Whole‐exome sequencing of pancreatic neoplasms with acinar differentiation

Abstract

Pancreatic carcinomas with acinar differentiation, including acinar cell carcinoma, pancreatoblastoma, and carcinomas with mixed differentiation, are distinct pancreatic neoplasms with poor prognosis. Although recent whole exome sequencing analyses have defined the somatic mutations that characterize the other major neoplasms of the pancreas, the molecular alterations underlying pancreatic carcinomas with acinar differentiation remain largely unknown. In the current study, we sequenced the exomes of 23 surgically resected pancreatic carcinomas with acinar differentiation. These analyses revealed a relatively large number of genetic alterations at both the individual base pair and chromosomal levels. There was an average of 119 somatic mutations per carcinoma. When three outliers were excluded, there was an average of 64 somatic mutations per tumor (range 12–189). The mean fractional allelic loss (FAL) was 0.27 (range 0–0.89) and heterogeneity at the chromosome level was confirmed in selected cases using fluorescent in situ hybridization (FISH). No gene was mutated in >30% of the cancers. Genes altered in other neoplasms of the pancreas were occasionally targeted in carcinomas with acinar differentiation; SMAD4 was mutated in six tumors (26%), TP53 in three (13%), GNAS in two (9%), RNF43 in one (4%) and MEN1 in one tumor (4%). Somatic mutations were identified in genes in which constitutional alterations are associated with familial pancreatic ductal adenocarcinoma, such as ATM, BRCA2, and PALB2 (one tumor each), as well as in genes altered in extra-pancreatic neoplasms, such as JAK1 in four tumors (17%) BRAF in three (13%), RB1 in three (13%), APC in two (9%), PTEN in two (9%), ARID1A in two (9%), MLL3 in two (9%), and BAP1 in one (4%). Perhaps most importantly, we found that more than a third of these carcinomas have potentially targetable genetic alterations including mutations in BRCA2, PALB2, ATM, BAP1, BRAF and JAK1.

Comprehensive Genomic Profiling of Pancreatic Acinar Cell Carcinomas Identifies Recurrent RAF Fusions and Frequent Inactivation of DNA Repair Genes

“…However, to identify clinically relevant molecular targets, one must use appropriate profi ling techniques. Of note, prior WES that focused on identifi cation of somatic mutations failed to identify oncogenic RAF fusions and identifi ed a low frequency of BRCA2 and ATM mutations ( 8 ). The diversity of BRAF breakpoints and fusion partners suggests that a single test looking for the frequent SND1-BRAF fusion would only identify a fraction of patients whose tumors are dependent on rearrangement-induced activation of this gene.…”

The genetic classification of pancreatic neoplasia

“…In 2014 Jiao et al [11] sequenced the exomes of pancreatic neoplasms with acinar differentiation, and they found that ACCs have dramatic chromosomal instability and genetic heterogeneity. They detected an average of 64 somatic mutations per neoplasm (and this is not considering three outliers), which is higher than for PDAs.…”

“…They detected an average of 64 somatic mutations per neoplasm (and this is not considering three outliers), which is higher than for PDAs. Genes implicated in other pancreatic neoplasms were altered in some of the ACCs, including SMAD4 mutations in 25 %, TP53 mutations in 15 %, and GNAS mutations in 10 %, as well as mutations in RNF43 and MEN1 (4 %) [11]. A small number of patients harbored somatic mutations in genes associated with familial pancreatic cancer syndromes.…”

“…Marked chromosomal instability may explain the general resistance of most ACCs to traditional systemic therapy regimens [11,17]. In spite of a vast genetic heterogeneity in ACC, the whole-exome sequencing did identify genetic mutations in 40 % of the cancers that might be amenable for targeted therapies.…”

“…All of the major types of tumors of the pancreas, including all of the cystic and all of the solid tumors, have been sequenced [4][5][6][7][8][9][10][11]. The results of these sequencing studies have enormously improved our understanding of pancreatic neoplasia, they have created a foundation for novel research [8,[12][13][14], and they have significant clinical applications [15][16][17] (Table 1).…”