Clinical MedicineOncology Open Access | 10.1172/JCI176230

Shuchi Gulati,1 Pedro C. Barata,2 Andrew Elliott,3 Mehmet Asim Bilen,4 Earle F. Burgess,5 Toni K. Choueiri,6 Sourat Darabi,7 Nancy Ann Dawson,8 Benjamin Adam Gartrell,9 Hans J. Hammers,10 Elisabeth I. Heath,11 Daniel Magee,3 Arpit Rao,12 Charles J. Ryan,13 Przemyslaw Twardowski,14 Shuanzeng Wei,15 James Brugarolas,10 Tian Zhang,10 Matthew R. Zibelman,15 Chadi Nabhan,3 and Rana R. McKay16

1UC Davis Comprehensive Cancer Center, Sacramento, California, USA.

2University Hospitals Seidman Cancer Center, Cleveland, Ohio, USA.

3Caris Life Sciences, Irving, Texas, USA.

4Emory University School of Medicine, Atlanta, Georgia, USA.

5Levine Cancer Institute, Charlotte, North Carolina, USA.

6Dana Farber Cancer Institute, Boston, Massachusetts, USA.

7Hoag Memorial Hospital Presbyterian, Newport Beach, California, USA.

8Georgetown University Lombardi Comprehensive Cancer Center, Washington, DC, USA.

9Montefiore Medical Center and Albert Einstein College of Medicine, New York, New York, USA.

10UT Southwestern Medical Center, Dallas, Texas, USA.

11Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan, USA.

12Baylor College of Medicine, Houston, Texas, USA.

13University of Minnesota, Minneapolis, Minnesota, USA.

14Saint John’s Cancer Institute at Providence Saint John’s Health Center, Santa Monica, California, USA.

15Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.

16University of California San Diego, La Jolla, California, USA.

Address correspondence to: Shuchi Gulati, UC Davis Comprehensive Cancer Center, 4501 X Street, Suite 3016, Sacramento, California 95817-2229, USA. Phone: 916.734.3772; Email: sigulati@ucdavis.edu.

Find articles by Gulati, S. in: JCI | PubMed | Google Scholar

1UC Davis Comprehensive Cancer Center, Sacramento, California, USA.

2University Hospitals Seidman Cancer Center, Cleveland, Ohio, USA.

3Caris Life Sciences, Irving, Texas, USA.

4Emory University School of Medicine, Atlanta, Georgia, USA.

5Levine Cancer Institute, Charlotte, North Carolina, USA.

6Dana Farber Cancer Institute, Boston, Massachusetts, USA.

7Hoag Memorial Hospital Presbyterian, Newport Beach, California, USA.

8Georgetown University Lombardi Comprehensive Cancer Center, Washington, DC, USA.

9Montefiore Medical Center and Albert Einstein College of Medicine, New York, New York, USA.

10UT Southwestern Medical Center, Dallas, Texas, USA.

11Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan, USA.

12Baylor College of Medicine, Houston, Texas, USA.

13University of Minnesota, Minneapolis, Minnesota, USA.

14Saint John’s Cancer Institute at Providence Saint John’s Health Center, Santa Monica, California, USA.

15Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.

16University of California San Diego, La Jolla, California, USA.

Address correspondence to: Shuchi Gulati, UC Davis Comprehensive Cancer Center, 4501 X Street, Suite 3016, Sacramento, California 95817-2229, USA. Phone: 916.734.3772; Email: sigulati@ucdavis.edu.

Find articles by Barata, P. in: JCI | PubMed | Google Scholar

1UC Davis Comprehensive Cancer Center, Sacramento, California, USA.

2University Hospitals Seidman Cancer Center, Cleveland, Ohio, USA.

3Caris Life Sciences, Irving, Texas, USA.

4Emory University School of Medicine, Atlanta, Georgia, USA.

5Levine Cancer Institute, Charlotte, North Carolina, USA.

6Dana Farber Cancer Institute, Boston, Massachusetts, USA.

7Hoag Memorial Hospital Presbyterian, Newport Beach, California, USA.

8Georgetown University Lombardi Comprehensive Cancer Center, Washington, DC, USA.

9Montefiore Medical Center and Albert Einstein College of Medicine, New York, New York, USA.

