Body composition and lung cancer-associated cachexia in TRACERx

Item Type:	Article
Title:	Body composition and lung cancer-associated cachexia in TRACERx
Creators Name:	Al-Sawaf, O. and Weiss, J. and Skrzypski, M. and Lam, J.M. and Karasaki, T. and Zambrana, F. and Kidd, A.C. and Frankell, A.M. and Watkins, T.B.K. and Martínez-Ruiz, C. and Puttick, C. and Black, J.R.M. and Huebner, A. and Bakir, M.A. and Sokač, M. and Collins, S. and Veeriah, S. and Magno, N. and Naceur-Lombardelli, C. and Prymas, P. and Toncheva, A. and Ward, S. and Jayanth, N. and Salgado, R. and Bridge, C.P. and Christiani, D.C. and Mak, R.H. and Bay, C. and Rosenthal, M. and Sattar, N. and Welsh, P. and Liu, Y. and Perrimon, N. and Popuri, K. and Beg, M.F. and McGranahan, N. and Hackshaw, A. and Breen, D.M. and O'Rahilly, S. and Birkbak, N.J. and Aerts, H.J.W.L. and Jamal-Hanjani, M. and Swanton, C.
Abstract:	Cancer-associated cachexia (CAC) is a major contributor to morbidity and mortality in individuals with non-small cell lung cancer. Key features of CAC include alterations in body composition and body weight. Here, we explore the association between body composition and body weight with survival and delineate potential biological processes and mediators that contribute to the development of CAC. Computed tomography-based body composition analysis of 651 individuals in the TRACERx (TRAcking non-small cell lung Cancer Evolution through therapy (Rx)) study suggested that individuals in the bottom 20th percentile of the distribution of skeletal muscle or adipose tissue area at the time of lung cancer diagnosis, had significantly shorter lung cancer-specific survival and overall survival. This finding was validated in 420 individuals in the independent Boston Lung Cancer Study. Individuals classified as having developed CAC according to one or more features at relapse encompassing loss of adipose or muscle tissue, or body mass index-adjusted weight loss were found to have distinct tumor genomic and transcriptomic profiles compared with individuals who did not develop such features. Primary non-small cell lung cancers from individuals who developed CAC were characterized by enrichment of inflammatory signaling and epithelial-mesenchymal transitional pathways, and differentially expressed genes upregulated in these tumors included cancer-testis antigen MAGEA6 and matrix metalloproteinases, such as ADAMTS3. In an exploratory proteomic analysis of circulating putative mediators of cachexia performed in a subset of 110 individuals from TRACERx, a significant association between circulating GDF15 and loss of body weight, skeletal muscle and adipose tissue was identified at relapse, supporting the potential therapeutic relevance of targeting GDF15 in the management of CAC.
Keywords:	Body Composition, Body Weight, Cachexia, Local Neoplasm Recurrence, Lung Neoplasms, Neoplasm Antigens, Neoplasm Proteins, Non-Small-Cell Lung Carcinoma, Proteomics, Skeletal Muscle
Source:	Nature Medicine
ISSN:	1078-8956
Publisher:	Nature Publishing Group
Volume:	29
Number:	4
Page Range:	846-858
Date:	April 2023
Additional Information:	Tom L. Kaufmann (19184) is a member of the TRACERx Consortium. - Copyright © 2023. The Author(s) under exclusive license to Springer Nature America, Inc.
Official Publication:	https://doi.org/10.1038/s41591-023-02232-8
External Fulltext:	View full text on PubMed Central
PubMed:	View item in PubMed

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