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Oncotarget. 2017 Oct 23;8(61):103428-103436. doi: 10.18632/oncotarget.21952. eCollection 2017 Nov 28.

Differential expression of c-Met between primary and metastatic sites in clear-cell renal cell carcinoma and its association with PD-L1 expression.

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Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
Institut Goustave Roussy, Villejuif, France.
Department of Pathology, Ospedale San Raffaele, Milan, Italy.
Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
Division of Nephrology, Boston Children's Hospital, Boston, MA, USA.
Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA.
Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston, MA, USA.
Georgetown Lombardi Comprehensive Cancer Center, Washington D.C., USA.
Van Andel Research Institute, Grand Rapids, MA, USA.


In preclinical models, c-Met promotes survival of renal cancer cells through the regulation of programmed death-ligand 1 (PD-L1). However, this relationship in human clear cell renal cell carcinoma (ccRCC) is not well characterized. We evaluated c-Met expression in ccRCC patients using paired primary and metastatic samples and assessed the association with PD-L1 expression and other clinical features. Areas with predominant and highest Fuhrman nuclear grade (FNG) were selected. c-Met expression was evaluated by IHC using an anti-Met monoclonal antibody (MET4 Ab) and calculated by a combined score (CS, 0-300): intensity of c-Met staining (0-3) x % of positive cells (0-100). PD-L1 expression in tumor cells was previously assessed by IHC and PD-L1+ was defined as PD-L1 > 0% positive cells. Our cohort consisted of 45 pairs of primary and metastatic ccRCC samples. Overall, c-Met expression was higher in metastatic sites compared to primary sites (average c-Met CS: 55 vs. 28, p = 0.0003). Higher c-Met expression was associated with higher FNG (4 vs. 3) in primary tumors (average c-Met CS: 52 vs. 20, p = 0.04). c-Met expression was numerically greater in PD-L1+ vs. PD-L1- tumors. Higher c-Met expression in metastatic sites compared to primary tumors suggests that testing for biomarkers of response to c-Met inhibitors should be conducted in metastases. While higher c-Met expression in PD-L1+ tumors requires further investigation, it supports exploring these targets in combination clinical trials.


PD-L1; c-Met; metastasis; primary; renal cell carcinoma

Conflict of interest statement

CONFLICTS OF INTEREST AAL: educational travel support from Pfizer. KPG: stock and other ownership interests in MDGN. LA: research funding from Novartis and Pfizer; advisory role at Novartis, Pfizer, Amgen and Sanofi. DFM: consulting/advisory role at Alexion Pharmaceuticals, Array BioPharma, Bristol-Myers Squibb, Eisai, Exelixis, Genentech/Roche, Merck, Novartis, Pfizer, X4 Pharma; institutional research funding from Prometheus Labs. MBA: honoraria from Bristol-Myers Squibb; consulting/advisory role at Alkermes, Amgen, Bristol-Myers Squibb, C-Cam, Genentech, Genoptix, GlaxoSmithKline, Infinity Pharmaceuticals, Lilly, Merck, Nektar, Novartis, Pfizer, X4 Pharma. LCH: consulting/advisory role at Dendreon, Genentech, KEW Group, Medivation/Astellas, NCCN, Pfizer, PlatformQ Health, Theragene; institutional research funding from Bayer, Dendreon, Genentech/Roche, Medivation/Astellas, Sotio, Takeda, Bristol-Myers Squibb; Travel, Accommodations, and Expenses from Sanofi. TKC: honoraria from NCCN, UpToDate; consulting/advisory role at Bayer, Bristol-Myers Squibb, GlaxoSmithKline, Merck, Novartis, Pfizer; institutional research funding from AstraZeneca, Bristol-Myers Squibb, Exelixis, GlaxoSmithKline, Merck, Novartis, Peloton Therapeutics, Pfizer, Roche/Genentech, TRACON Pharma. SS: consulting/advisory role at AstraZeneca, Merck, Verastem; institutional research funding from AstraZeneca and Exelixis; patents or other intellectual property at Biogenex. The remaining authors declare no conflicts of interest.

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