10UT Southwestern Medical Center, Dallas, Texas, USA.

11Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan, USA.

12Baylor College of Medicine, Houston, Texas, USA.

13University of Minnesota, Minneapolis, Minnesota, USA.

14Saint John’s Cancer Institute at Providence Saint John’s Health Center, Santa Monica, California, USA.

15Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.

16University of California San Diego, La Jolla, California, USA.

Address correspondence to: Shuchi Gulati, UC Davis Comprehensive Cancer Center, 4501 X Street, Suite 3016, Sacramento, California 95817-2229, USA. Phone: 916.734.3772; Email: sigulati@ucdavis.edu.

Find articles by Elliott, A. in: JCI | PubMed | Google Scholar

1UC Davis Comprehensive Cancer Center, Sacramento, California, USA.

2University Hospitals Seidman Cancer Center, Cleveland, Ohio, USA.

3Caris Life Sciences, Irving, Texas, USA.

4Emory University School of Medicine, Atlanta, Georgia, USA.

5Levine Cancer Institute, Charlotte, North Carolina, USA.

6Dana Farber Cancer Institute, Boston, Massachusetts, USA.

7Hoag Memorial Hospital Presbyterian, Newport Beach, California, USA.

8Georgetown University Lombardi Comprehensive Cancer Center, Washington, DC, USA.

9Montefiore Medical Center and Albert Einstein College of Medicine, New York, New York, USA.

10UT Southwestern Medical Center, Dallas, Texas, USA.

11Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan, USA.

12Baylor College of Medicine, Houston, Texas, USA.

13University of Minnesota, Minneapolis, Minnesota, USA.

14Saint John’s Cancer Institute at Providence Saint John’s Health Center, Santa Monica, California, USA.

15Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.

16University of California San Diego, La Jolla, California, USA.

Address correspondence to: Shuchi Gulati, UC Davis Comprehensive Cancer Center, 4501 X Street, Suite 3016, Sacramento, California 95817-2229, USA. Phone: 916.734.3772; Email: sigulati@ucdavis.edu.

Find articles by Bilen, M. in: JCI | PubMed | Google Scholar

1UC Davis Comprehensive Cancer Center, Sacramento, California, USA.

2University Hospitals Seidman Cancer Center, Cleveland, Ohio, USA.

3Caris Life Sciences, Irving, Texas, USA.

4Emory University School of Medicine, Atlanta, Georgia, USA.

5Levine Cancer Institute, Charlotte, North Carolina, USA.

6Dana Farber Cancer Institute, Boston, Massachusetts, USA.

7Hoag Memorial Hospital Presbyterian, Newport Beach, California, USA.

8Georgetown University Lombardi Comprehensive Cancer Center, Washington, DC, USA.

9Montefiore Medical Center and Albert Einstein College of Medicine, New York, New York, USA.

10UT Southwestern Medical Center, Dallas, Texas, USA.

11Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan, USA.

12Baylor College of Medicine, Houston, Texas, USA.

13University of Minnesota, Minneapolis, Minnesota, USA.

14Saint John’s Cancer Institute at Providence Saint John’s Health Center, Santa Monica, California, USA.

15Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.

16University of California San Diego, La Jolla, California, USA.

Address correspondence to: Shuchi Gulati, UC Davis Comprehensive Cancer Center, 4501 X Street, Suite 3016, Sacramento, California 95817-2229, USA. Phone: 916.734.3772; Email: sigulati@ucdavis.edu.

Find articles by Burgess, E. in: JCI | PubMed | Google Scholar

1UC Davis Comprehensive Cancer Center, Sacramento, California, USA.

2University Hospitals Seidman Cancer Center, Cleveland, Ohio, USA.

3Caris Life Sciences, Irving, Texas, USA.

4Emory University School of Medicine, Atlanta, Georgia, USA.

5Levine Cancer Institute, Charlotte, North Carolina, USA.

6Dana Farber Cancer Institute, Boston, Massachusetts, USA.

7Hoag Memorial Hospital Presbyterian, Newport Beach, California, USA.

8Georgetown University Lombardi Comprehensive Cancer Center, Washington, DC, USA.

9Montefiore Medical Center and Albert Einstein College of Medicine, New York, New York, USA.

