Genomic and TCR Repertoire Intratumor Heterogeneity of Small-cell Lung Cancer and its Impact on Survival

Ming Chen; Runzhe Chen; Ying Jin; Jun Li; Jiexin Zhang; Junya Fujimoto; Won‐Chul Lee; Xin Yang Hu; Shawna Marie Hubert; Julie George; Xiao Hu; Yamei Chen; Carmen Behrens; Chi-Wan B. Chow; Hoa Hoang Ngoc Pham; Junya Fukuoka; Edwin Roger Parra; Carl Michael Gay; Latasha Little; Curtis E. Gumbs; Xingzhi Song; Lixia Diao; Qi Wang; Robert J. Cardnell; Jianhua Zhang; Jing Wang; Don Lynn Gibbons; John Victor Heymach; J. Jack Lee; William N. William

doi:10.1101/2020.06.30.180844

GenomicsbioRxivJun 30, 2020

Preprint

Genomic and TCR Repertoire Intratumor Heterogeneity of Small-cell Lung Cancer and its Impact on Survival

Ming Chen iD, Runzhe Chen iD, Ying Jin iD, Jun Li iD, Jiexin Zhang iD, Junya Fujimoto iD, Won‐Chul Lee iD, Xin Yang Hu iD, Shawna Marie Hubert iD, Julie George iD, Xiao Hu iD, Yamei Chen iD, Carmen Behrens iD, Chi-Wan B. Chow, Hoa Hoang Ngoc Pham iD, Junya Fukuoka iD, Edwin Roger Parra iD, Carl Michael Gay iD, Latasha Little iD, Curtis E. Gumbs iD, Xingzhi Song iD, Lixia Diao iD, Qi Wang iD, Robert J. Cardnell iD, Jianhua Zhang iD, , Jianjun J. Zhang iD

Abstract

Small-cell lung cancer (SCLC) is speculated to harbor complex genomic intratumor heterogeneity (ITH) associated with high recurrence rate and suboptimal response to immunotherapy. Here, we revealed a rather homogeneous mutational landscape but extremely suppressed and heterogeneous T cell receptor (TCR) repertoire in SCLCs. Higher mutational burden, lower chromosomal copy number aberration (CNA) burden, less CNA ITH and less TCR ITH were associated with longer overall survival of SCLC patients. Compared to non-small cell lung cancers (NSCLCs), SCLCs had similar predicted neoantigen burden and mutational ITH, but significantly more suppressed and heterogeneous TCR repertoire that may be associated with higher CNA burden and CNA ITH in SCLC. Novel therapeutic strategies targeting CNA could potentially improve the tumor immune microenvironment and response to immunotherapy in SCLC.

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