19 Whole-exome sequencing based immunogenomic profiling with potential clinical applicability in circulating cell-free DNA and tissue from advanced stage colorectal cancer patients. (9th November 2020)

• Record Type: Journal Article
• Authors: Feng, Zheng; Scheuenpflug, Juergen; Tan, Mengyao; Wang, Danyi
• Is Part Of: Journal for immunotherapy of cancer. Volume 8(2020)Supplement 3
• Page Start: A19
• Page End: A19
• Publication Date: 2020-11-09
• Subjects: Cancer -- Immunotherapy -- Periodicals; Cancer -- Immunological aspects -- Periodicals; Tumors -- Immunological aspects -- Periodicals; Immunotherapy -- Periodicals; 616.99406105
• DOI: 10.1136/jitc-2020-SITC2020.0019
• Languages: English
• ISSNs: 2051-1426

Abstract

Abstract : Background: Assessing cfDNA at a whole-exome scale (WES) enables comprehensive immunogenomic profiling and interrogation of tumor heterogeneity. We comprehensively investigate genomic alterations and neoantigens in cfDNA at WES-scale using Personalis' NeXT Liquid Biopsy™. Genomic alterations, neoantigens, and molecular tumor micro-environment (mTME) from matched solid tumor are evaluated using Personalis' ImmunoID NeXT Platform®. Methods: Matched plasma, tumor, and adjacent normal tissues were collected from 13 late-stage, treatment-naive CRC patients. cfDNA was extracted and assessed exome-wide, then the mutational landscape and immunogenomic profile were analyzed. 1 gDNA extracted from tumor was analyzed by the ImmunoID NeXT Platform, where somatic variants and neoantigens were evaluated. RNA analysis of the solid tumor enabled the investigation of the mTME. 2 3 Results: The average number of somatic SNVs in plasma samples was 100.5 (Range 50–250). KRAS, APC, PIK3CA, SMAD4, FBXW7, ARID1A were identified. Specifically, two components of SWI/SNF complex, ARID1A and BRD9, were both mutated in plasma samples, suggesting the potential dysregulation of epigenetic pathways. RTK-RAS and Notch pathways were also frequently mutated. Further, 1, 195 somatic events were found in genes not covered by commercially available targeted panels. 27 of these SNVs are in immuno-oncology related genes, which highlight the importance of somatic evidence observable through an exome-scale cfDNA approach. In solid tumor, the average number of detected somatic SNVs was 133.4 (Range 69–230), with similar mutation landscape. Concordance is observed between tumor and plasma samples (mean: 40.6%; range: 15.13%-94.2%). However, a number of variants are plasma-specific, suggesting that cfDNA WES detects tumor mutations that might be missed by a single site biopsy. We evaluated neoantigens and determined that the fraction of variants predicted as neoantigens are similar between plasma and tumor. Importantly, several of the top neoepitopes are uniquely predicted in plasma, suggesting the potential clinical value of using WES cfDNA. RNA-sequencing of solid tumor samples enabled mTME profiling. CD8 T cell immune infiltration, TCR beta clonality and clone counts were low, suggesting these patients have cold tumors. Myeloid dendritic cells and macrophages demonstrated uniform abundance across samples, while B and T regulatory cells showed variable tumor infiltration Conclusions: Results demonstrate potential clinical utility and highlight the advantages of whole-exome scale profiling of plasma and matched tumor samples, which enables a systematic interrogation of tumor biology, including mTME. Notably, a whole-exome based liquid biopsy assay offers indispensable insights that might be otherwise missed by a single site tumor biopsy or targeted liquid biopsy panels. Ethics Approval: The study protocol was in accordance with the tenets of the Declaration of Helsinki. Commercial samples used in this study were procured from Bioreclamation IVT and BioChain following protocols approved by the local Institutional Review Board (IRB) committee. Informed consent forms were obtained from all the human subjects in this study. Consent: N/A References: Simo V. Zhang, Mengyao Tan, Josette M. Northcott, Shuyuan Ma, Christopher S. Nelson, L. Gordon Bentley, Manju Chinnappa, Devayani P. Bhave, Dan Norton, Jason Harris, Sean M. Boyle, John West, Richard Chen. Enhanced whole exome profiling of tumor circulating cell-free DNA enables sensitive assessment of tumor mutations [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; Apr 27–28 and Jun 22–24. Philadelphia (PA): AACR; Cancer Res 2020;80 (16 Suppl): Abstract nr 1989. Sean Michael Boyle, Charles W. Abbott, Eric Levy, Rachel Marty Pyke, Datta Mellacheruvu, Simo V. Zhang, Mengyao Tan, Nick A. Phillips, Rena McClory, John West, Richard Chen. A pan-cancer characterization of both the tumor and micro environment highlights the importance of an integrated approach for immuno-oncology [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; Apr 27–28 and Jun 22–24. Philadelphia (PA): AACR; Cancer Res 2020;80 (16 Suppl): Abstract nr 2512. Juan-Sebstian Saldivar, Jason Harris, Sejal Desai, Erin Ayash, Prateek Tandon, Twinkal Marfatia, Robert Power, Massimo Morra, Manju Chinnappa, Michael James Clark, Rena McClory, Richard Chen. Validation of an exome and transcriptome based diagnostic platform enabling clinical cancer therapy selection and emerging composite biomarkers for immunotherapy [abstract]. In: Proceedings of the American Society of Clinical Oncology 2020; May 29–31 and Aug 8–10: ASCO; Journal of Clinical Oncology 2020; 38, no. 15_suppl: Abstract nr e15583.