10UT Southwestern Medical Center, Dallas, Texas, USA.

11Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan, USA.

12Baylor College of Medicine, Houston, Texas, USA.

13University of Minnesota, Minneapolis, Minnesota, USA.

14Saint John’s Cancer Institute at Providence Saint John’s Health Center, Santa Monica, California, USA.

15Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.

16University of California San Diego, La Jolla, California, USA.

Address correspondence to: Shuchi Gulati, UC Davis Comprehensive Cancer Center, 4501 X Street, Suite 3016, Sacramento, California 95817-2229, USA. Phone: 916.734.3772; Email: sigulati@ucdavis.edu.

Find articles by Choueiri, T. in: JCI | PubMed | Google Scholar |

1UC Davis Comprehensive Cancer Center, Sacramento, California, USA.

2University Hospitals Seidman Cancer Center, Cleveland, Ohio, USA.

3Caris Life Sciences, Irving, Texas, USA.

4Emory University School of Medicine, Atlanta, Georgia, USA.

5Levine Cancer Institute, Charlotte, North Carolina, USA.

6Dana Farber Cancer Institute, Boston, Massachusetts, USA.

7Hoag Memorial Hospital Presbyterian, Newport Beach, California, USA.

8Georgetown University Lombardi Comprehensive Cancer Center, Washington, DC, USA.

9Montefiore Medical Center and Albert Einstein College of Medicine, New York, New York, USA.

10UT Southwestern Medical Center, Dallas, Texas, USA.

11Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan, USA.

12Baylor College of Medicine, Houston, Texas, USA.

13University of Minnesota, Minneapolis, Minnesota, USA.

14Saint John’s Cancer Institute at Providence Saint John’s Health Center, Santa Monica, California, USA.

15Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.

16University of California San Diego, La Jolla, California, USA.

Address correspondence to: Shuchi Gulati, UC Davis Comprehensive Cancer Center, 4501 X Street, Suite 3016, Sacramento, California 95817-2229, USA. Phone: 916.734.3772; Email: sigulati@ucdavis.edu.

Find articles by Darabi, S. in: JCI | PubMed | Google Scholar

1UC Davis Comprehensive Cancer Center, Sacramento, California, USA.

2University Hospitals Seidman Cancer Center, Cleveland, Ohio, USA.

3Caris Life Sciences, Irving, Texas, USA.

4Emory University School of Medicine, Atlanta, Georgia, USA.

5Levine Cancer Institute, Charlotte, North Carolina, USA.

6Dana Farber Cancer Institute, Boston, Massachusetts, USA.

7Hoag Memorial Hospital Presbyterian, Newport Beach, California, USA.

8Georgetown University Lombardi Comprehensive Cancer Center, Washington, DC, USA.

9Montefiore Medical Center and Albert Einstein College of Medicine, New York, New York, USA.

10UT Southwestern Medical Center, Dallas, Texas, USA.

11Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan, USA.

12Baylor College of Medicine, Houston, Texas, USA.

13University of Minnesota, Minneapolis, Minnesota, USA.

14Saint John’s Cancer Institute at Providence Saint John’s Health Center, Santa Monica, California, USA.

15Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.

16University of California San Diego, La Jolla, California, USA.

Address correspondence to: Shuchi Gulati, UC Davis Comprehensive Cancer Center, 4501 X Street, Suite 3016, Sacramento, California 95817-2229, USA. Phone: 916.734.3772; Email: sigulati@ucdavis.edu.

Find articles by Dawson, N. in: JCI | PubMed | Google Scholar

1UC Davis Comprehensive Cancer Center, Sacramento, California, USA.

2University Hospitals Seidman Cancer Center, Cleveland, Ohio, USA.

3Caris Life Sciences, Irving, Texas, USA.

4Emory University School of Medicine, Atlanta, Georgia, USA.

5Levine Cancer Institute, Charlotte, North Carolina, USA.

6Dana Farber Cancer Institute, Boston, Massachusetts, USA.

7Hoag Memorial Hospital Presbyterian, Newport Beach, California, USA.

8Georgetown University Lombardi Comprehensive Cancer Center, Washington, DC, USA.

9Montefiore Medical Center and Albert Einstein College of Medicine, New York, New York, USA.

