Background: Ampullary adenocarcinoma (AMPAC) are a rare entity of gastrointestinal malignancies arising from the Ampulla of Vater. Together with distal cholangiocarcinoma (DCC) and duodenal adenocarcinoma (DUOAC) AMPAC form the group of periampullary tumors. Primary resection is the only potentially curative option and adjuvant therapy may be beneficial in AMPAC subgroups. A profound proteomic characterization is warranted in order to guide clinical decision making in AMPAC.

Methods: Patients with resected AMPAC, DCC and DUOAC were identified from prospectively maintained databases at four high-volume centers of pancreatic surgery. Tumor-bearing areas including the in situ and the invasive component were marked in formalin-fixed, paraffin-embedded specimens by two pathologists and further processed for the mass spectrometry workflow. The total proteome of processed samples was obtained by semi-quantitative data-independent mass spectrometry employing a timsTOF fleX (Bruker). Mass spectrometric raw data are analyzed with the DIA-NN workflow and the ‘in library free mode’. Proteomic profiles of AMPAC, DCC and DUOAC were correlated with patients’ clinical and prognostic parameters as well as long-term outcomes following adjuvant therapy.

Results: A total of 284 patients from four high-volume centers were included. 241 were AMPAC, 28 DCC and 14 DUOAC. 41% of the patients had received adjuvant therapy. Patients with more advanced T and N stage or positive resection margins were more likely to undergo adjuvant therapy. Differential proteomic profiles were obtained for patients with AMPAC, DCC and DUOAC. Furthermore, distinct marker profiles of patients with short- vs. long-term overall survival following adjuvant therapy in AMPAC were identified. Proteomic markers ontologically associated with cancer cell motility and dedifferentiation were exclusive to patients with short-term survival after adjuvant therapy while those with long-term survival were characterized by cell proliferation and metabolism markers.

Conclusion: Profound proteomic profiling of AMPAC, DCC and DUOAC helps to elucidate the heterogeneous landscape of periampullary carcinomas. Proteomic profiles of therapy response can help to guide clinical decision making.

Gennaro Nappo

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