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Supplementary Tables 1 and 6-8 from Obesity Is Associated with Altered Tumor Metabolism in Metastatic Melanoma

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posted on 2023-04-01, 00:02 authored by Andrew W. Hahn, Ashley V. Menk, Dayana B. Rivadeneira, Ryan C. Augustin, Mingchu Xu, Jun Li, Xiaogang Wu, Aditya K. Mishra, Tuba N. Gide, Camelia Quek, Yan Zang, Christine N. Spencer, Alexander M. Menzies, Carrie R. Daniel, Courtney W. Hudgens, Theodore Nowicki, Lauren E. Haydu, M.A. Wadud Khan, Vancheswaran Gopalakrishnan, Elizabeth M. Burton, Jared Malke, Julie M. Simon, Chantale Bernatchez, Nagireddy Putluri, Scott E. Woodman, Y.N. Vashisht Gopal, Renato Guerrieri, Grant M. Fischer, Jian Wang, Khalida M. Wani, John F. Thompson, Jeffrey E. Lee, Patrick Hwu, Nadim Ajami, Jeffrey E. Gershenwald, Georgina V. Long, Richard A. Scolyer, Michael T. Tetzlaff, Alexander J. Lazar, Dirk Schadendorf, Jennifer A. Wargo, John M. Kirkwood, Ralph J. DeBerardinis, Han Liang, Andrew Futreal, Jianhua Zhang, James S. Wilmott, Weiyi Peng, Michael A. Davies, Greg M. Delgoffe, Yana G. Najjar, Jennifer L. McQuade

Supplementary Table 1: Baseline characteristics for patients included in the integrated gene set enrichment analysis (Figure 2-3) by cohort; Supplementary Table 6: The most frequent somatic alterations (alts) in patients with regionally metastatic melanoma by body mass index from The Cancer Genome Atlas cohort; Supplemental Table 7: Integrated gene set enrichment analysis for pathways associated with fatty acid metabolism by body mass index; Supplemental Table 8: Gene expression of selected genes of interest involved in fatty acid metabolism.

Funding

Conquer Cancer Foundation (CCF)

Transdisciplinary Research in Energetics and Cancer Research Training Workshop

MD Anderson Cancer Center for Energy Balance in Cancer Prevention and Survivorship

Melanoma Research Alliance (MRA)

Elkins Foundation

Seerave Foundation (Seerave)

Rising Tide Foundation (RTF)

Mark Foundation For Cancer Research (The Mark Foundation for Cancer Research)

MD Anderson Cancer Center Moonshot Program

Prostate Cancer Foundation (PCF)

Howard Hughes Medical Institute (HHMI)

National Cancer Institute (NCI)

United States Department of Health and Human Services

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Cancer Prevention and Research Institute of Texas (CPRIT)

U.S. Department of Defense (DOD)

Welch Foundation (The Welch Foundation)

Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (AMRF)

AIM at Melanoma (AIM at Melanoma Foundation)

Cancer Fighters of Houston

Booker Family Foundation

American Cancer Society (ACS)

National Institutes of Health (NIH)

Tower Cancer Research Foundation (TCRF)

Hyundai Hope On Wheels (Hope On Wheels)

Cancer Institute NSW (Cancer Institute New South Wales)

US-Israel Binational Science Foundation

Stand Up To Cancer (SU2C)

National Health and Medical Research Council (NHMRC)

History

ARTICLE ABSTRACT

Overweight/obese (OW/OB) patients with metastatic melanoma unexpectedly have improved outcomes with immune checkpoint inhibitors (ICI) and BRAF-targeted therapies. The mechanism(s) underlying this association remain unclear, thus we assessed the integrated molecular, metabolic, and immune profile of tumors, as well as gut microbiome features, for associations with patient body mass index (BMI). Associations between BMI [normal (NL < 25) or OW/OB (BMI ≥ 25)] and tumor or microbiome characteristics were examined in specimens from 782 patients with metastatic melanoma across 7 cohorts. DNA associations were evaluated in The Cancer Genome Atlas cohort. RNA sequencing from 4 cohorts (n = 357) was batch corrected and gene set enrichment analysis (GSEA) by BMI category was performed. Metabolic profiling was conducted in a subset of patients (x = 36) by LC/MS, and in flow-sorted melanoma tumor cells (x = 37) and patient-derived melanoma cell lines (x = 17) using the Seahorse XF assay. Gut microbiome features were examined in an independent cohort (n = 371). DNA mutations and copy number variations were not associated with BMI. GSEA demonstrated that tumors from OW/OB patients were metabolically quiescent, with downregulation of oxidative phosphorylation and multiple other metabolic pathways. Direct metabolite analysis and functional metabolic profiling confirmed decreased central carbon metabolism in OW/OB metastatic melanoma tumors and patient-derived cell lines. The overall structure, diversity, and taxonomy of the fecal microbiome did not differ by BMI. These findings suggest that the host metabolic phenotype influences melanoma metabolism and provide insight into the improved outcomes observed in OW/OB patients with metastatic melanoma treated with ICIs and targeted therapies.See related commentary by Smalley, p. 5

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