Genomic and Transcriptomic Features of Relapsed SCLC
Siddhartha Devarakonda1, My Hoang2, Sumithra Sankararaman2
1Thoracic Medical Oncology, Providence Swedish Cancer Institute, Seattle, Washington; Paul G. Allen Research Center, Seattle, Washington.
Introduction:
Relapsed SCLC is characterized by treatment resistance and poor outcomes. Genomic and transcriptomic alterations in relapsed SCLC have not been well characterized. We comprehensively profiled relapsed SCLC samples along with patient-matched treatment-naive samples, when available, using whole-exome, whole-genome, and RNA sequencing to describe the molecular landscape of relapsed SCLC. Our goal is to identify potential novel pathways for additional functional validation and eventually novel therapeutic options.
Methods:
We analyzed 54 relapsed and 27 treatment-naive SCLC samples using whole-exome sequencing (with 26 patient-matched paired samples). Subsets of the samples were also analyzed through whole-genome sequencing (n = 28) and RNA sequencing (n = 31). Differences in mutational signatures, gene expression, structural variants, splicing, and neoantigen profiles between diagnosis and relapse were investigated.
Results:
Relapsed SCLC samples had mutation signatures characteristic of platinum and APOBEC mutagenesis. Furthermore, these samples were characterized by MYC, MYCL, and MYCN amplifications. Both treatment-naive and relapsed SCLC samples had high prevalences of mutation-associated neoantigens (median = 86 in treatment-naive and 90 in relapsed SCLC; p = 0.8), and TP53 was the most frequently altered gene to result in a neoantigen (48% of analyzed samples). Potential mechanisms of immune evasion, including amplification of CD24, overexpression of IDO1, increased M2 macrophage presence, and upregulation of HLA-E, were also observed in relapse samples. Differences in alternative splicing patterns were observed between treatment-naive and relapsed small cell samples. Retained intron events were substantially enriched in treatment-naive samples and affected genes involved in DNA repair, metabolism, and the Wingless/Intergrated-1 (WNT) and MYC pathways.
Conclusions:
This study highlights the genomic and transcriptomic features of relapsed SCLC. These samples were characterized by genomic instability, WNT and MYC dysregulation, and splicing aberrations. Additional studies targeting the splicing machinery, WNT signaling, and immune evasion pathways could identify novel therapeutic vulnerabilities in SCLC.