The researchers performed whole-genome sequencing and copy number variation analysis of 100 samples to reveal mutational landscape of pancreatic ductal adenocarcinomas. Their findings led to classification of pancreatic ductal adenocarcinomas into 4 subtypes with potential clinical utility.
The team of international researchers, working with the Australian Pancreatic Cancer Genome Initiative, emphasise the need for new strategies in the treatment of pancreatic cancer, pointing out that it remains one of the most lethal cancers.
In their study, chromosomal rearrangements leading to gene disruption were prevalent, affecting genes known to be important in pancreatic cancer (TP53, SMAD4, CDKN2A, ARID1A and ROBO2) and new candidate drivers of pancreatic carcinogenesis (KDM6A and PREX2).
Variation in chromosomal structure classified pancreatic ductal adenocarcinomas into 4 subtypes. The subtypes were termed stable, locally rearranged, scattered and unstable. A significant proportion harboured focal amplifications, many of which contained druggable oncogenes (ERBB2, MET, FGFR1, CDK6, PIK3R3 and PIK3CA), but at low individual patient prevalence.
Genomic instability co-segregated with inactivation of DNA maintenance genes (BRCA1, BRCA2 or PALB2) and a mutational signature of DNA damage repair deficiency. Of 8 patients who received platinum therapy, 4 of 5 individuals with these measures of defective DNA maintenance responded.
This study provides the most comprehensive description to date of the genomic events that characterise pancreatic cancer. It also demonstrates that structural variation is a prominent mechanism of genomic damage in this cancer.