Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer, with a 5-year survival rate below 10%, and a median survival of 6–12 months for most patients. However, a small subset of patients achieve long-term survival, presenting an unique opportunity to explore the mechanisms underlying this outcome.
In a multinational effort, our team has performed extensive genomic, transcriptomic, and epigenomic analyses of >1000 PDAC samples from the Australia ICGC (International Cancer Genome Consortium) program, Avner Pancreatic Cancer Biobank and PURPLE Registry. Within this cohort, we systematically screened for patients with survival of 4.9 years or more for detailed genomics and transcriptomic investigations.
Our long-term survivors (LTS) cohort consists of 34 samples with whole-genome sequencing, of which 24 with whole-transcriptomic and 8 with matched single-nuclei RNA-sequencing (snRNA-seq) data. Initial analyses revealed shared genetic characteristics among LTS, including driver mutations in KRAS, TP53, CDKN2A, and SMAD4. To further explore genomic distinctions, we randomly selected 40 samples from the ICGC as a short-term survivor (STS) cohort and performed GISTIC (Genomic Identification of Significant Targets in Cancer) analysis to identify frequently altered genomic regions. Preliminary results indicate that, while both LTS and STS cohorts exhibit similar genomic alterations, unique peaks in the LTS cohort—such as amplifications on chromosomes 9p13 and 12p13, and a loss on 10p15—suggest potential genes and biomarkers in the regions could contribute to prolonged survival.
This work is ongoing, with plans for deeper analysis of bulk RNA-seq data to elucidate transcriptomic profiles that may further distinguish LTS from STS cohorts. The inclusion of snRNA-seq will provide insights into cell-specific activation states and pathways associated with extended survival in PDAC.