TY - JOUR
T1 - Representation of genomic intratumor heterogeneity in multi-region non-small cell lung cancer patient-derived xenograft models
AU - Hynds, Robert E.
AU - Huebner, Ariana
AU - Pearce, David R.
AU - Hill, Mark S.
AU - Akarca, Ayse U.
AU - Moore, David A.
AU - Ward, Sophia
AU - Gowers, Kate H.C.
AU - Karasaki, Takahiro
AU - Al Bakir, Maise
AU - Wilson, Gareth A.
AU - Pich, Oriol
AU - Martínez-Ruiz, Carlos
AU - Hossain, A. S.Md Mukarram
AU - Pearce, Simon P.
AU - Sivakumar, Monica
AU - Ben Aissa, Assma
AU - Grönroos, Eva
AU - Chandrasekharan, Deepak
AU - Kolluri, Krishna K.
AU - Towns, Rebecca
AU - Wang, Kaiwen
AU - Cook, Daniel E.
AU - Bosshard-Carter, Leticia
AU - Naceur-Lombardelli, Cristina
AU - Rowan, Andrew J.
AU - Veeriah, Selvaraju
AU - Litchfield, Kevin
AU - Crosbie, Philip A.J.
AU - Dive, Caroline
AU - Quezada, Sergio A.
AU - Janes, Sam M.
AU - Jamal-Hanjani, Mariam
AU - Marafioti, Teresa
AU - Al Bakir, Maise
AU - Lester, Jason F.
AU - Bajaj, Amrita
AU - Nakas, Apostolos
AU - Sodha-Ramdeen, Azmina
AU - Tufail, Mohamad
AU - Scotland, Molly
AU - Boyles, Rebecca
AU - Rathinam, Sridhar
AU - Wilson, Claire
AU - Marrone, Domenic
AU - Birkbak, Nicolai J.
AU - Kisistok, Judit
AU - Sokac, Mateo
AU - Wilson, James
AU - Ahmed, Asia
AU - TRACERx Consortium
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/12
Y1 - 2024/12
N2 - Patient-derived xenograft (PDX) models are widely used in cancer research. To investigate the genomic fidelity of non-small cell lung cancer PDX models, we established 48 PDX models from 22 patients enrolled in the TRACERx study. Multi-region tumor sampling increased successful PDX engraftment and most models were histologically similar to their parent tumor. Whole-exome sequencing enabled comparison of tumors and PDX models and we provide an adapted mouse reference genome for improved removal of NOD scid gamma (NSG) mouse-derived reads from sequencing data. PDX model establishment caused a genomic bottleneck, with models often representing a single tumor subclone. While distinct tumor subclones were represented in independent models from the same tumor, individual PDX models did not fully recapitulate intratumor heterogeneity. On-going genomic evolution in mice contributed modestly to the genomic distance between tumors and PDX models. Our study highlights the importance of considering primary tumor heterogeneity when using PDX models and emphasizes the benefit of comprehensive tumor sampling.
AB - Patient-derived xenograft (PDX) models are widely used in cancer research. To investigate the genomic fidelity of non-small cell lung cancer PDX models, we established 48 PDX models from 22 patients enrolled in the TRACERx study. Multi-region tumor sampling increased successful PDX engraftment and most models were histologically similar to their parent tumor. Whole-exome sequencing enabled comparison of tumors and PDX models and we provide an adapted mouse reference genome for improved removal of NOD scid gamma (NSG) mouse-derived reads from sequencing data. PDX model establishment caused a genomic bottleneck, with models often representing a single tumor subclone. While distinct tumor subclones were represented in independent models from the same tumor, individual PDX models did not fully recapitulate intratumor heterogeneity. On-going genomic evolution in mice contributed modestly to the genomic distance between tumors and PDX models. Our study highlights the importance of considering primary tumor heterogeneity when using PDX models and emphasizes the benefit of comprehensive tumor sampling.
UR - http://www.scopus.com/inward/record.url?scp=85195007910&partnerID=8YFLogxK
U2 - 10.1038/s41467-024-47547-3
DO - 10.1038/s41467-024-47547-3
M3 - Journal article
C2 - 38821942
AN - SCOPUS:85195007910
SN - 2041-1723
VL - 15
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 4653
ER -