Body composition and lung cancer-associated cachexia in TRACERx

Al-Sawaf, Othman; Weiss, Jakob; Skrzypski, Marcin; Lam, Jie Min; Karasaki, Takahiro; Zambrana, Francisco; Kidd, Andrew C; Frankell, Alexander M; Watkins, Thomas BK; Martinez-Ruiz, Carlos; Puttick, Clare; Black, James RM; Huebner, Ariana; Al Bakir, Maise; Sokac, Mateo; Collins, Susie; Veeriah, Selvaraju; Magno, Neil; Naceur-Lombardelli, Cristina; Prymas, Paulina; Toncheva, Antonia; Ward, Sophia; Jayanth, Nick; Salgado, Roberto; Bridge, Christopher P; Christiani, David C; Mak, Raymond H; Bay, Camden; Rosenthal, Michael; Sattar, Naveed; Welsh, Paul; Liu, Ying; Perrimon, Norbert; Popuri, Karteek; Beg, Mirza Faisal; McGranahan, Nicholas; Hackshaw, Allan; Breen, Danna M; O'Rahilly, Stephen; Birkbak, Nicolai J; Aerts, Hugo JWL; Jamal-Hanjani, Mariam; Swanton, Charles; Lester, Jason F; Bajaj, Amrita; Nakas, Apostolos; Sodha-Ramdeen, Azmina; Ang, Keng; Tufail, Mohamad; Chowdhry, Mohammed Fiyaz; Scotland, Molly; Boyles, Rebecca; Rathinam, Sridhar; Wilson, Claire; Marrone, Domenic; Dulloo, Sean; Fennell, Dean A; Matharu, Gurdeep; Shaw, Jacqui A; Riley, Joan; Primrose, Lindsay; Boleti, Ekaterini; Cheyne, Heather; Khalil, Mohammed; Richardson, Shirley; Cruickshank, Tracey; Price, Gillian; Kerr, Keith M; Benafif, Sarah; Gilbert, Kayleigh; Naidu, Babu; Patel, Akshay J; Osman, Aya; Lacson, Christer; Langman, Gerald; Shackleford, Helen; Djearaman, Madava; Kadiri, Salma; Middleton, Gary; Leek, Angela; Hodgkinson, Jack Davies; Totten, Nicola; Montero, Angeles; Smith, Elaine; Fontaine, Eustace; Granato, Felice; Doran, Helen; Novasio, Juliette; Rammohan, Kendadai; Joseph, Leena; Bishop, Paul; Shah, Rajesh; Moss, Stuart; Joshi, Vijay; Crosbie, Philip; Gomes, Fabio; Brown, Kate; Carter, Mathew; Chaturvedi, Anshuman; Priest, Lynsey; Oliveira, Pedro; Lindsay, Colin R; Blackhall, Fiona H; Krebs, Matthew G; Summers, Yvonne; Clipson, Alexandra; Tugwood, Jonathan; Kerr, Alastair; Rothwell, Dominic G; Kilgour, Elaine; Dive, Caroline; Schwarz, Roland F; Kaufmann, Tom L; Wilson, Gareth A; Rosenthal, Rachel; Van Loo, Peter; Szallasi, Zoltan; Kisistok, Judit; Sokac, Mateo; Diossy, Miklos; Demeulemeester, Jonas; Bunkum, Abigail; Stewart, Aengus; Magness, Alastair; Rowan, Andrew; Karamani, Angeliki; Chain, Benny; Campbell, Brittany B; Castignani, Carla; Bailey, Chris; Abbosh, Christopher; Weeden, Clare E; Lee, Claudia; Richard, Corentin; Hiley, Crispin T; Moore, David A; Pearce, David R; Karagianni, Despoina; Biswas, Dhruva; Levi, Dina; Hoxha, Elena; Cadieux, Elizabeth Larose; Lim, Emilia