American journal of clinical pathology · 2026
TP53/KRAS variant allele frequency ratio predicts advanced disease in mucin-producing cystic neoplasms of the pancreas.
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Lin Ming-Tseh, Afghani Elham, Canto Marcia I, Zhu Jing, Ali Syed Z, Wood Laura D, He Jin, Lafaro Kelly J, Hruban Ralph H, Eshleman James R
Аннотация
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.
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.