Genomic Analysis Reveals Novel Specific Metastatic Mutations in Chinese Clear Cell Renal Cell Carcinoma

Abstract

Clear cell renal cell carcinoma (ccRCC) accounts for more than 75% of renal cell carcinoma. Nearly 25% of ccRCC patients were diagnosed with metastasis. Though the genomic profile of ccRCC has been widely studied, the difference between localized and metastatic ccRCC was not clarified. Primary tumor samples and matched whole blood were collected from 106 sporadic patients diagnosed with renal clear cell carcinoma at Qilu Hospital of Shandong University from January 2017 to November 2019, and 17 of them were diagnosed with metastasis. A hybridization capture-based next-generation sequencing of 618 cancer-related genes was performed to investigate the somatic and germline variants, tumor mutation burden (TMB), and microsatellite instability (MSI). Five genes with significantly different prevalence were identified in the metastatic group, especially TOP1 (17.65% vs. 0%) and SNCAIP (17.65% vs. 0%). The altered frequency of PBRM1 (0% vs. 27%) and BAP1 (24% vs. 10%) differed between the metastatic and nonmetastatic groups, which may relate to the prognosis. Of these 106 patients, 42 patients (39.62%) had at least one alteration in DNA damage repair (DDR) genes, including 58.82% of metastatic ccRCC patients and 35.96% of ccRCC patients without metastasis. Ten pathogenic or likely pathogenic (P/LP) variants were identified in 11 sporadic clear cell renal cell carcinoma patients (10.38%), including rarely reported ATM (n=1), MUTYH (n=1), NBN (n=1), RAD51D (n=1), and BRCA2 (n=1). No significant difference in the ratio of P/LP variant carriers or TMB was identified between the metastatic and nonmetastatic groups. We found a unique genomic feature of Chinese metastatic ccRCC patients with a higher prevalence of alterations in DDR, TOP1, and SNCAIP. Further investigated studies and drug development are needed in the future.

Exploration of Morphological Features of Clear Cell Renal Cell Carcinoma With PBRM1, SETD2, BAP1, or KDM5C Mutations

“…A genomic study sequenced 106 clear cell RCCs and found no altered PBRM1 in the metastatic group and a relatively high frequency of BAP1 (24% vs 10%) between the metastatic and non-metastatic groups. 20 Other studies have shown that mutated BAP1 , but not PBRM1 , correlates with decreased survival in clear cell RCC. 1 A model for clear cell RCC development proposed that the PBRM1 mutation results in low-grade clear cell RCC, whereas the BAP1 mutation results in high-grade clear cell RCC.…”

Identification of pathogenic germline variants in a large Chinese lung cancer cohort by clinical sequencing

“…To sum up, the two genes may not be lung cancer specific susceptible genes, and the association of their P/LP variants and cancer risk warrants further investigation. In terms of the other two significant variants in the case–control analysis (FDR < 0.05), germline BRIP p.L340F variant was detected in breast cancer patients [ 71 ] and MUTYH p.R19* variant was detected in patients with colorectal cancer [ 72 ], clear cell renal cell carcinoma [ 73 ], and breast cancer [ 74 ].…”

Development and validation of the prognostic value of the immune-related genes in clear cell renal cell carcinoma

“…Low expression of TEK has been noted in aggressive ccRCC for years (41). Recently, when compared gene prevalence between nonmetastatic and metastatic ccRCC by target next generation sequencing from 106 sporadic cases, higher frequencies of TEK mutations involved in metastatic cohort (42). Since Tie2 signaling influences vascular permeability, low expression of Tie2 may potentiate inflammatory cells migration into tumor microenvironment (43).…”