Differential expression of immunoregulatory molecules and highly-associated cancer genes may provide novel insights into strategic trial design for therapeutics
| Autor: | Christopher Szeto, P.E. Spiess, Jacob J. Adashek, Sandeep K. Reddy |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Oncology medicine.medical_specialty business.industry medicine.medical_treatment Hematology Immunotherapy Gene mutation medicine.disease Head and neck squamous-cell carcinoma Chemotherapy regimen 03 medical and health sciences 030104 developmental biology 0302 clinical medicine CDKN2A 030220 oncology & carcinogenesis Internal medicine Concomitant medicine Carcinoma Adenocarcinoma business |
| Zdroj: | Annals of Oncology. 30:v504-v505 |
| ISSN: | 0923-7534 |
| Popis: | Background The use of immunotherapy in multiple cancer types is becoming mainstay along with next-generation sequencing (NGS) to identify potential actionable targets. We hypothesized that some immunoregulatory molecules are often found upregulated with certain gene mutations regardless of cancer subtype. Methods 2740 TCGA patients were identified to have at least one potentially oncogenic mutation (mt) within an established 50-gene hotspot panel, including stomach/esophageal carcinoma (N = 255), skin cutaneous melanoma (N = 226), stomach adenocarcinoma (N = 163), breast invasive carcinoma (N = 143), and lung adenocarcinoma (N = 139), among others. Differential expression of 10 immunoregulatory molecules (IRM) was analyzed between mt vs. wt. To ensure observed significant associations were not confounded by tumor-type, differential IRM expression within mt-enriched tumor-types was compared to that of mt vs. wt. Results 19/50 gene mutations were found to be significantly associated with ≥1 IRM expression. This included elevated CTLA4in CDKN2A mt (adj. p = 1.9e-9), elevated IDO1in FBXW7 mt (adj. p = 0.007), and decreased PDL1 in APCmt (adj, p = 0.02). In many, the mt effect-size was larger than that of tumor-type; e.g. head & neck carcinomas (HNSCC) are highly enriched for CDKN2Amt (OR = 4.9, p = 4.3e-9), yet CDKN2Amt are more associated with CTLA4expression than HNSCC location (t = 7.0 vs. 5.4). Similarly, FBXW7mt are more associated with high IDO1 than colorectal adenocarcinoma (CRC) (t = 4.3 vs. 0.9), and APC mt are more associated with low PDL1 (t=-4.1 vs. -3.2) than CRC. In total, 15 strong mt-gene/immune-regulator associations were identified. Conclusions The presented differential checkpoint expression patterns are strongly associated with mutation status and are not primarily driven by tissue type. NGS data continues to drive agnostic approvals while immunotherapeutic efforts work to replace chemotherapy providing better efficacy with milder toxicities. This data hopes to shed light on the future studies that may analyze optimization of concomitant versus sequential therapies in various genomic-driven targeted therapies combined with immunotherapy trials. Legal entity responsible for the study The authors. Funding NantWorks. Disclosure C.W. Szeto: Full / Part-time employment: NantCell. S.K. Reddy: Full / Part-time employment, Officer / Board of Directors: NantHealth. All other authors have declared no conflicts of interest. |
| Databáze: | OpenAIRE |
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