TY - JOUR
T1 - Body composition and lung cancer-associated cachexia in TRACERx
AU - TRACERx Consortium
AU - Al-Sawaf, Othman
AU - Weiss, Jakob
AU - Skrzypski, Marcin
AU - Lam, Jie Min
AU - Karasaki, Takahiro
AU - Zambrana, Francisco
AU - Kidd, Andrew C.
AU - Frankell, Alexander M.
AU - Watkins, Thomas B.K.
AU - Martínez-Ruiz, Carlos
AU - Puttick, Clare
AU - Black, James R.M.
AU - Huebner, Ariana
AU - Bakir, Maise Al
AU - Sokač, Mateo
AU - Collins, Susie
AU - Veeriah, Selvaraju
AU - Magno, Neil
AU - Naceur-Lombardelli, Cristina
AU - Prymas, Paulina
AU - Toncheva, Antonia
AU - Ward, Sophia
AU - Jayanth, Nick
AU - Salgado, Roberto
AU - Bridge, Christopher P.
AU - Christiani, David C.
AU - Mak, Raymond H.
AU - Bay, Camden
AU - Rosenthal, Michael
AU - Sattar, Naveed
AU - Welsh, Paul
AU - Liu, Ying
AU - Perrimon, Norbert
AU - Popuri, Karteek
AU - Beg, Mirza Faisal
AU - McGranahan, Nicholas
AU - Hackshaw, Allan
AU - Breen, Danna M.
AU - O’Rahilly, Stephen
AU - Birkbak, Nicolai J.
AU - Aerts, Hugo J.W.L.
AU - Watkins, Thomas B.K.
AU - Aerts, Hugo Jwl
AU - Lester, Jason F.
AU - Bajaj, Amrita
AU - Nakas, Apostolos
AU - Sodha-Ramdeen, Azmina
AU - Van Loo, Peter
AU - Pan, Xiaoxi
AU - Yuan, Yinyin
N1 - Publisher Copyright:
© 2023, The Author(s) under exclusive license to Springer Nature America, Inc.
PY - 2023/4
Y1 - 2023/4
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85152430047&partnerID=8YFLogxK
U2 - 10.1038/s41591-023-02232-8
DO - 10.1038/s41591-023-02232-8
M3 - Article
C2 - 37045997
AN - SCOPUS:85152430047
SN - 1078-8956
VL - 29
SP - 846
EP - 858
JO - Nature medicine
JF - Nature medicine
IS - 4
ER -