10UT Southwestern Medical Center, Dallas, Texas, USA.

11Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan, USA.

12Baylor College of Medicine, Houston, Texas, USA.

13University of Minnesota, Minneapolis, Minnesota, USA.

14Saint John’s Cancer Institute at Providence Saint John’s Health Center, Santa Monica, California, USA.

15Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.

16University of California San Diego, La Jolla, California, USA.

Address correspondence to: Shuchi Gulati, UC Davis Comprehensive Cancer Center, 4501 X Street, Suite 3016, Sacramento, California 95817-2229, USA. Phone: 916.734.3772; Email: sigulati@ucdavis.edu.

Find articles by Gartrell, B. in: JCI | PubMed | Google Scholar

1UC Davis Comprehensive Cancer Center, Sacramento, California, USA.

2University Hospitals Seidman Cancer Center, Cleveland, Ohio, USA.

3Caris Life Sciences, Irving, Texas, USA.

4Emory University School of Medicine, Atlanta, Georgia, USA.

5Levine Cancer Institute, Charlotte, North Carolina, USA.

6Dana Farber Cancer Institute, Boston, Massachusetts, USA.

7Hoag Memorial Hospital Presbyterian, Newport Beach, California, USA.

8Georgetown University Lombardi Comprehensive Cancer Center, Washington, DC, USA.

9Montefiore Medical Center and Albert Einstein College of Medicine, New York, New York, USA.

10UT Southwestern Medical Center, Dallas, Texas, USA.

11Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan, USA.

12Baylor College of Medicine, Houston, Texas, USA.

13University of Minnesota, Minneapolis, Minnesota, USA.

14Saint John’s Cancer Institute at Providence Saint John’s Health Center, Santa Monica, California, USA.

15Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.

16University of California San Diego, La Jolla, California, USA.

Address correspondence to: Shuchi Gulati, UC Davis Comprehensive Cancer Center, 4501 X Street, Suite 3016, Sacramento, California 95817-2229, USA. Phone: 916.734.3772; Email: sigulati@ucdavis.edu.

Find articles by Hammers, H. in: JCI | PubMed | Google Scholar

1UC Davis Comprehensive Cancer Center, Sacramento, California, USA.

2University Hospitals Seidman Cancer Center, Cleveland, Ohio, USA.

3Caris Life Sciences, Irving, Texas, USA.

4Emory University School of Medicine, Atlanta, Georgia, USA.

5Levine Cancer Institute, Charlotte, North Carolina, USA.

6Dana Farber Cancer Institute, Boston, Massachusetts, USA.

7Hoag Memorial Hospital Presbyterian, Newport Beach, California, USA.

8Georgetown University Lombardi Comprehensive Cancer Center, Washington, DC, USA.

9Montefiore Medical Center and Albert Einstein College of Medicine, New York, New York, USA.

10UT Southwestern Medical Center, Dallas, Texas, USA.

11Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan, USA.

12Baylor College of Medicine, Houston, Texas, USA.

13University of Minnesota, Minneapolis, Minnesota, USA.

14Saint John’s Cancer Institute at Providence Saint John’s Health Center, Santa Monica, California, USA.

15Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.

16University of California San Diego, La Jolla, California, USA.

Address correspondence to: Shuchi Gulati, UC Davis Comprehensive Cancer Center, 4501 X Street, Suite 3016, Sacramento, California 95817-2229, USA. Phone: 916.734.3772; Email: sigulati@ucdavis.edu.

Find articles by Heath, E. in: JCI | PubMed | Google Scholar

1UC Davis Comprehensive Cancer Center, Sacramento, California, USA.

2University Hospitals Seidman Cancer Center, Cleveland, Ohio, USA.

3Caris Life Sciences, Irving, Texas, USA.

4Emory University School of Medicine, Atlanta, Georgia, USA.

5Levine Cancer Institute, Charlotte, North Carolina, USA.

6Dana Farber Cancer Institute, Boston, Massachusetts, USA.

7Hoag Memorial Hospital Presbyterian, Newport Beach, California, USA.

8Georgetown University Lombardi Comprehensive Cancer Center, Washington, DC, USA.

9Montefiore Medical Center and Albert Einstein College of Medicine, New York, New York, USA.

