Abstract
Purpose: Pancreatic adenocarcinomas (PAAD) often are not diagnosed until their late stages, leaving no effective treatments. Currently, immunotherapy provides a promising treatment option against this malignancy. However, a set of immunotherapy agents benefit patients with many types of cancer, but not PAAD. Sharing the origin in the same organ, diabetes and PAAD tend to occur concurrently. We aimed to identify the impact of diabetes on immunotherapy of PAAD by conducting a comparative genomics analysis. Experimental Design: We analyzed level 3 PAAD genomics data (RNAseq, miRNAseq, DNA methylation, somatic copy number, and somatic mutation) from The Cancer Genome Atlas (TCGA) and Firehose. The differential molecular profiles in PAAD with/out diabetes were performed by the differential gene expression, pathway analysis, epigenetic regulation, somatic copy-number alteration, and somatic gene mutation. Results: Differential gene expression analysis revealed a strong enrichment of immunogenic signature genes in diabetic individuals, including PD-1 and CTLA4, that were currently targetable for immunotherapy. Pathway analysis further implied that diabetic individuals were defective in immune modulation genes. Somatic copy-number aberration (SCNA) analysis showed a higher frequency of amplification and deletion occurred in the cohort without diabetes. Integrative analysis revealed strong association between differential gene expression, and epigenetic regulations, however, seemed not affected by SCNAs. Importantly, our somatic mutation analysis showed that the occurrence of diabetes in PAAD was associated with a large set of gene mutations encoding genes participating in immune modulation. Conclusions: Our analysis reveals the impact of diabetes on immunodeficiency in PAAD patients and provides novel insights into new therapeutic opportunities.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 6363-6374 |
| Number of pages | 12 |
| Journal | Clinical Cancer Research |
| Volume | 23 |
| Issue number | 20 |
| DOIs | |
| State | Published - Oct 15 2017 |
Funding
The Cancer Genome Atlas (TCGA) sponsored by National Cancer Institute is publicly available resource depositing multidimensional cancer genomics and clinical data set. We downloaded PAAD clinical information, level 3 genomics data (RNAseqV2, miRNASeq, DNA Methylation, and somatic mutation data) from the TCGA data portal (https://gdc.cancer.gov/). Somatic copy-number aberration (SCNA) data were downloaded from Firehose (http://gdac.broadinstitute.org/). These studies were partially supported by the NIH:EY012601-17, EY007739-25, HL110170-05, EY023629-03, and EY025383-01A1, to M.B. Grant.
ASJC Scopus subject areas
- Oncology
- Cancer Research
