Preservation of truncal genomic alterations in clear cell and papillary renal cell carcinomas with sarcomatoid features: An intra‐ and intertumoral, multifocal fluorescence in situ hybridization analysis reveals limited genetic heterogeneity

Abstract

Understanding tumor genomic heterogeneity may offer vital information in an age of targeted therapy for renal cell carcinoma. We sought to investigate hallmark truncal chromosomal alterations between conventional, sarcomatoid, and matched metastatic tumor foci in clear cell and papillary renal cell carcinomas. A retrospective review identified 58 cases including clear cell (CCRCC) and papillary renal cell carcinomas (PRCC). All cases contained sarcomatoid transformation. Additionally, 10 of 58 patients had matched metastatic disease available for analysis. Three separate foci of conventional and sarcomatoid morphologies were analyzed in each tumor using dual color interphase fluorescence in situ hybridization. In the CCRCC cohort, hallmark chromosome 3p deletion was identified in 71% of cases (37/52). Complete concordance of chromosomal status between intratumoral foci in sarcomatoid and conventional foci was 89% and 86%, respectively. Overall chromosome 3p status between matched conventional and sarcomatoid morphologies was identified in 98% of cases (51/52). Hallmark 3p deletion was present in 91% of CCRCC metastatic samples (10/11) and was concordant with the matched primary CCRCC tumor in 91% (10/11). In the PRCC cohort, trisomy 7 and 17 was identified in all six cases (6/6). Complete concordance between intratumoral foci of trisomy 7 and 17 was 83% (5/6). Trisomy 7 and 17 were identified in all metastatic PRCC samples with 100% concordance with the matched primary tumor. These data show the relative preservation of truncal chromosomal abnormalities between conventional and sarcomatoid morphologic as well as matched metastatic settings.

Clinicopathologic and Immunohistochemical Characterization of Sarcomatoid Chromophobe Renal Cell Carcinoma

“…EZH2 activation can promote the development of metastatic disease and preclinical studies have demonstrated that EZH2 inhibitors attenuate some renal diseases 41. Other studies that have investigated the genomics of sarcomatoid carcinoma have not revealed driver mutations, but increased expression of programmed cell death protein 1 and PD-L1 has been shown 42,43. Clinical trials have shown efficacy with anti–programmed cell death protein 1 and anti–vascular endothelial growth factor (vs. sunitinib) combination first-line 44.…”

“…41 Other studies that have investigated the genomics of sarcomatoid carcinoma have not revealed driver mutations, but increased expression of programmed cell death protein 1 and PD-L1 has been shown. 42,43 Clinical trials have shown efficacy with anti-programmed cell death protein 1 and endothelial growth factor (vs. sunitinib) combination first-line. 44 Immunohistochemical expression of antibodies directed against PD-L1 have been demonstrated in sarcomatoid renal cell carcinoma (not otherwise specified) 45,46 and clear cell renal carcinoma 9,[47][48][49] and to a lesser extent sarcomatoid papillary renal cell carcinoma, 47,49,50 and sarcomatoid ChRCC.…”

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

“…p1RCC is typically smaller, lower grade, more indolent, and less metastatic than p2RCC [55]. Sporadic p1RCC is associated with MET gene alteration, whereas sporadic p2RCC is characterized by CDKN2A silencing, SETD2 mutations, NF2 mutations, CUL3 mutations, TERT promoter mutations, increased expression of the NRF2-antioxidant pathway, and gains of chromosomes 7, 12, 16, and 17 [9,[56][57][58][59][60]. Hereditary p1RCC is characterized by bilateral, multifocal tumors and germline MET activation mutations [61,62].…”

“…The term 'translation oncology' emphasizes 'the application of learned research knowledge for the improvement of human cancer care'. Facing the ever-increasing complexity of treatment modalities [1] and the demonstrated marked tumor heterogeneity [60,[85][86][87] in RCC, the notion of applying molecular pathology to future patient management is exciting yet challenging [6]. Here, we illustrate some recent human RCC cancer genomic advances that might have translational values through which they could complement current histological subtypes [65,88] and refine prevalent risk-stratification schemes [89][90][91].…”

“…One of the striking discoveries in ccRCC genomics was the close genomic localization of four prevalent tumor suppressor genes, VHL , PBRM1 , SETD2 , and BAP1 , spanning chromosome 3p21–3p25 that is lost in more than 90% of ccRCCs . Hence, the near universal singular chromosome 3 short arm loss in ccRCC results in a simultaneous one‐copy loss of four tumor suppressors, which is unprecedented . Furthermore, the fact that PBRM1 , SETD2 , and BAP1 encode chromatin‐ and histone‐regulating tumor suppressor proteins suggests epigenetic dysregulation as a convergent pathogenic theme in ccRCC .…”