Genomics meets gene tectonics in a pancreatic cancer study that describes large-scale genomic rearrangements, disruptions that can be likened to geological events. In pancreatic cancer, large slabs of DNA can slide from one genomic region to another, changing the genomic landscape. While DNA fault lines and ridges have been exposed by whole exome analysis, the broader picture is emerging only now, with the application of whole genome analysis.
With the benefit of the whole genome perspective, which takes in the whole genome, not just the genome’s protein-coding sequences, four kinds of genomic rearrangement have been uncovered—“stable,” “locally rearranged,” “scattered,” and “unstable.” These four pancreatic cancer types roughly correspond to different degrees of genomic upheaval and account for the frequency, location, and types of DNA redisposition. For example, genes can be inverted, deleted, or multiplied. Also, genes can sustain damage, much like landforms can be scarred near geologic fault lines.
These findings appeared February 25 in Nature, in an article entitled, “Whole genomes redefine the mutational landscape of pancreatic cancer.” Besides recognizing distinct forms of pancreatic cancer, the article emphasizes that the newly found categories could be used to improve treatments for the disease. In the case of “unstable” genomes, treatment prospects seemed especially promising.
“We performed whole-genome sequencing and copy number variation (CNV) analysis of 100 pancreatic ductal adenocarcinomas (PDACs),” wrote the authors. “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).”
Besides pointing out four distinct pancreatic cancer subtypes, the authors noted that DNA rearrangements caused genetic chaos, with genes deleted, wrongly switched on and off, or entirely new versions created. Some of the genetic faults, however, may be treatable with existing drugs. According to the authors, potentially druggable oncogenes include ERBB2, MET, FGFR1, CDK6, PIK3R3, and PIK3CA.
The study’s authors, which included scientists from Cancer Research UK and the Garvin Institute of Medical Research, also suggested certain pancreatic cancer patients could benefit from platinum-based drugs.
“Genomic instability co-segregated with inactivation of DNA maintenance genes (BRCA1, BRCA2, or PALB2) and a mutational signature of DNA damage repair deficiency,” they reported. “Of eight patients who received platinum therapy, four of five individuals with these measures of defective DNA maintenance responded.”
The study’s co-lead, Professor Andrew Biankin, affiliated with both Cancer Research UK and Garvin, and currently at the University of Glasgow, indicated that being able to identify which patients would benefit from platinum-based treatments would be a “game-changing moment, potentially improving survival for a group of patients.” More generally, Professor Biankin added, “Our crucial study sheds light on how the chaotic chromosomal rearrangements cause a huge range of genetic faults that are behind the disease and provide opportunities for more personalized pancreatic cancer treatment.”