Mutational Landscape in Resected Periampullary Adenocarcinoma: Relationship With Morphology and Clinical Outcome

Abstract

PURPOSE Periampullary adenocarcinomas encompass a heterogeneous group of tumors with dismal prognosis and limited treatment options. Emerging evidence shows that tumor morphology (ie, intestinal type [I-type] or pancreatobiliary type [PB-type]) is a more relevant prognostic factor than tumor origin. Knowledge is sparse, however, on whether key mutations differ according to morphology. MATERIALS AND METHODS Next-generation sequencing was applied to assess the mutational status of 70 genes in 102 tumors from a retrospective cohort of 175 patients with resected periampullary adenocarcinoma. Brahma-related gene 1 protein expression was examined by immunohistochemistry on tissue microarrays with primary tumors from the original cohort. RESULTS APC mutations were significantly more common in I-type than in PB-type tumors (27.5% v 0%; P < .001), as were ERBB3 mutations (20.8% v 4.8%; P = .016), whereas CDKN2A mutations were more common in PB-type than in I-type tumors (19.4% v 2.5%; P = .013). KRAS mutation was an independent factor of poor prognosis in I-type tumors (hazard ratio, 3.73; 95% CI, 1.10 to 12.67). In PB-type tumors, SMARCA4 mutation was an adverse prognostic factor in patients not receiving adjuvant chemotherapy, and there was a significant treatment interaction between expression of Brahma-related gene 1 protein, the protein encoded by SMARCA4, and adjuvant chemotherapy ( Pinteraction = .007). CONCLUSION To our knowledge, this is the first description of the mutational landscape in the full spectrum of periampullary adenocarcinoma that demonstrates that the distribution and prognostic and predictive significance of commonly mutated genes differ by morphology. The results emphasize that morphology is an important factor to consider in the search for novel biomarkers and targeted personalized treatment of these patients. In addition, the findings support the concept that molecular profiling of these tumors could be of clinical benefit.

Topographical Distribution and Spatial Interactions of Innate and Semi-Innate Immune Cells in Pancreatic and Other Periampullary Adenocarcinoma

“…NKT cells were more abundant in APC mutated tumors, which may well be explained by the fact that APC mutations were exclusively found in I-type tumors in the current cohort (4). The significantly lower infiltration of CD68 + macrophages in CDKN2A mutated tumors is in line with findings for other types of immune cells (12,22), but may also merely be due to the fact that CDKN2A mutations are more common in PBtype tumors (4). Moreover, in the present study, mDC infiltration was found to be higher in SMAD4 wt tumors, which is in line with a previous study using a different method to assess both immune cell infiltration and mutational status (23).…”

“…Next generation DNA sequencing was performed as previously described (4). In brief, the mutational status of 70 commonly cancer-associated genes was assessed using the Illumina TruSeq custom amplicon assay (Illumina, San Diego, United States) according to the instructions obtained from the manufacturer.…”

“…Periampullary adenocarcinomas encompass cancers arising in the area around the ampulla of Vater, i.e., in the distal bile duct, the pancreatic head, the duodenum or the ampulla. There is increasing evidence that tumor morphology, i.e., classification into intestinal type (I-type) or pancreatobiliary type (PB-type), is a more important determinant of patient outcome than tumor origin ( 1 – 4 ). Despite recent therapeutic advances, the overall survival rates for patients with periampullary adenocarcinoma remain as low as around 5% ( 5 ), and pancreatic cancer is the fourth leading cause of cancer related death in Europe ( 6 ).…”

Quantitative, qualitative and spatial analysis of lymphocyte infiltration in periampullary and pancreatic adenocarcinoma

“…Next‐generation DNA sequencing was performed as previously described . In brief, tissue cores were taken from tumor enriched areas.…”

“…Periampullary adenocarcinomas are currently classified by their anatomic location of origin according to the seventh edition of the American Joint Committee on Cancer staging system . They can be divided into two subgroups based on morphology, either intestinal type (I‐type) or pancreatobiliary type (PB‐type), and there is increasing evidence that morphology is a more important determinant of survival than anatomical origin . Survival rates remain dismally low for this group of patients, with 5‐year overall survival (OS) rates of around 6%, partly due to late presentation of the disease, but also because both conventional and targeted therapies have shown limited efficacy.…”