Abstract
BackgroundClear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cancer and one of the most common cancers. While survival for localized ccRCC is good, the survival of metastatic disease is not, and thirty percent of patients with ccRCC develop metastases during follow-up. Although current scoring methods accurately identify patients at low progression risk, a small subgroup of those patients still experience metastasis. We therefore aimed to identify ccRCC progression biomarkers in “low-risk” patients who were potentially eligible for adjuvant treatments or more intensive follow-up.MethodsWe assembled a cohort of ccRCC patients (n = 443) and identified all “low-risk” patients who later developed progressing tumors (n = 8). Subsequently, we performed genome-wide expression profiling from formalin-fixed samples obtained at initial surgery from these “low-risk” patients and 16 matched patients not progressing to recurrence with metastasis. The patients were matched for Leibovich sore, creatinine, age, sex, tumor size and tumor stage. Key results were confirmed with qPCR and external data from The Cancer Genome Atlas.ResultsPrincipal component analysis indicated that systematic transcriptomic differences were already detectable at the time of initial surgery. One thousand one hundred sixty-seven genes, mainly associated with cancer and immune-related pathways, were differentially expressed between progressors and nonprogressors. A search for a classifier revealed that overexpression of AGAP2-AS1, an antisense long noncoding RNA, correctly classified 23 of 24 samples, years (4.5 years average) in advance of the discovery of metastasis and without requiring larger gene panels. Subsequently, we confirmed AGAP2-AS1 gene overexpression by qPCR in the same samples (p < 0.05). Additionally, in external data from The Cancer Genome Atlas, overexpression of AGAP2-AS1 is correlated with overall unfavorable survival outcome in ccRCC, irrespective of other prognostic predictors (p = 2.44E−7).ConclusionAGAP2-AS1 may represent a novel biomarker identifying high-risk ccRCC patients currently classified as “low risk” at the time of surgery.
Highlights
IntroductionClear cell renal cell carcinoma (ccRCC), the most common subtype of renal cancer, is characterized by an especially poor prognosis [1]
The incidence of kidney cancer is rising worldwide, especially in Western countries [1,2,3].Clear cell renal cell carcinoma, the most common subtype of renal cancer, is characterized by an especially poor prognosis [1]
We performed genome-wide expression profiling from formalin-fixed samples obtained at initial surgery from these “low-risk” patients and 16 matched patients not progressing to recur‐
Summary
Clear cell renal cell carcinoma (ccRCC), the most common subtype of renal cancer, is characterized by an especially poor prognosis [1]. (2021) 21:690 survival rate for patients with localized disease is 93%. Of patients with localized disease develop distant metastases during follow-up [5, 6]. Since treatment effectiveness is contingent upon early discovery of the disease or its recurrence, it is critically important to accurately predict the risk of progression, to determine the frequency and type of follow-up, and to increase the chances of timely and successful therapy [5]. While survival for localized ccRCC is good, the survival of metastatic disease is not, and thirty percent of patients with ccRCC develop metastases during follow-up. We aimed to identify ccRCC progression biomarkers in “low-risk” patients who were potentially eligible for adjuvant treat‐
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