L; Colliver, Emma; Nye, Emma; Gronroos, Eva; Galvez-Cancino, Felip; Athanasopoulou, Foteini; Gimeno-Valiente, Francisco; Kassiotis, George; Stavrou, Georgia; Mastrokalos, Gerasimos; Zhai, Haoran; Lowe, Helen L; Matos, Ignacio Garcia; Goldman, Jacki; Reading, James L; Herrero, Javier; Rane, Jayant K; Nicod, Jerome; Hartley, John A; Peggs, Karl S; Enfield, Katey SS; Selvaraju, Kayalvizhi; Thol, Kerstin; Litchfield, Kevin; Ng, Kevin W; Chen, Kezhong; Dijkstra, Krijn; Grigoriadis, Kristiana; Thakkar, Krupa; Ensell, Leah; Shah, Mansi; Duran, Marcos Vasquez; Litovchenko, Maria; Sunderland, Mariana Werner; Hill, Mark S; Dietzen, Michelle; Leung, Michelle; Escudero, Mickael; Angelova, Mihaela; Tanic, Miljana; Sivakumar, Monica; Kanu, Nnennaya; Chervova, Olga; Lucas, Olivia; Pich, Oriol; Hobson, Philip; Pawlik, Piotr; Stone, Richard Kevin; Bentham, Robert; Hynds, Robert E; Vendramin, Roberto; Saghafinia, Sadegh; Lopez, Saioa; Gamble, Samuel; Ung, Seng Kuong Anakin; Quezada, Sergio A; Vanloo, Sharon; Zaccaria, Simone; Hessey, Sonya; Boeing, Stefan; Beck, Stephan; Bola, Supreet Kaur; Denner, Tamara; Marafioti, Teresa; Mourikis, Thanos P; Spanswick, Victoria; Barbe, Vittorio; Lu, Wei-Ting; Hill, William; Liu, Wing Kin; Wu, Yin; Naito, Yutaka; Ramsden, Zoe; Veiga, Catarina; Royle, Gary; Collins-Fekete, Charles-Antoine; Fraioli, Francesco; Ashford, Paul; Clark, Tristan; Forster, Martin D; Lee, Siow Ming; Borg, Elaine; Falzon, Mary; Papadatos-Pastos, Dionysis; Wilson, James; Ahmad, Tanya; Procter, Alexander James; Ahmed, Asia; Taylor, Magali N; Nair, Arjun; Lawrence, David; Patrini, Davide; Navani, Neal; Thakrar, Ricky M; Janes, Sam M; Hoogenboom, Emilie Martinoni; Monk, Fleur; Holding, James W; Choudhary, Junaid; Bhakhri, Kunal; Scarci, Marco; Hayward, Martin; Panagiotopoulos, Nikolaos; Gorman, Pat; Khiroya, Reena; Stephens, Robert CM; Wong, Yien Ning Sophia; Bandula, Steve; Sharp, Abigail; Smith, Sean; Gower, Nicole; Dhanda, Harjot Kaur; Chan, Kitty; Pilotti, Camilla; Leslie, Rachel; Grapa, Anca; Zhang, Hanyun; AbdulJabbar, Khalid; Pan, Xiaoxi; Yuan, Yinyin; Chuter, David; MacKenzie, Mairead; Chee, Serena; Alzetani, Aiman; Cave, Judith; Scarlett, Lydia; Richards, Jennifer; Ingram, Papawadee; Austin, Silvia; Lim, Eric; De Sousa, Paulo; Jordan, Simon; Rice, Alexandra; Raubenheimer, Hilgardt; Bhayani, Harshil; Ambrose, Lyn; Devaraj, Anand; Chavan, Hema; Begum, Sofina; Buderi, Silviu; Kaniu, Daniel; Malima, Mpho; Booth, Sarah; Nicholson, Andrew G; Fernandes, Nadia; Shah, Pratibha; Proli, Chiara; Hewish, Madeleine; Danson, Sarah; Shackcloth, Michael J; Robinson, Lily; Russell, Peter; Blyth, Kevin G; Dick, Craig; Le Quesne, John; Kirk, Alan; Asif, Mo; Bilancia, Rocco; Kostoulas, Nikos; Thomas, Mathew

