)(7)(8)(9). ChRCC is relatively indolent despite its usual presentation as larger tumors (10), yet ~5%-10% of patients eventually develop metastases (11,12).…”

Renal cell carcinoma

“…1). The remaining subtypes are very rare (each with ≤1% total incidence) 5 and in cases where a tumour does not fit any subtype diagnostic criteria, it is designated as unclassified RCC (uRCC, ~4% total incidence) 10 . ccRCC is the most common subtype and accounts for the majority of kidney cancer deaths and is the focus of this Primer 11 .…”

Overcome tumor heterogeneity-imposed therapeutic barriers through convergent genomic biomarker discovery: A braided cancer river model of kidney cancer

“…Major subtypes are clear cell RCC (ccRCC; ~75%) [38], papillary RCC (pRCC, ~15%) [39], and chromophobe RCC (chRCC, ~5%) [37, 40–43]. Unclassified RCC (uRCC) accounts for 4–5% of RCC that is not classifiable [36, 44] as one of the major (>5%) or the rare (<1%) subtypes such as medullary, collecting duct, mucinous tubular and spindle cell carcinoma, and MiTF family translocation renal cell carcinoma [36, 45]. Importantly, individual histological subtypes of RCC carry distinct clinical histories and therapeutic outcomes [37, 46], highlighting the importance of microscopic heterogeneity.…”

“…Recent molecular technologies, especially NGS, have begun to provide molecular details concerning individual RCC subtypes [24, 37–39, 44, 47]. As ccRCC is most prevalent, most lethal, and best studied among RCC [27], we focus on the molecular heterogeneity of ccRCC in this section.…”