Research Papers:

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

Aly-Khan A. Lalani, Kathryn P. Gray, Laurence Albiges, Marcella Callea, Jean-Christophe Pignon, Soumitro Pal, Mamta Gupta, Rupal S. Bhatt, David F. McDermott, Michael B. Atkins, G.F. Vande Woude, Lauren C. Harshman, Toni K. Choueiri _ and Sabina Signoretti

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Oncotarget. 2017; 8:103428-103436. https://doi.org/10.18632/oncotarget.21952

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Aly-Khan A. Lalani1, Kathryn P. Gray2, Laurence Albiges3, Marcella Callea4, Jean-Christophe Pignon5, Soumitro Pal6, Mamta Gupta7, Rupal S. Bhatt8, David F. McDermott8, Michael B. Atkins9, G.F. Vande Woude10, Lauren C. Harshman1, Toni K. Choueiri1,* and Sabina Signoretti5,*

1Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

2Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA

3Institut Goustave Roussy, Villejuif, France

4Department of Pathology, Ospedale San Raffaele, Milan, Italy

5Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA

6Division of Nephrology, Boston Children’s Hospital, Boston, MA, USA

7Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA

8Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston, MA, USA

9Georgetown Lombardi Comprehensive Cancer Center, Washington D.C., USA

10Van Andel Research Institute, Grand Rapids, MA, USA

*Co-senior authors contributed equally to this work

Correspondence to:

Toni K. Choueiri, email: [email protected]

Sabina Signoretti, email: [email protected]

Keywords: c-Met, PD-L1, primary, metastasis, renal cell carcinoma

Received: August 24, 2017     Accepted: September 29, 2017     Published: October 23, 2017


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.

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