Risk Prediction Tool for Aggressive Tumors in Clinical T1 Stage Clear Cell Renal Cell Carcinoma Using Molecular Biomarkers

Jee Soo Park, Hyo Jung Lee, Nam Hoon Cho, Jongchan Kim, Won Sik Jang, Ji Eun Heo, Won Sik Ham

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)

Abstract

Some early-stage clear cell renal cell carcinomas (ccRCCs) of ≤7 cm are associated with a poor clinical outcome. In this study, we investigated molecular biomarkers associated with aggressive clinical T1 stage ccRCCs of ≤7 cm, which were used to develop a risk prediction tool toward guiding the decision of treatment. Among 1069 nephrectomies performed for ccRCC of ≤7 cm conducted between January 2008 and December 2014, 177 cases with available formalin-fixed paraffin-embedded tissue were evaluated. An aggressive tumor was defined as a tumor exhibiting synchronous metastasis, recurrence, or leading to cancer-specific death. Expression levels of six genes (FOXC2, CLIP4, PBRM1, BAP1, SETD2, and KDM5C) were measured by reverse-transcription polymerase chain reaction (qRT-PCR) and their relation to clinical outcomes was investigated. Immunohistochemistry was performed to validate the expression profiles of selected genes significantly associated with clinical outcomes in multivariate analysis. Using these genes, we developed a prediction model of aggressive ccRCC based on logistic regression and deep-learning methods. FOXC2, PBRM1, and BAP1 expression levels were significantly lower in aggressive ccRCC than non-aggressive ccRCC both in univariate and multivariate analysis. The immunohistochemistry result demonstrated the significant downregulation of FOXC2, PBRM1, and BAP1 expression in aggressive ccRCC. Adding immunohistochemical staining results to qRT-PCR, the aggressive ccRCC prediction models had the area under the curve (AUC) of 0.760 and 0.796 and accuracy of 0.759 and 0.852 using the logistic regression method and deep-learning method, respectively. Use of these biomarkers and the developed prediction model can help stratify patients with clinical T1 stage ccRCC.

Original languageEnglish
Pages (from-to)371-377
Number of pages7
JournalComputational and Structural Biotechnology Journal
Volume17
DOIs
Publication statusPublished - 2019 Jan 1

Bibliographical note

Funding Information:
This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI17C1095 ).

Funding Information:
BAP1 has been reported to be associated with uveal melanoma and mesothelioma [25,26]. BAP1 mutation in uveal melanoma is associated with an aggressive subtype; however, in mesothelioma, BAP1 mutation is not associated with inferior clinical outcomes [27]. BAP1 was reported to be a critical gatekeeper for disease progression [28]. Peña-Llopis et al. [29] reported the mutually exclusive characteristics of PBRM1 and BAP1 mutations, in which BAP1-mutant tumors were associated with worse survival and a higher Fuhrman grade than PBRM1-mutant tumors [28]. This finding was supported by the MSKCC cohort study, which indicated an association of BAP1 mutations with poor prognostic factors such as a higher T stage, higher nuclear grade, large size, more necrosis, and the presence of metastatic disease at presentation [16].This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI17C1095).

Publisher Copyright:
© 2019 The Authors

All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Biophysics
  • Structural Biology
  • Biochemistry
  • Genetics
  • Computer Science Applications

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