title: A multigene assay identifying distinct prognostic subtypes of clear cell renal cell carcinoma with differential response to tyrosine kinase inhibition.
abstract: Patients with clear cell renal cell carcinoma (ccRCC) have divergent survival outcomes and therapeutic responses, which may be determined by underlying molecular diversity. We aimed to develop a practical molecular assay that can identify subtypes with differential prognosis and response to targeted therapy. Whole-genome expression analysis of formalin-fixed paraffin-embedded (FFPE) material from 55 ccRCC patients was performed and two molecular subtypes with differential clinical outcomes were identified by hierarchical clustering. An eight-gene quantitative polymerase chain reaction assay for classification into two subtypes was developed for FFPE material. The primary objective was to assess assay performance by correlating ccRCC prognostic subtypes to cancer-specific survival (CSS) and, for patients receiving targeted therapy, radiologic response. In three validation cohorts, patients could be distinguished into prognostic subtypes with differential CSS (Singapore General Hospital FFPE cohort: n = 224; p = 1.48 × 10(-8); the Cancer Genome Atlas RNA-Sequencing cohort: n = 419; p = 3.06 × 10(-7); Van Andel Research Institute microarray cohort: n=174; p=0.00743). For 48 patients receiving tyrosine kinase inhibitor (TKI) treatment, the prognostic classification was associated with radiologic response to treatment (p = 5.96 × 10(-4)) and prolonged survival on TKI treatment (p=0.019). The multigene assay can classify ccRCCs into clinical prognostic subtypes, which may be predictive of response in patients receiving TKI therapy.
authors.affiliation: Institute of Bioengineering and Nanotechnology, Republic of Singapore.
authors.forename: Yukti
authors.initials: Y
authors.lastname: Choudhury
authors.affiliation: Institute of Bioengineering and Nanotechnology, Republic of Singapore.
authors.forename: Xiaona
authors.initials: X
authors.lastname: Wei
authors.affiliation: Institute of Bioengineering and Nanotechnology, Republic of Singapore; National Taiwan University, Republic of China (Taiwan).
authors.forename: Ying-Hsia
authors.initials: YH
authors.lastname: Chu
authors.affiliation: Singapore General Hospital, Republic of Singapore.
authors.forename: Lay Guat
authors.initials: LG
authors.lastname: Ng
authors.affiliation: National Cancer Centre Singapore, Republic of Singapore.
authors.forename: Hui Shan
authors.initials: HS
authors.lastname: Tan
authors.affiliation: Singapore General Hospital, Republic of Singapore.
authors.forename: Valerie
authors.initials: V
authors.lastname: Koh
authors.affiliation: Singapore General Hospital, Republic of Singapore.
authors.forename: Aye Aye
authors.initials: AA
authors.lastname: Thike
authors.affiliation: National Cancer Centre Singapore, Republic of Singapore.
authors.forename: Eileen
authors.initials: E
authors.lastname: Poon
authors.affiliation: National Cancer Centre Singapore, Republic of Singapore.
authors.forename: Quan Sing
authors.initials: QS
authors.lastname: Ng
authors.affiliation: National Cancer Centre Singapore, Republic of Singapore.
authors.forename: Chee Keong
authors.initials: CK
authors.lastname: Toh
authors.affiliation: National Cancer Centre Singapore, Republic of Singapore.
authors.forename: Ravindran
authors.initials: R
authors.lastname: Kanesvaran
authors.affiliation: Singapore General Hospital, Republic of Singapore.
authors.forename: Puay Hoon
authors.initials: PH
authors.lastname: Tan
authors.affiliation: Institute of Bioengineering and Nanotechnology, Republic of Singapore; National Cancer Centre Singapore, Republic of Singapore. Electronic address: mhtan@ibn.a-star.edu.sg.
authors.forename: Min-Han
authors.initials: MH
authors.lastname: Tan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D026921:Amino Acid Transport Systems, Neutral / Q000235:genetics; D000951:Antigens, Neoplasm / Q000235:genetics; D002292:Carcinoma, Renal Cell / Q000145:classification* / Q000188:drug therapy / Q000235:genetics*; D015815:Cell Adhesion Molecules / Q000235:genetics; D054365:Chemokine CXCL5 / Q000235:genetics; D036386:Ephrin-A5 / Q000235:genetics; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D007680:Kidney Neoplasms / Q000145:classification* / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D010958:Plasminogen / Q000235:genetics; D011237:Predictive Value of Tests; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D012189:Retrospective Studies; D052116:Sialomucins / Q000235:genetics; D015996:Survival Rate; D000097794:Kalinin
chemical_list: D026921:Amino Acid Transport Systems, Neutral; D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; D054365:Chemokine CXCL5; D036386:Ephrin-A5; D008565:Membrane Proteins; D010958:Plasminogen; D047428:Protein Kinase Inhibitors; D052116:Sialomucins; D000097794:Kalinin; C486263:CXCL5 protein, human; C404944:PRAME protein, human; C452562:RARRES1 protein, human; C491436:SLC6A19 protein, human
keywords: Clear cell renal cell carcinoma; Drug response; Metastasis; Prediction; Prognosis; Subtype; Tyrosine kinase inhibitors