10UT Southwestern Medical Center, Dallas, Texas, USA.

11Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan, USA.

12Baylor College of Medicine, Houston, Texas, USA.

13University of Minnesota, Minneapolis, Minnesota, USA.

14Saint John’s Cancer Institute at Providence Saint John’s Health Center, Santa Monica, California, USA.

15Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.

16University of California San Diego, La Jolla, California, USA.

Address correspondence to: Shuchi Gulati, UC Davis Comprehensive Cancer Center, 4501 X Street, Suite 3016, Sacramento, California 95817-2229, USA. Phone: 916.734.3772; Email: sigulati@ucdavis.edu.

Find articles by Magee, D. in: JCI | PubMed | Google Scholar

1UC Davis Comprehensive Cancer Center, Sacramento, California, USA.

2University Hospitals Seidman Cancer Center, Cleveland, Ohio, USA.

3Caris Life Sciences, Irving, Texas, USA.

4Emory University School of Medicine, Atlanta, Georgia, USA.

5Levine Cancer Institute, Charlotte, North Carolina, USA.

6Dana Farber Cancer Institute, Boston, Massachusetts, USA.

7Hoag Memorial Hospital Presbyterian, Newport Beach, California, USA.

8Georgetown University Lombardi Comprehensive Cancer Center, Washington, DC, USA.

9Montefiore Medical Center and Albert Einstein College of Medicine, New York, New York, USA.

10UT Southwestern Medical Center, Dallas, Texas, USA.

11Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan, USA.

12Baylor College of Medicine, Houston, Texas, USA.

13University of Minnesota, Minneapolis, Minnesota, USA.

14Saint John’s Cancer Institute at Providence Saint John’s Health Center, Santa Monica, California, USA.

15Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.

16University of California San Diego, La Jolla, California, USA.

Address correspondence to: Shuchi Gulati, UC Davis Comprehensive Cancer Center, 4501 X Street, Suite 3016, Sacramento, California 95817-2229, USA. Phone: 916.734.3772; Email: sigulati@ucdavis.edu.

Find articles by Rao, A. in: JCI | PubMed | Google Scholar

1UC Davis Comprehensive Cancer Center, Sacramento, California, USA.

2University Hospitals Seidman Cancer Center, Cleveland, Ohio, USA.

3Caris Life Sciences, Irving, Texas, USA.

4Emory University School of Medicine, Atlanta, Georgia, USA.

5Levine Cancer Institute, Charlotte, North Carolina, USA.

6Dana Farber Cancer Institute, Boston, Massachusetts, USA.

7Hoag Memorial Hospital Presbyterian, Newport Beach, California, USA.

8Georgetown University Lombardi Comprehensive Cancer Center, Washington, DC, USA.

9Montefiore Medical Center and Albert Einstein College of Medicine, New York, New York, USA.

10UT Southwestern Medical Center, Dallas, Texas, USA.

11Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan, USA.

12Baylor College of Medicine, Houston, Texas, USA.

13University of Minnesota, Minneapolis, Minnesota, USA.

14Saint John’s Cancer Institute at Providence Saint John’s Health Center, Santa Monica, California, USA.

15Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.

16University of California San Diego, La Jolla, California, USA.

Address correspondence to: Shuchi Gulati, UC Davis Comprehensive Cancer Center, 4501 X Street, Suite 3016, Sacramento, California 95817-2229, USA. Phone: 916.734.3772; Email: sigulati@ucdavis.edu.

Find articles by Ryan, C. in: JCI | PubMed | Google Scholar

1UC Davis Comprehensive Cancer Center, Sacramento, California, USA.

2University Hospitals Seidman Cancer Center, Cleveland, Ohio, USA.

3Caris Life Sciences, Irving, Texas, USA.

4Emory University School of Medicine, Atlanta, Georgia, USA.

5Levine Cancer Institute, Charlotte, North Carolina, USA.

6Dana Farber Cancer Institute, Boston, Massachusetts, USA.

7Hoag Memorial Hospital Presbyterian, Newport Beach, California, USA.

8Georgetown University Lombardi Comprehensive Cancer Center, Washington, DC, USA.

9Montefiore Medical Center and Albert Einstein College of Medicine, New York, New York, USA.

10UT Southwestern Medical Center, Dallas, Texas, USA.

11Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan, USA.

12Baylor College of Medicine, Houston, Texas, USA.

13University of Minnesota, Minneapolis, Minnesota, USA.

14Saint John’s Cancer Institute at Providence Saint John’s Health Center, Santa Monica, California, USA.

15Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.

16University of California San Diego, La Jolla, California, USA.

Address correspondence to: Shuchi Gulati, UC Davis Comprehensive Cancer Center, 4501 X Street, Suite 3016, Sacramento, California 95817-2229, USA. Phone: 916.734.3772; Email: sigulati@ucdavis.edu.

Find articles by Twardowski, P. in: JCI | PubMed | Google Scholar

1UC Davis Comprehensive Cancer Center, Sacramento, California, USA.

2University Hospitals Seidman Cancer Center, Cleveland, Ohio, USA.

3Caris Life Sciences, Irving, Texas, USA.

4Emory University School of Medicine, Atlanta, Georgia, USA.

5Levine Cancer Institute, Charlotte, North Carolina, USA.

6Dana Farber Cancer Institute, Boston, Massachusetts, USA.

7Hoag Memorial Hospital Presbyterian, Newport Beach, California, USA.

8Georgetown University Lombardi Comprehensive Cancer Center, Washington, DC, USA.

9Montefiore Medical Center and Albert Einstein College of Medicine, New York, New York, USA.

10UT Southwestern Medical Center, Dallas, Texas, USA.

11Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan, USA.

12Baylor College of Medicine, Houston, Texas, USA.

13University of Minnesota, Minneapolis, Minnesota, USA.

14Saint John’s Cancer Institute at Providence Saint John’s Health Center, Santa Monica, California, USA.

15Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.

16University of California San Diego, La Jolla, California, USA.

Address correspondence to: Shuchi Gulati, UC Davis Comprehensive Cancer Center, 4501 X Street, Suite 3016, Sacramento, California 95817-2229, USA. Phone: 916.734.3772; Email: sigulati@ucdavis.edu.

Find articles by Wei, S. in: JCI | PubMed | Google Scholar

1UC Davis Comprehensive Cancer Center, Sacramento, California, USA.

2University Hospitals Seidman Cancer Center, Cleveland, Ohio, USA.

3Caris Life Sciences, Irving, Texas, USA.

4Emory University School of Medicine, Atlanta, Georgia, USA.

5Levine Cancer Institute, Charlotte, North Carolina, USA.

6Dana Farber Cancer Institute, Boston, Massachusetts, USA.

7Hoag Memorial Hospital Presbyterian, Newport Beach, California, USA.

8Georgetown University Lombardi Comprehensive Cancer Center, Washington, DC, USA.

9Montefiore Medical Center and Albert Einstein College of Medicine, New York, New York, USA.

10UT Southwestern Medical Center, Dallas, Texas, USA.

11Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan, USA.

12Baylor College of Medicine, Houston, Texas, USA.

13University of Minnesota, Minneapolis, Minnesota, USA.

14Saint John’s Cancer Institute at Providence Saint John’s Health Center, Santa Monica, California, USA.

15Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.

16University of California San Diego, La Jolla, California, USA.

Address correspondence to: Shuchi Gulati, UC Davis Comprehensive Cancer Center, 4501 X Street, Suite 3016, Sacramento, California 95817-2229, USA. Phone: 916.734.3772; Email: sigulati@ucdavis.edu.

Find articles by Brugarolas, J. in: JCI | PubMed | Google Scholar

1UC Davis Comprehensive Cancer Center, Sacramento, California, USA.

2University Hospitals Seidman Cancer Center, Cleveland, Ohio, USA.

3Caris Life Sciences, Irving, Texas, USA.

4Emory University School of Medicine, Atlanta, Georgia, USA.

5Levine Cancer Institute, Charlotte, North Carolina, USA.

6Dana Farber Cancer Institute, Boston, Massachusetts, USA.

7Hoag Memorial Hospital Presbyterian, Newport Beach, California, USA.

8Georgetown University Lombardi Comprehensive Cancer Center, Washington, DC, USA.

9Montefiore Medical Center and Albert Einstein College of Medicine, New York, New York, USA.

10UT Southwestern Medical Center, Dallas, Texas, USA.

11Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan, USA.

12Baylor College of Medicine, Houston, Texas, USA.

13University of Minnesota, Minneapolis, Minnesota, USA.

14Saint John’s Cancer Institute at Providence Saint John’s Health Center, Santa Monica, California, USA.

15Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.

16University of California San Diego, La Jolla, California, USA.

Address correspondence to: Shuchi Gulati, UC Davis Comprehensive Cancer Center, 4501 X Street, Suite 3016, Sacramento, California 95817-2229, USA. Phone: 916.734.3772; Email: sigulati@ucdavis.edu.

Find articles by Zhang, T. in: JCI | PubMed | Google Scholar

1UC Davis Comprehensive Cancer Center, Sacramento, California, USA.

2University Hospitals Seidman Cancer Center, Cleveland, Ohio, USA.

3Caris Life Sciences, Irving, Texas, USA.

4Emory University School of Medicine, Atlanta, Georgia, USA.

5Levine Cancer Institute, Charlotte, North Carolina, USA.

6Dana Farber Cancer Institute, Boston, Massachusetts, USA.

7Hoag Memorial Hospital Presbyterian, Newport Beach, California, USA.

8Georgetown University Lombardi Comprehensive Cancer Center, Washington, DC, USA.

9Montefiore Medical Center and Albert Einstein College of Medicine, New York, New York, USA.

10UT Southwestern Medical Center, Dallas, Texas, USA.

11Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan, USA.

12Baylor College of Medicine, Houston, Texas, USA.

13University of Minnesota, Minneapolis, Minnesota, USA.

14Saint John’s Cancer Institute at Providence Saint John’s Health Center, Santa Monica, California, USA.

15Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.

16University of California San Diego, La Jolla, California, USA.

Address correspondence to: Shuchi Gulati, UC Davis Comprehensive Cancer Center, 4501 X Street, Suite 3016, Sacramento, California 95817-2229, USA. Phone: 916.734.3772; Email: sigulati@ucdavis.edu.

Find articles by Zibelman, M. in: JCI | PubMed | Google Scholar

1UC Davis Comprehensive Cancer Center, Sacramento, California, USA.

2University Hospitals Seidman Cancer Center, Cleveland, Ohio, USA.

3Caris Life Sciences, Irving, Texas, USA.

4Emory University School of Medicine, Atlanta, Georgia, USA.

5Levine Cancer Institute, Charlotte, North Carolina, USA.

6Dana Farber Cancer Institute, Boston, Massachusetts, USA.

7Hoag Memorial Hospital Presbyterian, Newport Beach, California, USA.

8Georgetown University Lombardi Comprehensive Cancer Center, Washington, DC, USA.

9Montefiore Medical Center and Albert Einstein College of Medicine, New York, New York, USA.

10UT Southwestern Medical Center, Dallas, Texas, USA.

11Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan, USA.

12Baylor College of Medicine, Houston, Texas, USA.

13University of Minnesota, Minneapolis, Minnesota, USA.

14Saint John’s Cancer Institute at Providence Saint John’s Health Center, Santa Monica, California, USA.

15Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.

16University of California San Diego, La Jolla, California, USA.

Address correspondence to: Shuchi Gulati, UC Davis Comprehensive Cancer Center, 4501 X Street, Suite 3016, Sacramento, California 95817-2229, USA. Phone: 916.734.3772; Email: sigulati@ucdavis.edu.

Find articles by Nabhan, C. in: JCI | PubMed | Google Scholar

1UC Davis Comprehensive Cancer Center, Sacramento, California, USA.

2University Hospitals Seidman Cancer Center, Cleveland, Ohio, USA.

3Caris Life Sciences, Irving, Texas, USA.

4Emory University School of Medicine, Atlanta, Georgia, USA.

5Levine Cancer Institute, Charlotte, North Carolina, USA.

6Dana Farber Cancer Institute, Boston, Massachusetts, USA.

7Hoag Memorial Hospital Presbyterian, Newport Beach, California, USA.

8Georgetown University Lombardi Comprehensive Cancer Center, Washington, DC, USA.

9Montefiore Medical Center and Albert Einstein College of Medicine, New York, New York, USA.

10UT Southwestern Medical Center, Dallas, Texas, USA.

11Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan, USA.

12Baylor College of Medicine, Houston, Texas, USA.

13University of Minnesota, Minneapolis, Minnesota, USA.

14Saint John’s Cancer Institute at Providence Saint John’s Health Center, Santa Monica, California, USA.

15Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.

16University of California San Diego, La Jolla, California, USA.

Address correspondence to: Shuchi Gulati, UC Davis Comprehensive Cancer Center, 4501 X Street, Suite 3016, Sacramento, California 95817-2229, USA. Phone: 916.734.3772; Email: sigulati@ucdavis.edu.

Find articles by McKay, R. in: JCI | PubMed | Google Scholar

Published July 15, 2024 - More info

Published in Volume 134, Issue 14 on July 15, 2024
J Clin Invest. 2024;134(14):e176230. https://doi.org/10.1172/JCI176230.
© 2024 Gulati et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Published July 15, 2024 - Version history
Received: September 27, 2023; Accepted: May 17, 2024 View PDF Abstract

BACKGROUND. Metastases are the hallmark of lethal cancer, though underlying mechanisms that drive metastatic spread to specific organs remain poorly understood. Renal cell carcinoma (RCC) is known to have distinct sites of metastases, with lung, bone, liver, and lymph nodes being more common than brain, gastrointestinal tract, and endocrine glands. Previous studies have shown varying clinical behavior and prognosis associated with the site of metastatic spread; however, little is known about the molecular underpinnings that contribute to the differential outcomes observed by the site of metastasis.

METHODS. We analyzed primary renal tumors and tumors derived from metastatic sites to comprehensively characterize genomic and transcriptomic features of tumor cells as well as to evaluate the tumor microenvironment at both sites.

RESULTS. We included a total of 657 tumor samples (340 from the primary site [kidney] and 317 from various sites of metastasis). We show distinct genomic alterations, transcriptomic signatures, and immune and stromal tumor microenvironments across metastatic sites in a large cohort of patients with RCC.

CONCLUSION. We demonstrate significant heterogeneity among primary tumors and metastatic sites and elucidate the complex interplay between tumor cells and the extrinsic tumor microenvironment that is vital for developing effective anticancer therapies.

Introduction

Renal cell carcinoma (RCC) is one of the most common cancers in the United States, affecting close to 80,000 patients annually (1). While most patients present with localized disease, up to 30% develop distant metastases after definitive resection, and a small fraction present with metastatic disease at diagnosis (2, 3). Metastasis is a multidirectional process, balanced between mitosis, “self-seeding” within the primary tumor, circulating tumor cells disseminating into circulation, and “seeding” of the distant site (4). Metastatic organotropism, the “seed and soil” hypothesis, (5) has been explored in several cancers as a complex phenomenon where metastatic spread from a primary tumor to metastatic sites is a nonrandom selective event driven by the characteristics of underlying cancer and the microenvironment at the metastatic site (6–8). As our understanding of cancer has evolved over the last few decades, we recognize that the interplay of tumor genomic and transcriptomic characteristics within the tumor microenvironment (TME), including immune cells, fibroblasts, endothelial cells, and other cell types (dependent on the site of metastasis), contribute to tumor behavior and potential therapeutic response (9).

RCC has a distinct and broad pattern of metastatic spread, with lung, bone, liver, and lymph node metastases being more common, while brain, endocrine glands, and the gastrointestinal tract metastases are less common (2, 10). In patients with RCC, there is heterogeneity in the disease’s natural history, dependent on the sites of metastases present. For example, liver, bone, and brain metastases portend inferior overall survival (OS), while glandular metastases, including those to the pancreas, lead to better outcomes (11–14). Investigators from the TRACERx cohort (15), have previously presented data on somatic alterations at primary and metastatic sites while examining metastasis-competent clones. We analyzed primary renal tumors and tumors derived from metastatic sites to comprehensively characterize genomic and transcriptomic features of tumor cells and evaluated the TME at both sites. We hypothesized that differential clinical behavior is likely driven by distinct molecular features of specific sites of metastasis. A better understanding of the molecular underpinnings and heterogeneity across sites of metastasis may ultimately pave a path for improved therapeutic targeting and combination treatments for patients with metastatic RCC.

Results