TP53/KRAS variant allele frequency ratio predicts advanced disease in mucin-producing cystic neoplasms of the pancreas

Objective To identify molecular markers that predict advanced disease in mucin-producing cystic neoplasms of the pancreas. Methods In this single-institution study, 454 pancreatic cystic fluid specimens were examined by a clinical next-generation sequencing assay. Results TP53 mutations were detected in 25 (7.9%) of 318 specimens harboring KRAS (BRAF or GNAS) mutation(s). Of the 25, 12 had advanced cytology/histology (positive group), and 5 did not have advanced cytology/histology (negative group). Eight cases were classified as indeterminate. Since KRAS and TP53 variant allele frequencies (VAFs) can be as low as 1% to 5%, we analyzed the TP53/KRAS VAF ratio and demonstrated a significantly higher VAF ratio in the positive group (P=.005). A VAF ratio of 1 or higher, interpreted as an indicator of a dominant TP53 clone, and concurrent TP53, CDKN2A, and SMAD4 mutations were seen only in the positive group. Lower TP53 ratios, interpreted as a minor TP53 clone, were seen in all 5 negative group specimens. Conclusions These results suggest that VAF ratios and concurrent mutations can be incorporated into multimodality assessments of pancreatic cysts. Longitudinal studies in patients with a lower initial TP53 VAF ratio are warranted to elucidate whether serial VAF ratios are more accurate markers than a single VAF measurement.