doi:10.1038/s41591-023-02232-8

Body composition and lung cancer-associated cachexia in TRACERx

Author:

Al-Sawaf, Othman

Weiss, Jakob ; Skrzypski, Marcin ; Lam, Jie Min ; Karasaki, Takahiro ; Zambrana, Francisco ; Kidd, Andrew C ; Frankell, Alexander M ; Watkins, Thomas BK ; Martinez-Ruiz, Carlos ; Puttick, Clare ; Black, James RM ; Huebner, Ariana ; Al Bakir, Maise ; Sokac, Mateo ; Collins, Susie ; Veeriah, Selvaraju ; Magno, Neil ; Naceur-Lombardelli, Cristina ; Prymas, Paulina ; Toncheva, Antonia ; Ward, Sophia ; Jayanth, Nick ; Salgado, Roberto ; Bridge, Christopher P ; Christiani, David C ; Mak, Raymond H ; Bay, Camden ; Rosenthal, Michael ; Sattar, Naveed ; Welsh, Paul ; Liu, Ying ; Perrimon, Norbert ; Popuri, Karteek ; Beg, Mirza Faisal ; McGranahan, Nicholas ; Hackshaw, Allan ; Breen, Danna M ; O'Rahilly, Stephen ; Birkbak, Nicolai J ; Aerts, Hugo JWL ; Jamal-Hanjani, Mariam ; Swanton, Charles ; Lester, Jason F ; Bajaj, Amrita ; Nakas, Apostolos ; Sodha-Ramdeen, Azmina ; Ang, Keng ; Tufail, Mohamad ; Chowdhry, Mohammed Fiyaz ; Scotland, Molly ; Boyles, Rebecca ; Rathinam, Sridhar ; Wilson, Claire ; Marrone, Domenic ; Dulloo, Sean ; Fennell, Dean A ; Matharu, Gurdeep ; Shaw, Jacqui A ; Riley, Joan ; Primrose, Lindsay ; Boleti, Ekaterini ; Cheyne, Heather ; Khalil, Mohammed ; Richardson, Shirley ; Cruickshank, Tracey ; Price, Gillian ; Kerr, Keith M ; Benafif, Sarah ; Gilbert, Kayleigh ; Naidu, Babu ; Patel, Akshay J ; Osman, Aya ; Lacson, Christer ; Langman, Gerald ; Shackleford, Helen ; Djearaman, Madava ; Kadiri, Salma ; Middleton, Gary ; Leek, Angela ; Hodgkinson, Jack Davies ; Totten, Nicola ; Montero, Angeles ; Smith, Elaine ; Fontaine, Eustace ; Granato, Felice ; Doran, Helen ; Novasio, Juliette ; Rammohan, Kendadai ; Joseph, Leena ; Bishop, Paul ; Shah, Rajesh ; Moss, Stuart ; Joshi, Vijay ; Crosbie, Philip ; Gomes, Fabio ; Brown, Kate ; Carter, Mathew ; Chaturvedi, Anshuman ; Priest, Lynsey ; Oliveira, Pedro ; Lindsay, Colin R ; Blackhall, Fiona H ; Krebs, Matthew G ; Summers, Yvonne ; Clipson, Alexandra ; Tugwood, Jonathan ; Kerr, Alastair ; Rothwell, Dominic G ; Kilgour, Elaine ; Dive, Caroline ; Schwarz, Roland F ; Kaufmann, Tom L ; Wilson, Gareth A ; Rosenthal, Rachel ; Van Loo, Peter ; Szallasi, Zoltan ; Kisistok, Judit ; Sokac, Mateo ; Diossy, Miklos ; Demeulemeester, Jonas ; Bunkum, Abigail ; Stewart, Aengus ; Magness, Alastair ; Rowan, Andrew ; Karamani, Angeliki ; Chain, Benny ; Campbell, Brittany B ; Castignani, Carla ; Bailey, Chris ; Abbosh, Christopher ; Weeden, Clare E ; Lee, Claudia ; Richard, Corentin ; Hiley, Crispin T ; Moore, David A ; Pearce, David R ; Karagianni, Despoina ; Biswas, Dhruva ; Levi, Dina ; Hoxha, Elena ; Cadieux, Elizabeth Larose ; Lim, Emilia L ; Colliver, Emma ; Nye, Emma ; Gronroos, Eva ; Galvez-Cancino, Felip ; Athanasopoulou, Foteini ; Gimeno-Valiente, Francisco ; Kassiotis, George ; Stavrou, Georgia ; Mastrokalos, Gerasimos ; Zhai, Haoran ; Lowe, Helen L ; Matos, Ignacio Garcia ; Goldman, Jacki ; Reading, James L ; Herrero, Javier ; Rane, Jayant K ; Nicod, Jerome ; Hartley, John A ; Peggs, Karl S ; Enfield, Katey SS ; Selvaraju, Kayalvizhi ; Thol, Kerstin ; Litchfield, Kevin ; Ng, Kevin W ; Chen, Kezhong ; Dijkstra, Krijn ; Grigoriadis, Kristiana ; Thakkar, Krupa ; Ensell, Leah ; Shah, Mansi ; Duran, Marcos Vasquez ; Litovchenko, Maria ; Sunderland, Mariana Werner ; Hill, Mark S ; Dietzen, Michelle ; Leung, Michelle ; Escudero, Mickael ; Angelova, Mihaela ; Tanic, Miljana ; Sivakumar, Monica ; Kanu, Nnennaya ; Chervova, Olga ; Lucas, Olivia ; Pich, Oriol ; Hobson, Philip ; Pawlik, Piotr ; Stone, Richard Kevin ; Bentham, Robert ; Hynds, Robert E ; Vendramin, Roberto ; Saghafinia, Sadegh ; Lopez, Saioa ; Gamble, Samuel ; Ung, Seng Kuong Anakin ; Quezada, Sergio A ; Vanloo, Sharon ; Zaccaria, Simone ; Hessey, Sonya ; Boeing, Stefan ; Beck, Stephan ; Bola, Supreet Kaur ; Denner, Tamara ; Marafioti, Teresa ; Mourikis, Thanos P ; Spanswick, Victoria ; Barbe, Vittorio ; Lu, Wei-Ting ; Hill, William ; Liu, Wing Kin ; Wu, Yin ; Naito, Yutaka ; Ramsden, Zoe ; Veiga, Catarina ; Royle, Gary ; Collins-Fekete, Charles-Antoine ; Fraioli, Francesco ; Ashford, Paul ; Clark, Tristan ; Forster, Martin D ; Lee, Siow Ming ; Borg, Elaine ; Falzon, Mary ; Papadatos-Pastos, Dionysis ; Wilson, James ; Ahmad, Tanya ; Procter, Alexander James ; Ahmed, Asia ; Taylor, Magali N ; Nair, Arjun ; Lawrence, David ; Patrini, Davide ; Navani, Neal ; Thakrar, Ricky M ; Janes, Sam M ; Hoogenboom, Emilie Martinoni ; Monk, Fleur ; Holding, James W ; Choudhary, Junaid ; Bhakhri, Kunal ; Scarci, Marco ; Hayward, Martin ; Panagiotopoulos, Nikolaos ; Gorman, Pat ; Khiroya, Reena ; Stephens, Robert CM ; Wong, Yien Ning Sophia ; Bandula, Steve ; Sharp, Abigail ; Smith, Sean ; Gower, Nicole ; Dhanda, Harjot Kaur ; Chan, Kitty ; Pilotti, Camilla ; Leslie, Rachel ; Grapa, Anca ; Zhang, Hanyun ; AbdulJabbar, Khalid ; Pan, Xiaoxi ; Yuan, Yinyin ; Chuter, David ; MacKenzie, Mairead ; Chee, Serena ; Alzetani, Aiman ; Cave, Judith ; Scarlett, Lydia ; Richards, Jennifer ; Ingram, Papawadee ; Austin, Silvia ; Lim, Eric ; De Sousa, Paulo ; Jordan, Simon ; Rice, Alexandra ; Raubenheimer, Hilgardt ; Bhayani, Harshil ; Ambrose, Lyn ; Devaraj, Anand ; Chavan, Hema ; Begum, Sofina ; Buderi, Silviu ; Kaniu, Daniel ; Malima, Mpho ; Booth, Sarah ; Nicholson, Andrew G ; Fernandes, Nadia ; Shah, Pratibha ; Proli, Chiara ; Hewish, Madeleine ; Danson, Sarah ; Shackcloth, Michael J ; Robinson, Lily ; Russell, Peter ; Blyth, Kevin G ; Dick, Craig ; Le Quesne, John ; Kirk, Alan ; Asif, Mo ; Bilancia, Rocco ; Kostoulas, Nikos ; Thomas, Mathew

Keywords:

Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, Cell Biology, Medicine, Research & Experimental, Research & Experimental Medicine, GENOME-WIDE ASSOCIATION, SKELETAL-MUSCLE, WEIGHT-LOSS, MASS INDEX, OBESITY, LOCI, MORTALITY, ANOREXIA, INSIGHTS, GDF15, Male, Humans, Cachexia, Lung Neoplasms, Carcinoma, Non-Small-Cell Lung, Proteomics, Neoplasm Recurrence, Local, Body Composition, Body Weight, Muscle, Skeletal, Antigens, Neoplasm, Neoplasm Proteins, TRACERx Consortium, 11 Medical and Health Sciences, Immunology, 32 Biomedical and clinical sciences, 42 Health sciences

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.