Summary
Overall, we showed that even in those patients with chronic pancreatitis severe enough to warrant total pancreatectomy with islet autotransplantation, pancreatic cancer–related mutational burden is not appreciably increased.
Original Article
Pancreatic Cancer–Related Mutational Burden Is Not Increased in a Patient Cohort With Clinically Severe Chronic Pancreatitis
Clinical and Translational Gastroenterology
Cowan, Robert W. PhD; Pratt, Erica D. PhD; Kang, Jin Muk PhD; Zhao, Jun PhD; Wilhelm, Joshua J. MS; Abdulla, Muhamad BS; Qiao, Edmund M. BS; Brennan, Luke P. MS; Ulintz, Peter J. PhD; Bellin, Melena D. MD; Rhim, Andrew D. MD
Abstract
INTRODUCTION:
Chronic pancreatitis is associated with an increased risk of developing pancreatic cancer, and patients with inherited forms of pancreatitis are at greatest risk. We investigated whether clinical severity of pancreatitis could also be an indicator of cancer risk independent of etiology by performing targeted DNA sequencing to assess the mutational burden in 55 cancer-associated genes.
METHODS:
Using picodroplet digital polymerase chain reaction and next-generation sequencing, we reported the genomic profiles of pancreases from severe clinical cases of chronic pancreatitis that necessitated palliative total pancreatectomy with islet autotransplantation.
RESULTS:
We assessed 57 tissue samples from 39 patients with genetic and idiopathic etiologies and found that despite the clinical severity of disease, there was no corresponding increase in mutational burden. The average allele frequency of somatic variants was 1.19% (range 1.00%–5.97%), and distinct regions from the same patient displayed genomic heterogeneity, suggesting that these variants are subclonal. Few oncogenic KRAS mutations were discovered (7% of all samples), although we detected evidence of frequent cancer-related variants in other genes such as TP53, CDKN2A, and SMAD4. Of note, tissue samples with oncogenic KRAS mutations and samples from patients with PRSS1 mutations harbored an increased total number of somatic variants, suggesting that these patients may have increased genomic instability and could be at an increased risk of developing pancreatic cancer.
DISCUSSION:
Overall, we showed that even in those patients with chronic pancreatitis severe enough to warrant total pancreatectomy with islet autotransplantation, pancreatic cancer–related mutational burden is not appreciably increased.
CONFLICTS OF INTEREST
Guarantor of the article: Robert W. Cowan, PhD
Specific author contributions: R.W.C., E.D.P., J.M.K., E.M.Q., L.P.B.: designed and performed experiments. J.J.W., M.A., M.D.B., A.D.R.: designed experiments and provided critical resources. R.W.C., E.D.P., J.M.K., J.Z., P.J.U.: performed analyses. R.W.C., E.D.P., J.M.K., P.J.U., A.D.R. interpreted data. M.D.B. and A.D.R.: conceived the study design. A.D.R.: conceived the project. R.W.C.: drafted the manuscript; all other authors revised the manuscript. All authors approved the final version of the manuscript.
Financial support: A.D.R. is supported by the Doris Duke Foundation (Clinical Scholar Grant), Andrew Sabin Family Foundation, National Institutes of Health, MD Anderson Cancer Center (Physician Scientist Program, Pancreatic Cancer Moonshot) and Cancer Prevention and Research Institute of Texas (Rising Stars Award).
Potential competing interests: None to report.