Author: Singhi AD, George B, Greenbowe JR, Chung J, Suh J, Maitra A, Klempner SJ, Hendifar A, Milind JM, Golan T, Brand RE, Zureikat AH, Roy S, Schrock AB, Miller VA, Ross JS, Ali SM, Bahary N
Title: Real-time Targeted Genome Profile Analysis of Pancreatic Ductal Adenocarcinomas Identifies Genetic Alterations that Might be Targeted with Existing Drugs or Used as Biomarkers
Summary: BACKGROUND AND AIMS: It has been a challenge to select treatment for patients with pancreatic ductal adenocarcinomas (PDACs) based on genome alterations. We performed targeted genomic profile analyses of a large number of PDACs to assess the full spectrum of actionable genomic alterations METHODS: We performed targeted genomic profile analyses of 3594 PDAC samples from an international cohort, including capture-based targeted genomic profiling of as many as 315 cancer-associated genes and intron regions of 28 genes that are rearranged in cancer cells. Tumor mutation burden (TMB) and microsatellite instability (MSI) status were also assessed. TMB was calculated across a 1.14 Mb region; TMB-high (TMB-H) was defined as ≥20 mutations/Mb. MSI-high (MSI-H) status was assigned based on analysis of 114 intron homopolymer loci.
RESULTS: KRAS, TP53, CDKN2A, and SMAD4 were the most frequently altered genes in the PDAC tissues. We found KRAS mutations in 88% of samples. Among PDACs without mutations in KRAS, we found alterations in genes whose products are in the mitogen-activated protein kinase signaling pathway and are candidate drug targets (actionable targets; n=132; 4%), as well as gene fusions (n=51), gene amplifications (n=35), genes with missense mutations (n=30), and genes that contain deletions (n=16). Many of these encode proteins in receptor tyrosine kinase, RAS, or mitogen-activated protein kinase signaling pathways. Aside from TP53, alterations in genes encoding DNA damage repair proteins (BRCA and FANC) were detected in in 14% of PDACs. Among PDACs evaluated for MSI (n=2563) and TMB (n=1021), MSI-H and/or TMB-H phenotypes were detected in 0.5% of samples. Alterations in FGF23, CCND2, PIK3CA, and FGF6 were more commonly detected in intraductal papillary mucinous neoplasm-associated PDACs.
CONCLUSIONS: In targeted genomic profile analyses of 3594 PDACs, we found 17% to contain genomic alterations that might make the tumor cells susceptible to currently used anti-cancer agents. We identified mutations in genes that could contribute to progression of intraductal papillary mucinous neoplasms into malignancies. These alterations might be used as biomarkers for early detection.
Source: Gastroenterology. 2019 Mar 2. pii: S0016-5085(19)32505-3. doi: 10.1053/j.gastro.2019.02.037. [Epub ahead of print]