Real-Time Targeted Genome Profile Analysis of Pancreatic Ductal Adenocarcinomas Identifies Genetic Alterations That Might Be Targeted With Existing Drugs or Used as Biomarkers

Abstract

This article has an accompanying continuing medical education activity, also eligible for MOC credit, on page e19 (https://www. gastrojournal.org/cme/home). Learning Objective: Upon completion of this CME activity, successful leaners will be able to identify current clinically relevant genomic alterations in pancreatic ductal adenocarcinoma.

Comprehensive characterisation of pancreatic ductal adenocarcinoma with microsatellite instability: histology, molecular pathology and clinical implications

“…Singhi et al also reported results from NGS of a large PDAC cohort (3594 cases): interestingly, one case among the three detected MSI/dMMR PDACs harboured the druggable FGFR2-POC1B fusion. 44 Regarding the presence of any potential specific driver genes in MSI/dMMR PDAC, we found a bi-univocal correspondence regarding genes belonging to the JAK/STAT pathway and those of KMT2 family. Indeed, these have been described as frequently mutated in MSI/dMMR cancers of different extrapancreatic sites 45 46 ; the review of all molecular data of MSI/ dMMR PDAC showed the involvement of the JAK/STAT pathway also in MSI/dMMR PDAC, given that the paper by Wartenberg et al, 39 reported a higher mutation rate of JAK3 specifically in this genetic subgroup (3/5 MSI/dMMR cases vs 4/105 microsatellite-stable PDAC, p<0.01, Fisher's exact test; all these cases were KRAS mutated), and in the paper by Singhi et al, two of the three reported MSI/dMMR PDAC harboured a JAK1 mutation (2/3 MSI/dMMR PDAC vs 0/608 microsatellitestable PDAC with actionable targets, p<0.01, Fisher's exact test).…”

“…Indeed, these have been described as frequently mutated in MSI/dMMR cancers of different extrapancreatic sites 45 46 ; the review of all molecular data of MSI/ dMMR PDAC showed the involvement of the JAK/STAT pathway also in MSI/dMMR PDAC, given that the paper by Wartenberg et al, 39 reported a higher mutation rate of JAK3 specifically in this genetic subgroup (3/5 MSI/dMMR cases vs 4/105 microsatellite-stable PDAC, p<0.01, Fisher's exact test; all these cases were KRAS mutated), and in the paper by Singhi et al, two of the three reported MSI/dMMR PDAC harboured a JAK1 mutation (2/3 MSI/dMMR PDAC vs 0/608 microsatellitestable PDAC with actionable targets, p<0.01, Fisher's exact test). 44 Furthermore, we found that alterations affecting the KMT2 family were involved as well, since 3/3 MSI/dMMR cases described by Singhi et al harboured KMT2 mutations (two cases with KMT2D and one case KMT2C mutation; 3/3 KMT2 mutated MSI/dMMR PDAC vs 32/608 KMT2 mutated microsatellite-stable PDAC with actionable targets, p<0.01, Fisher's exact test; the MSI/dMMR and KMT2 mutated cases were KRAS wild type).…”

“…44 53 Notably, one case with FGFR2 fusion has been described in the context of MSI/dMMR. 44 Moreover, TMB resulted high in the majority of MSI/dMMR PDAC, and this represents another variable strictly associated with benefits from immunotherapy. Further studies in PDAC should also address whether better response to immunotherapy could be reached where there is co-existence of MSI/ dMMR and high TMB, such as in colorectal cancer.…”

Efficacy of EUS-guided FNB using a Franseen needle for tissue acquisition and microsatellite instability evaluation in unresectable pancreatic lesions

“…However, frequencies of MSI-high tumors of more than 10% were reported in small studies. In a study with a large number of patients (n = 3954) [27], MSI-high pancreatic cancer was found in very few patients (0.5%). In a study that targeted 12,019 patients with 32 types of cancer, the rate of MSI-high tumors was less than 2% in pancreatic cancer [31].…”

“…In past reports, the frequency of MSI-high tumors was 0-29% in pancreatic cancer [25][26][27][28][29][30]. However, frequencies of MSI-high tumors of more than 10% were reported in small studies.…”